8-K/A
false 0001399529 0001399529 2020-08-05 2020-08-05

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549

 

 

FORM 8-K/A

 

 

CURRENT REPORT

PURSUANT TO SECTION 13 OR 15(d)

OF THE SECURITIES EXCHANGE ACT OF 1934

Date of Report (Date of earliest event reported): August 5, 2020

 

 

DICERNA PHARMACEUTICALS, INC.

(Exact name of registrant as specified in its charter)

 

 

 

Delaware   001-36281   20-5993609

(State or other jurisdiction

of incorporation)

  (Commission
File Number)
 

(IRS Employer

Identification Number)

 

33 Hayden Avenue

Lexington, Massachusetts

02421
(Address of registrant’s principal executive office)   (Zip code)

(617) 621-8097

(Registrant’s telephone number, including area code)

(Former name or former address, if changed since last report)

 

 

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

 

Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

 

Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

 

Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

 

Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

 

Title of each class

 

Trading symbol(s)

 

Name of each exchange on which registered

Common Stock, par value $0.0001 per share   DRNA   The Nasdaq Global Select Market

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 or Rule 12b-2 of the Securities Exchange Act of 1934.

Emerging growth company  

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.  ☐

 

 

 


Explanatory Note

The purpose of this amendment to the Current Report on Form 8-K/A (the “Form 8-K/A”) filed by Dicerna Pharmaceuticals, Inc. (the “Company”) with the Securities and Exchange Commission on August 6, 2020 (the “Form 8-K”), is to add Inline eXtensible Business Reporting Language (“iXBRL”) tagging to the cover page of this Form 8-K/A and to furnish Exhibit 104 to this Form 8-K/A relating to the same that was inadvertently omitted from the original Form 8-K.


Item 2.02

Results of Operations and Financial Condition.

On August 6, 2020, Dicerna Pharmaceuticals, Inc., a Delaware corporation (the “Company”), issued a press release announcing its financial and operational results for the quarter ended June 30, 2020. A copy of the press release is furnished herewith as Exhibit 99.1.

 

Item 7.01

Regulation FD Disclosure.

The Company previously announced that it would host its virtual research and development day event (the “R&D Day”) on August 6, 2020 from 10:00 a.m. to 12:00 p.m. Eastern time. On August 6, 2020, the Company issued a press release related to its R&D Day, a copy of which is furnished herewith as Exhibit 99.2. In addition, the Company is posting to the “Investors” portion of its website at http://investors.dicerna.com/ a copy of its slide presentation to be used at the R&D Day. This slide presentation is attached to this Current Report on Form 8-K as Exhibit 99.3.

The information in Items 2.02 and 7.01 of this Form 8-K (including Exhibits 99.1, 99.2 and 99.3 attached hereto) is being furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liability of that section, nor shall such information be deemed to be incorporated by reference in any registration statement or other document filed under the Securities Act of 1933, as amended, or the Exchange Act, except as otherwise stated in such filing.

 

Item 8.01

Other Events.

On August 5, 2020, the Company announced that Shreeram Aradhye, M.D. was appointed to serve as the Company’s Chief Medical Officer, effective as of September 8, 2020. In connection with such appointment, the Company issued a press release on August 5, 2020, a copy of which is attached as Exhibit 99.4 to this Current Report on Form 8-K.

 

Item 9.01

Financial Statements and Exhibits

(d) Exhibits

 

Exhibit No.

  

Description

99.1    Press Release, entitled “DicernaTM Announces Second Quarter Ended June 30, 2020 Financial Results and Provides Corporate Updates.”
99.2    Press Release, entitled “Dicerna Announces Positive Clinical Data for Investigational Treatments RG6346 for Chronic Hepatitis B Virus and Nedosiran for Primary Hyperoxaluria, and Presents Preclinical Data Applying RNAi Technology in New Tissues.”
99.3    Dicerna 2020 Virtual R&D Update: Nedosiran, RG6346 and Going Beyond GalXCTM presentation.
99.4    Press Release, entitled “Dicerna Announces Appointment of Shreeram Aradhye, M.D., as Executive Vice President and Chief Medical Officer.”
104    Cover Page Interactive Data File - the cover page interactive data file does not appear in the Interactive Data File because its XBRL tags are embedded within the Inline XBRL document.


SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

 

Date: August 11, 2020    

DICERNA PHARMACEUTICALS, INC.

    By:  

/s/ Douglas M. Fambrough, III

     

Douglas M. Fambrough, III, Ph.D.

     

Chief Executive Officer

EX-99.1

Exhibit 99.1

 

LOGO

Dicerna Announces Second Quarter 2020 Financial Results and Provides a Business Update

– Company Targeting Enrollment Completion for Pivotal PHYOX2 Trial of Nedosiran in Fourth Quarter 2020 –

– Company Reported $669.2 Million in Cash, Cash Equivalents and Marketable Securities as of June 30, 2020 –

– Management to Host Virtual R&D Day Event Today at 10:00 a.m. ET –

LEXINGTON, Mass., Aug. 6, 2020Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA) (the “Company” or “Dicerna”), a leading developer of investigational ribonucleic acid interference (RNAi) therapeutics, today reported its financial results for the second quarter ended June 30, 2020.

“Our organization’s steady and consistent execution across all fronts, despite the impacts of COVID-19 on all facets of daily life, continues to advance our goals of expanding the reach of RNAi into numerous therapeutic categories and becoming a commercial-stage organization. The efforts of our employees, clinical sites, manufacturing and collaborative partners demonstrate an important shared dedication to bringing new RNAi-based therapies to patients in need,” said Douglas Fambrough, Ph.D., president and chief executive officer of Dicerna. “In addition to our financial results, today we also updated our guidance for completion of enrollment of our pivotal PHYOX2 trial of nedosiran in patients with primary hyperoxaluria types 1 or 2, to the fourth quarter of 2020. We look forward to discussing our clinical progress in detail at our R&D Day event today, which will include interim positive data from our ongoing PHYOX3 multidose trial of nedosiran, Phase 1 proof-of-concept data from our ongoing trial of RG6346 for the treatment of chronic hepatitis B virus infection, and our first public presentation of preclinical data demonstrating delivery of our proprietary technology to multiple tissues outside the liver – all of which reinforce Dicerna’s position as a best-in-class company in RNAi therapeutics.”

Clinical and Regulatory Updates

Since its first COVID-19-related update in March, the Company has continued to monitor developments related to the pandemic and potential impacts to its business and clinical development programs, including the timing of development milestones. Dicerna today provided an update on the progress of each of its core development programs and development timeline expectations.

 

   

RG6346 Phase 1 Proof-of-Concept Trial for Chronic Hepatitis B Virus Infection. RG6346 is an investigational candidate for the treatment of chronic hepatitis B virus (HBV) infection being developed in collaboration with Roche. Enrollment of the Phase 1 clinical study of RG6346 was completed in June 2020. In a separate news release today, Dicerna announced positive data from the ongoing trial in which patients from its multidose Group C reached a mean reduction in hepatitis B surface antigen (HBsAg) of 1.39, 1.80 and 1.84 log10 IU/mL at Day 112 end-of-treatment for the 1.5, 3.0 and 6.0 mg/kg cohorts, respectively. Notably, HBsAg suppression has been stably maintained beyond Day 112, with the 1.5 mg/kg cohort showing stable mean HBsAg reduction through Day 336, confirming preclinical predictions of a long duration of effect for Dicerna’s X-sparing HBV targeting strategy. No serious adverse events (SAEs) were observed with RG6346 treatment in any group. The most commonly reported adverse events were mild or moderate injection-site events. No dose-limiting toxicities were observed, and there were no safety-related discontinuations. Under the collaboration agreement, Roche will be responsible for initiating Phase 2 development of RG6346.

 

   

Positive Interim Data from PHYOX3 Multidose, Open-Label Extension Trial of Nedosiran. In April 2020, in response to COVID-19 impacts at clinical trial sites, the Company implemented a protocol amendment with local Institutional Review Boards and transitioned certain site visits to a combination of at-home nurse visits with investigator telehealth assessments for dose administration and safety follow-up.


Updated interim data from this ongoing trial, which were released in a separate news release this morning, demonstrated that of the 11 participants included in the analysis (eight PH1 and three PH2) who had reached Day 120 receiving once-monthly nedosiran, nine participants (82%) had achieved normal or near-normal urinary oxalate (Uox) levels, defined as below 0.46 mmol /1.73m2 body surface area adjusted (BSA)/24 hr (laboratory assay upper limit of normal [ULN] ) and from 0.46 to 0.6 mmol/ 1.73m2 BSA/24 hr (1.3xULN, defined per protocol as near-normal), respectively. To date, five of the 17 participants enrolled in PHYOX3 had achieved and maintained normal Uox concentrations on at least three consecutive visits, making them eligible for gradual reduction in fluid intake. In this interim analysis, nedosiran appeared generally well tolerated, with three injection-site reactions in the 16 enrolled patients and no drug-related severe adverse events. The overall adverse event profile was comparable to that observed in the PHYOX1 Phase 1 clinical trial.

 

   

Nedosiran PHYOX2 Pivotal Trial. In April and May 2020, Dicerna transitioned certain site visits in the PHYOX2 trial to a combination of at-home nurse visits and investigator telehealth assessments for drug administration and safety follow-up to align with trial sites’ operational changes resulting from the COVID-19 pandemic. Enrollment in the PHYOX2 trial continues at a limited number of sites globally. While subject to change pending potential future site impacts related to the pandemic, the Company currently expects to complete enrollment in the PHYOX2 trial in the fourth quarter of 2020.

 

   

Rare Pediatric Disease Designation for Nedosiran for Treatment of Primary Hyperoxaluria. In June 2020, the U.S. Food and Drug Administration (FDA) granted rare pediatric disease designation for nedosiran. Under the FDA’s rare pediatric disease designation program, the FDA may grant a priority review voucher to a sponsor who receives a product approval for a “rare pediatric disease.” Subject to FDA approval of nedosiran for the treatment of PH, Dicerna would be eligible to receive a voucher that may be redeemed to receive priority review for a subsequent marketing application for a different product candidate or which could be sold or transferred.

 

   

Preclinical Data From Dicernas Technology in New Tissues. In a separate news release today, Dicerna announced positive preclinical data demonstrating expansion of its technology and discovery efforts beyond its hepatocyte-focused GalXC RNAi technology to central nervous system (CNS), skeletal muscle and adipose tissues. The data demonstrated consistent and durable CNS-wide target mRNA knockdown using novel constructs regardless of route of administration (intrathecal [IT] or intracisterna magna [ICM]) and reduction in target mRNA (messenger RNA) in skeletal muscle and adipose tissue using optimized chemistries, resulting in equivalent and potentially highly durable target knockdown regardless of dosing regimens.

 

   

DCR-A1AT Phase 1/2 Trial and ALN-AAT02 Program Update. In late April 2020, the Scientific Review Committee for the DCR-A1AT Phase 1/2 trial confirmed that the study could continue, and the Company began enrolling the following dosing cohort in May, which has since been completed. The Company is currently targeting program selection and potential initiation of patient dosing in the first quarter of 2021.

Corporate and Collaboration Program Updates

 

   

Shreeram Aradhye, M.D. Appointed Executive Vice President and Chief Medical Officer. Dicerna announced yesterday the appointment of Dr. Aradhye as executive vice president and chief medical officer, effective Sept. 8, 2020. Dr. Aradhye brings over 20 years of pharmaceutical industry experience in clinical development and medical affairs, most recently as chief development officer of Axcella Health. Prior to Axcella, Dr. Aradhye served as global head of medical affairs and chief medical officer – pharmaceuticals for Novartis Pharmaceuticals.

 

   

Roche Collaboration Agreement. In April 2020, Roche formally nominated the first selected target and thus initiated the research and development portion of its agreement with the Company. In October 2019, Dicerna and Roche entered into an agreement related to the development and commercialization of RG6346 and the discovery, development and commercialization of oligonucleotide therapeutics targeting multiple gene targets implicated in chronic hepatitis B virus (HBV) infection.


Upcoming Milestones

 

   

Nedosiran: Expected completion of enrollment in PHYOX2 pivotal clinical trial in the fourth quarter of 2020 with last patient anticipated to complete the study in the first half of 2021 and subsequent New Drug Application submission in the third quarter of 2021

 

   

Collaborative Program: Investigational New Drug or Clinical Trial Authorization filing for LY3561774 by Lilly in late 2020

 

   

DCR-A1AT/ ALN-AAT02: Program selection and potential initiation of patient dosing in the first quarter of 2021

Supply Chain Update

The current supply of Dicerna’s investigational medicines continues to be sufficient to support ongoing clinical trials. Based on current evaluations, Dicerna’s supply chain continues to appear intact at this time to meet expected 2020 clinical, nonclinical, and chemistry, manufacturing and control supply demands across all programs. The Company has undertaken efforts to mitigate potential future impacts to the supply chain by increasing its stock of critical starting materials required to meet its needs and its collaborative partners’ needs through mid-2021 and by identifying and engaging alternative suppliers. The Company continues to be alert to the potential for disruptions that could arise from COVID-19 and remains in close contact with suppliers.

Financial Results for Second Quarter of 2020

 

   

Cash Position – As of June 30, 2020, Dicerna had $669.2 million in cash, cash equivalents and held-to-maturity investments, compared to $348.9 million as of Dec. 31, 2019. Additionally, the Company had $5.6 million and $3.9 million of restricted cash equivalents as of June 30, 2020 and Dec. 31, 2019, respectively, reflecting collateral securing the Company’s lease obligations.

 

   

Revenue – Dicerna recognized $40.4 million of revenue associated with its collaboration partners during the quarter ended June 30, 2020, compared to $5.7 million for the same period in 2019.

 

   

Research and Development (R&D) Expenses – R&D expenses were $53.4 million for the quarter ended June 30, 2020, compared to $22.8 million for the same period in 2019. The increase was primarily due to direct research and development expenses as a result of manufacturing and clinical study costs and employee-related expenses due to an increase in headcount necessary to support our growth.

 

   

General and Administrative (G&A) Expenses – G&A expenses were $20.6 million for the quarter ended June 30, 2020, compared to $8.8 million for the same period in 2019. The increase was primarily due to employee-related expenses as a result of increased headcount necessary to support our growth.

 

   

Net Loss – Net loss was $31.8 million, or $0.43 per share, for the quarter ended June 30, 2020, compared to $23.8 million, or $0.35 per share, for the same period in 2019.

Guidance

Dicerna believes that its cash, cash equivalents and held-to-maturity investments will be sufficient to fund the execution of its current clinical and operating plan into 2023, which includes our expectations to advance nedosiran through pivotal development, regulatory filing and potential commercial launch; completing the proof-of-concept study of RG6346 in participants with HBV infection; conducting nonclinical studies of ALN-AAT02 and advancing either ALN-AAT02 or DCR-A1AT through Phase 1/2; and initiating and conducting research and development programs with our collaborative partners. This estimate assumes no new funding from additional collaboration agreements or from external financing events and no significant unanticipated changes in costs and expenses. Dicerna expects its overall expenses to continue to increase significantly for the foreseeable future, primarily as the Company continues clinical


manufacturing activities, advances preclinical toxicology studies, continues clinical activities associated with its lead product candidates, prepares for commercialization of nedosiran and initiates or increases activities under the agreements with Novo Nordisk A/S, Roche, Eli Lilly, Alexion Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH and Alnylam Pharmaceuticals, Inc.

Virtual R&D Day Event Webcast Details

The Company will host a Virtual R&D Day Event to discuss the results from its Phase 1 proof-of-concept trial of RG6346, its PHYOX3 multidose trial of nedosiran and preclinical data related to its technology in extrahepatic tissues. The webcast presentation will begin at 10:00 a.m. ET, and may be accessed by visiting the “Investors & Media” section of the Dicerna website, www.dicerna.com. A conference line can be accessed by dialing (800) 708-4539 or +1 (847) 619-6396 and referencing conference ID 49860522. A replay of the webcast will be archived on Dicerna’s website following the conclusion of the live event.

About Dicerna Pharmaceuticals, Inc.

Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA) is a biopharmaceutical company focused on discovering, developing and commercializing medicines that are designed to leverage ribonucleic acid interference (RNAi) to selectively silence genes that cause or contribute to disease. Using our proprietary RNAi technology platform called GalXC, Dicerna is committed to developing RNAi-based therapies with the potential to treat both rare and more prevalent diseases. By silencing disease-causing genes, Dicerna’s GalXC platform has the potential to address conditions that are difficult to treat with other modalities. Initially focused on hepatocytes, Dicerna has continued to innovate and is exploring new applications of its RNAi technology beyond the liver, targeting additional tissues and enabling new therapeutic applications. In addition to our own pipeline of core discovery and clinical candidates, Dicerna has established collaborative relationships with some of the world’s leading pharmaceutical companies, including Novo Nordisk A/S, Roche, Eli Lilly and Company, Alexion Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH and Alnylam Pharmaceuticals, Inc. Between Dicerna and our collaborative partners, we currently have more than 20 active discovery, preclinical or clinical programs focused on rare, cardiometabolic, viral, chronic liver and complement-mediated diseases, as well as neurodegeneration and pain. At Dicerna, our mission is to interfere – to silence genes, to fight disease, to restore heath. For more information, please visit www.dicerna.com.

Cautionary Note on Forward-Looking Statements

This press release includes forward-looking statements. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Examples of forward-looking statements include, among others, statements we make regarding: (i) Phase 1 proof-of-concept data for RG6346, an investigational GalXC RNAi treatment candidate for chronic hepatitis B virus (HBV) infection in development with Roche; (ii) multidose data from the PHYOX3 trial of nedosiran, an investigational GalXC RNAi treatment candidate for primary hyperoxaluria (PH), (iii) preclinical data on Dicerna’s technology in extrahepatic tissues; (iv) the therapeutic and commercial potential of nedosiran; (v) guidance concerning future financial results, sufficient cash for future operations and corporate developments and (vi) clinical development timelines and review related to nedosiran and continued alignment on the regulatory pathway to approval. The process by which investigational therapies, such as nedosiran, could potentially lead to an approved product is long and subject to highly significant risks. Applicable risks and uncertainties include those relating to Dicerna’s clinical research and other risks identified under the heading “Risk Factors” included in the Company’s most recent filings on Forms 10-K and 10-Q and in other future filings with the Securities and Exchange Commission. These risks and uncertainties include, among others, the cost, timing and results of preclinical studies and clinical trials and other development activities by us and our collaborative partners; the likelihood of Dicerna’s clinical programs being executed on timelines provided and reliance on the Company’s contract research organizations and predictability of timely enrollment of subjects and patients to advance Dicerna’s clinical trials; the reliance of Dicerna on contract manufacturers to supply its products for research and development and the risk of supply interruption from a contract manufacturer; the potential for future data to alter initial and preliminary results of early-stage clinical trials; the impact of the ongoing COVID-19 pandemic on our business


operations, including the conduct of our research and development activities; the regulatory review and unpredictability of the duration and results of the regulatory review of Investigational New Drug applications (INDs) and Clinical Trial Applications (CTAs) that are necessary to continue to advance and progress the Company’s clinical programs; the timing, plans and reviews by regulatory authorities of marketing applications such as New Drug Applications (NDAs) and comparable foreign applications for one or more of Dicerna’s product candidates; the ability to secure, maintain and realize the intended benefits of collaborations with partners; market acceptance for approved products and innovative therapeutic treatments; competition; the possible impairment of, inability to obtain, and costs to obtain intellectual property rights; possible safety or efficacy concerns that could emerge as new data are generated in R&D; and general business, financial, and accounting risks and litigation. The forward-looking statements contained in this press release reflect Dicerna’s current views with respect to future events, and Dicerna does not undertake and specifically disclaims any obligation to update any forward-looking statements.

GalXC and PHYOX are trademarks of Dicerna Pharmaceuticals, Inc.

(tables follow)

DICERNA PHARMACEUTICALS, INC.

SELECTED FINANCIAL INFORMATION (UNAUDITED)

 

CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS    Three Months Ended
June 30, 2020
    Three Months Ended
June 30, 2019
 

(In thousands, except per share data)

Revenue

   $ 40,448   $ 5,682

Operating expenses:

    

Research and development

     53,376     22,832

General and administrative

     20,565     8,831
  

 

 

   

 

 

 

Total operating expenses

     73,941     31,663
  

 

 

   

 

 

 

Loss from operations

     (33,493     (25,981
  

 

 

   

 

 

 

Other income (expense):

    

Interest income

     1,729     2,136

Interest expense

     (6     —    

Other expense

     (50     —    
  

 

 

   

 

 

 

Total other income, net

     1,673     2,136
  

 

 

   

 

 

 

Net loss

   $ (31,820   $ (23,845
  

 

 

   

 

 

 

Net loss per share – basic and diluted

   $ (0.43   $ (0.35
  

 

 

   

 

 

 

Weighted-average common shares outstanding – basic and diluted

     74,001     68,324
  

 

 

   

 

 

 


     Six Months Ended
June 30, 2020
    Six Months Ended
June 30, 2019
 

CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS

(In thousands, except per share data)

Revenue

   $ 74,476   $ 8,789

Operating expenses:

    

Research and development

     96,547     44,435

General and administrative

     36,588     18,507
  

 

 

   

 

 

 

Total operating expenses

     133,135     62,942
  

 

 

   

 

 

 

Loss from operations

     (58,659     (54,153
  

 

 

   

 

 

 

Other income (expense):

    

Interest income

     4,342     4,154

Interest expense

     (10     —    

Other income

     15     —    
  

 

 

   

 

 

 

Total other income, net

     4,347     4,154
  

 

 

   

 

 

 

Net loss

   $ (54,312   $ (49,999
  

 

 

   

 

 

 

Net loss per share – basic and diluted

   $ (0.74   $ (0.73
  

 

 

   

 

 

 

Weighted-average common shares outstanding – basic and diluted

     73,460     68,292
  

 

 

   

 

 

 

 

CONDENSED CONSOLIDATED BALANCE SHEETS    June 30,
2020
     December 31,
2019
 

(In thousands)

Cash and cash equivalents

   $ 197,801    $ 152,816

Held-to-maturity investments

     471,408      196,065

Contract receivables

     12      200,354

Prepaid expenses and other current assets

     12,541      6,934

Property and equipment, net

     9,135      7,076

Right-of-use operating assets, net

     29,488      30,102

Restricted cash equivalents

     5,563      3,894

Other noncurrent assets

     6,462      168
  

 

 

    

 

 

 

Total Assets

   $ 732,410    $ 597,409
  

 

 

    

 

 

 

Accounts payable

   $ 7,764    $ 6,077

Accrued expenses and other current liabilities

     27,009      20,042

Lease liability, current

     2,810      3,358

Deferred revenue, current

     221,343      212,258

Lease liability, noncurrent

     19,819      20,141

Deferred revenue, noncurrent

     290,889      182,730

Other noncurrent liabilities

     608      608

Total stockholders’ equity

     162,168      152,195
  

 

 

    

 

 

 

Total Liabilities and Stockholders’ Equity

   $ 732,410    $ 597,409
  

 

 

    

 

 

 

Common stock outstanding

     74,321      71,573


###

Contacts

Media:

Amy Trevvett

+1 617-612-6253

atrevvett@dicerna.com

Investors:

Lauren Stival

+1 617-514-0461

lstival@dicerna.com

EX-99.2

Exhibit 99.2

 

LOGO

Dicerna Announces Positive Clinical Data for Investigational Treatments RG6346 for Chronic

Hepatitis B Virus and Nedosiran for Primary Hyperoxaluria, and Presents Preclinical Data Applying

RNAi Technology in New Tissues

– In the Ongoing Phase 1 Proof-of-Concept Trial Multidose Group, RG6346 1.5, 3.0 and 6.0 mg/kg Dosing

Cohorts Reached Mean HBsAg Reduction From Baseline of 1.39, 1.80 and 1.84 Log10 IU/mL, Respectively, at

Day 112 End-of-Treatment; Data for Earliest-Dose Cohort of 1.5 mg/kg Showed Durability of Response Through

Day 336 –

– Self-Resolving ALT Elevations With Preserved Liver Function in Several Participants Treated With RG6346

Suggest ALT Flares Potentially as a Result of Treatment-Induced Enhanced Immune Responses –

– In the Ongoing PHYOX3 Multidose, Open-Label Extension Trial of Nedosiran, 82% (Nine of 11 Participants)

Achieved Normal or Near-Normal Levels of Key Primary Hyperoxaluria Measure at Day 120 –

– Company Presents for First Time Preclinical Data of Proprietary RNAi Technology in Extrahepatic Tissues –

– Company to Host Virtual R&D Event Today at 10:00 a.m. ET –

LEXINGTON, Mass., Aug. 6, 2020Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA) (the “Company” or “Dicerna”), a leading developer of investigational ribonucleic acid interference (RNAi) therapeutics, today announced positive data from its Phase 1 proof-of-concept trial of RG6346, an investigational candidate for the treatment of chronic hepatitis B virus (HBV) infection in development in collaboration with Roche, and from its PHYOX3 open-label trial of nedosiran, an investigational candidate for the treatment of primary hyperoxaluria (PH). These data will be highlighted today as part of the Company’s virtual R&D Day event taking place from 10:00 a.m. to noon ET. Today’s event will also feature the Company’s first public presentation of preclinical data highlighting Dicerna’s proprietary RNAi technology in multiple new tissue types.

“The data presented today represent a cross-section of early- to late-stage results that highlight the power and significant potential of Dicerna’s RNAi technology platform, the benefit of innovative and thoughtfully designed development strategies, and our ability to generate a pipeline of potentially best-in-class new therapies for rare and prevalent diseases,” said Douglas Fambrough, Ph.D., president and chief executive officer of Dicerna. “I am very excited by the results we are seeing across our portfolio, demonstrating the strength of our RNAi technology platform and clinical enterprise, which together form the strong foundation upon which we are building our business to evolve into a fully integrated, commercial-stage biopharmaceutical company.”

RG6346 Phase 1 Proof-of-Concept Trial for Treatment of Chronic Hepatitis B Virus Infection

RG6346 is an investigational GalXC RNAi therapeutic candidate in Phase 1 for the treatment of chronic HBV infection. The ongoing Phase 1 proof-of-concept trial in adults comprises three groups: Group A, a dose-ranging cohort with healthy volunteers, which was completed last year; Group B, composed of newly diagnosed participants not on any antiviral therapy who received a single dose of RG6346; and Group C, which includes participants concurrently receiving nucleoside analog (NUC) therapy and four monthly doses of one of three dose levels of RG6346. In the Phase 1 study, nine of 10 participants who received RG6346 and have


completed the treatment period in Group C achieved ³1.0 log10 IU/mL reduction in hepatitis B surface antigen (HBsAg) at Day 112 and continued in the extended follow-up period. At Day 112, the mean reduction in HBsAg was 1.39 log10 IU/mL (n=4) for the 1.5 mg/kg cohort, 1.80 log10 IU/mL (n=4) for the 3.0 mg/kg cohort, and 1.84 log10 IU/mL (n=2) for the 6.0 mg/kg cohort; two participants have not yet reached Day 112. Of these 10 participants who received RG6346 and completed the treatment period, six had HBsAg <100 IU/mL at the last reported visit. Mean HBsAg reductions have been sustained through the extended follow-up period. The maximum HBsAg change observed was a 2.7 log10 IU/mL reduction on and after Day 112 end-of-treatment in a patient given 3.0 mg/kg of RG6346. The first patient dosed 1.5 mg/kg in the study has reached Day 392 with a 2.21 log10 IU/mL reduction in HBsAg (<100 IU/mL).

In addition, after a single 3.0 mg/kg dose of RG6346, two participants in Group B experienced protocol-defined transient alanine aminotransferase (ALT) flares, and one patient experienced a near-flare, each coinciding with a drop in HBsAg and preserved synthetic and excretory liver function, suggesting a potential enhanced immune response. One patient receiving 6.0 mg/kg of RG6346 in Group C demonstrated a similar self-resolving response.

“We are very encouraged by these early results from the RG6346 trial,” said John Young, global head of infectious diseases at Roche Pharma Early Research & Development. “Curing HBV infection requires development of a finite-duration therapeutic regimen that leads to sustained loss of circulating viral DNA and S-antigen in the bloodstream of patients. The level and durability of HBsAg reduction seen in this trial is of great interest, and we look forward to further evaluating the potential of RG6346 in an HBV therapeutic cure regimen.”

No serious adverse events (SAEs) were observed with RG6346 treatment in any group. The most commonly reported adverse events were mild or moderate injection-site events. No dose-limiting toxicities were observed, and there were no safety-related discontinuations. No dose-/exposure-dependent increases in frequency or severity of safety parameters were noted, and participants with ALT/AST (alanine aminotransferase and aspartate aminotransferase) or GGT (gamma-glutamyl transferase) elevations are all self-resolving, with preserved liver synthetic and excretory function.

“We took a unique and unconventional approach in our development of RG6346 by targeting just the conserved S region for the treatment of HBV,” commented Ralf Rosskamp, M.D., chief medical officer of Dicerna. “Our preclinical models showed that by sparing the X-gene, we could produce a therapy with a strong reduction in HBsAg and a long and stable duration of activity. The early data that we are now seeing from the RG6346 Phase 1 trial align with our predictions and signal its potential for the dual benefits of strong and sustained HBsAg knockdown in patients with HBV.”

Participants within Groups B and C were randomized 5:3 and 2:1, respectively, active versus placebo. Participants in Groups B and C are eligible to enter into an extended follow-up observation period if they achieve a reduction of ³1.0 log10 IU/mL of HBsAg from baseline at the end of the treatment period (12 weeks/85 days for Group B and 16 weeks/112 days for Group C). Enrollment was completed in June 2020, and results summarized below were as of June 25, 2020. Two participants have not yet reached Day 112, and the study is ongoing.

Under the terms of the agreement between the companies, Roche will be responsible for initiating Phase 2 development of RG6346.


Nedosiran PHYOX3 Multidose Open-Label Extension Trial Interim Analysis

The PHYOX3 trial (ClinicalTrials.gov: NCT04042402) is an ongoing open-label extension study evaluating nedosiran’s long-term safety and efficacy in participants with any of the three known types of primary hyperoxaluria – PH1, PH2 or PH3 – a family of ultra-rare, life-threatening genetic disorders that initially manifest with recurrent renal stones and can lead to kidney failure. The PHYOX3 trial is open to participants six years of age or older with PH who have participated in any previous PHYOX clinical development program trial, as well as their siblings with PH. All PHYOX3 participants who reached Day 120 and were evaluated in this interim analysis had previously completed the PHYOX1 single-ascending-dose Phase 1 trial. Of the 11 participants (eight PH1 and three PH2) who had reached Day 120 receiving once-monthly nedosiran, nine participants (82%) had achieved normal or near-normal urinary oxalate (Uox) levels, defined as below 0.46 mmol /1.73m2 body surface area adjusted (BSA)/24 hr (laboratory assay upper limit of normal [ULN] ) and from 0.46 to 0.6 mmol/ 1.73m2 BSA/24 hr (1.3xULN, defined per protocol as near-normal), respectively.

“The ultimate goal in treating patients with any PH type is to reduce their urinary oxalate levels to a normal range and give them the independence to not only live their life more free from the daily burden of hyperhydration, but even more importantly, with some reassurance that their PH won’t eventually lead to severe consequences such as chronic kidney failure or systemic oxalosis,” said Bernd Hoppe, M.D., vice president, global medical affairs at Dicerna and head, German Hyperoxaluria Center, Bonn, Germany. “As of this interim analysis, 82% of participants treated with five once-monthly doses of nedosiran reached normal or near-normal urinary oxalate levels. Five participants in the trial achieved these levels at three consecutive visits, making them eligible for weaning from hyperhydration disease management. The results observed so far in the PHYOX3 trial are very encouraging, and we look forward to seeing a more complete picture of nedosiran’s therapeutic profile as additional data from this trial and the PHYOX program become available.”

As of the July 10, 2020 interim analysis:

 

   

16 of the 18 participants in the PHYOX1 trial had enrolled in PHYOX3.

 

   

11 participants had received at least five monthly doses of 170 mg of nedosiran delivered subcutaneously (Days 1, 30, 60, 90 and 120).

 

   

There was an extended washout period between participants’ completion of PHYOX1 during which participants were anticipated to return to 80% of their Uox PHYOX1 baseline prior to starting in PHYOX3. Some patients did not return to this range and were permitted to enroll in PHYOX3 with lower baseline levels. The mean BSA-adjusted baseline Uox of these 11 participants in PHYOX1 was 1.323 mmol/1.73m2 BSA/24 hr, and the mean BSA adjusted observable baseline Uox levels for these same participants initiating PHYOX3 and included in this analysis was 0.926 mmol/1.73m2 BSA/24 hr.

 

   

100% of PH1 participants (eight of eight) that had rolled over from PHYOX1 and received five doses of nedosiran in the PHYOX3 study had achieved normalization or near-normalization at Day 120; of these, normalization was reached in 63% of the PH1 participants (five of eight).

 

   

For PH1 participants, the mean Uox level achieved was within the normal range (mean Uox= 0.404 mmol/1.73m2 BSA/24 hr).

 

   

All PH2 participants who had rolled over from PHYOX1 have received at least five doses of nedosiran. 33% of PH2 participants (one of three) achieved normalization at Day 120.

 

   

Five of the 17 participants enrolled in PHYOX3 had achieved and maintained normal Uox concentrations on at least three consecutive visits, making them eligible for gradual reduction in fluid intake.


In this interim analysis, nedosiran appeared generally well tolerated, with three injection-site reactions in the 16 enrolled patients and no drug-related severe adverse events. The overall adverse event profile was comparable to that observed in the PHYOX1 Phase 1 clinical trial. There was one participant who experienced a serious adverse event that was determined by the investigator to be unrelated to the study drug. Based on the cumulative number of days participants have participated in the PHYOX3 trial, total patient exposure to monthly dosing of nedosiran delivered subcutaneously has reached 5.8 years.

The results of this interim analysis comprised data from participants in the previously completed PHYOX1 single-dose Phase 1 trial. The study’s primary endpoint will evaluate annual rate of decline in estimated glomerular filtration rate (eGFR), a measure of kidney function and nedosiran’s ability to preserve remaining kidney function. Also, the PHYOX3 trial will evaluate nedosiran’s long-term effect on new stone formation, nephrocalcinosis, and the durability of reducing Uox levels, as well as its potential to enable the gradual decrease or elimination of their disease management practices.

Going Beyond GalXC: Dicerna’s Technology in New Tissues

Dicerna also announced preclinical data demonstrating expansion of its technology and discovery efforts beyond its hepatocyte-focused GalXC RNAi technology to central nervous system (CNS), skeletal muscle and adipose tissues. Among the key highlights were:

 

   

Results from preclinical assays demonstrated consistent and durable CNS-wide target mRNA knockdown using novel constructs regardless of route of administration (intrathecal [IT] or intracisterna magna [ICM]); and

 

   

Reduction in target mRNA (messenger RNA) in skeletal muscle and adipose tissue using optimized chemistries, resulting in equivalent and potentially highly durable target knockdown regardless of dosing regimens.

“We are very excited to present for the first time today preclinical data demonstrating the potential application of our technology platform beyond the liver,” said Bob D. Brown, chief scientific officer and executive vice president of R&D at Dicerna. “With the discovery and early success of GalXC– the technology platform underpinning our lead candidate nedosiran, core pipeline candidates, and our collaborations – we have continued to innovate and evolve our technology to provide flexibility for medicinal chemistry optimization and expansion. The preclinical data shown today generated by structurally and chemically modified and/or alternatively conjugated forms of our foundational GalXC technology can exhibit the potential to deliver therapeutic nucleic acids with potent and sustained activity in central nervous system, skeletal muscle and adipose tissues, as well as other tissues.”

Dr. Fambrough concluded, “The interim data today from our PHYOX3 study of nedosiran reinforce its potential to meaningfully interfere with the overproduction of urinary oxalate that can lead to serious systemic impacts in patients with PH, including kidney failure. The data from our Phase 1 study of RG6346 highlight its potential to be an important RNAi therapy in the treatment of HBV, with strong HBsAg knockdown sustained over a long duration. The preclinical data emerging from our labs supporting the extension of our technology to potential new therapeutic categories beyond the liver are demonstrating precisely the outcomes we intended. It’s an exciting time at Dicerna. I am energized by the caliber of data emerging from our preclinical and clinical programs and look forward to presenting the data in greater detail later today.”


Virtual Webcast Details

The virtual webcast presentation to discuss these data will begin at 10:00 a.m. ET and may be accessed by visiting the “Investors & Media” section of the Dicerna website, www.dicerna.com. A conference line can be accessed by dialing (800) 708-4539 or +1 (847) 619-6396 and referencing conference ID 49860522. A replay of the webcast will be archived on Dicerna’s website following the conclusion of the live event.

About Chronic Hepatitis B Virus (HBV) Infection

Hepatitis B virus (HBV) is the world’s most common serious liver infection and affects an estimated 292 million people worldwide.1 Chronic HBV infection, a condition characterized by the presence of the HBV surface antigen (HBsAg) for six months or more, claims more than 887,000 lives annually.2 HBV is also the primary cause of liver cancer (also known as hepatocellular carcinoma, or HCC), which is the second-leading cause of cancer deaths in the world.1

About RG6346

RG6346 is an investigational GalXC RNAi therapeutic candidate in development in collaboration with Roche for the treatment of chronic HBV infection. Dicerna is currently conducting a Phase 1 proof-of-concept trial of RG6346 in adult patients with non-cirrhotic chronic HBV infection. Current therapies for HBV, such as nucleoside analogs, can provide long-term viral suppression if taken continuously, but they rarely lead to long-term functional cures, as measured by the clearance of HBV surface antigen (HBsAg) and sustained HBV deoxyribonucleic acid (DNA) suppression in patient plasma or blood. By contrast, RG6346 is designed to employ RNA interference to selectively knock down specific genes involved in the creation of HBV messenger RNA (mRNA) and the entry of the virus into liver cells. Preclinical data have demonstrated greater than 99.9% reduction in circulating HBsAg, as observed in mouse models of HBV infection. Unlike current therapies that typically provide long-term suppression of the virus, RG6346 has the potential to provide a functional cure for patients living with chronic HBV.

About Primary Hyperoxaluria (PH)

Primary hyperoxaluria (PH) is a family of ultra-rare, life-threatening genetic disorders that initially manifest with complications in the kidneys. There are three known types of PH (PH1, PH2 and PH3), each resulting from a mutation in one of three different genes. These genetic mutations cause enzyme deficiencies that result in the overproduction of a substrate called oxalate. Abnormal production and accumulation of oxalate leads to recurrent kidney stones, nephrocalcinosis and chronic kidney disease that may progress to end-stage renal disease requiring intensive dialysis. Compromised renal function results eventually in the accumulation of oxalate in organs ranging from skin, bones, eyes and heart. In the most severe cases, symptoms start in the first year of life. A combined liver-kidney transplantation may be undertaken to resolve PH1 or PH2 but is an invasive solution with limited availability and high morbidity that requires lifelong immune suppression to prevent organ rejection. Currently, there is no approved therapy for the treatment of PH. Patients are limited to using hyperhydration and medication to attempt to increase solubility of oxalate in urine. Despite these interventions, oxalate may continue to accumulate in the kidneys, causing damage.


About Nedosiran

Nedosiran is the only RNAi drug candidate in development for primary hyperoxaluria (PH) types 1, 2 and 3 and is Dicerna’s most advanced product candidate utilizing the proprietary GalXC RNAi technology platform. Nedosiran is designed to inhibit the lactate dehydrogenase (LDH) enzyme – an enzyme that catalyzes the final step in a common pathway resulting in oxalate overproduction in patients with PH1, PH2 and PH3. Dicerna is evaluating the safety and efficacy of nedosiran in patients with all known forms of PH as part of its PHYOX clinical development program.

About the GalXC RNAi Technology Platform

Dicerna’s proprietary RNA interference (RNAi) technology platform, called GalXC, aims to advance the development of next-generation RNAi-based therapies designed to silence disease-driving genes in the liver. GalXC-based compounds enable subcutaneous delivery of RNAi therapies that are designed to bind specifically to receptors on liver cells, leading to internalization and access to the RNAi machinery within the cells. The GalXC approach seeks to optimize the activity of the RNAi pathway so that it operates in the most specific and potent fashion.

About Dicerna Pharmaceuticals, Inc.

Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA) is a biopharmaceutical company focused on discovering, developing and commercializing medicines that are designed to leverage ribonucleic acid interference (RNAi) to selectively silence genes that cause or contribute to disease. Using our proprietary RNAi technology platform called GalXC, Dicerna is committed to developing RNAi-based therapies with the potential to treat both rare and more prevalent diseases. By silencing disease-causing genes, Dicerna’s GalXC platform has the potential to address conditions that are difficult to treat with other modalities. Initially focused on hepatocytes, Dicerna has continued to innovate and is exploring new applications of its RNAi technology beyond the liver, targeting additional tissues and enabling new therapeutic applications. In addition to our own pipeline of core discovery and clinical candidates, Dicerna has established collaborative relationships with some of the world’s leading pharmaceutical companies, including Novo Nordisk A/S, Roche, Eli Lilly and Company, Alexion Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH and Alnylam Pharmaceuticals, Inc. Between Dicerna and our collaborative partners, we currently have more than 20 active discovery, preclinical or clinical programs focused on rare, cardiometabolic, viral, chronic liver and complement-mediated diseases, as well as neurodegeneration and pain. At Dicerna, our mission is to interfere – to silence genes, to fight disease, to restore heath. For more information, please visit www.dicerna.com.

Cautionary Note on Forward-Looking Statements

This press release includes forward-looking statements. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Examples of forward-looking statements include, among others, statements we make regarding: (i) Phase 1 proof-of-concept data for RG6346, an investigational GalXC RNAi treatment candidate for chronic hepatitis B virus (HBV) infection in development with Roche; (ii) multidose data from the PHYOX3 trial of nedosiran, an investigational GalXC RNAi treatment candidate for primary hyperoxaluria (PH), (iii) first preclinical data on Dicerna’s RNAi technology in extrahepatic tissues; (iv) the therapeutic and commercial potential of nedosiran and (v) clinical development timelines and review related to nedosiran and continued alignment on the regulatory pathway to approval. The process by which investigational therapies, such as nedosiran, could potentially lead to an approved product is long and subject to highly significant risks. Applicable risks and uncertainties include those relating to Dicerna’s clinical research and other risks identified under the heading “Risk Factors” included in the Company’s most recent filings on Forms 10-K and 10-Q and in other future filings with the Securities and Exchange Commission. These risks and uncertainties include, among others, the cost, timing and results of preclinical studies and clinical trials and other development activities by us and our collaborative partners; the likelihood of Dicerna’s clinical programs being executed on timelines provided and reliance on the Company’s contract research organizations and predictability of timely


enrollment of subjects and patients to advance Dicerna’s clinical trials; the reliance of Dicerna on contract manufacturers to supply its products for research and development and the risk of supply interruption from a contract manufacturer; the potential for future data to alter initial and preliminary results of early-stage clinical trials; the impact of the ongoing COVID-19 pandemic on our business operations, including the conduct of our research and development activities; the regulatory review and unpredictability of the duration and results of the regulatory review of Investigational New Drug applications (INDs) and Clinical Trial Applications (CTAs) that are necessary to continue to advance and progress the Company’s clinical programs; the timing, plans and reviews by regulatory authorities of marketing applications such as New Drug Applications (NDAs) and comparable foreign applications for one or more of Dicerna’s product candidates; the ability to secure, maintain and realize the intended benefits of collaborations with partners; market acceptance for approved products and innovative therapeutic treatments; competition; the possible impairment of, inability to obtain, and costs to obtain intellectual property rights; possible safety or efficacy concerns that could emerge as new data are generated in R&D; and general business, financial, and accounting risks and litigation. The forward-looking statements contained in this press release reflect Dicerna’s current views with respect to future events, and Dicerna does not undertake and specifically disclaims any obligation to update any forward-looking statements.

1 Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. The Lancet Gastroenterology and Hepatology. Volume 3, Issue 6, June 2018, Pages 383-403.

2 Hepatitis B Foundation. Facts and Figures. Available at: http://www.hepb.org/what-is-hepatitis-b/what-is-hepb/facts-and-figures/ . Accessed on Aug. 4, 2020.

GalXC and PHYOX are trademarks of Dicerna Pharmaceuticals, Inc.

###

Contacts

Media:

Amy Trevvett

+1 617-612-6253

atrevvett@dicerna.com

Investors:

Lauren Stival

+1 617-514-0461

lstival@dicerna.com

EX-99.3

Slide 1

Dicerna 2020 Virtual R&D Update: Nedosiran, RG6346 and Going Beyond GalXC™ August 6, 2020 Exhibit 99.3


Slide 2

Forward-Looking Statements This presentation includes forward-looking statements. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Examples of forward-looking statements include, among others, statements we make regarding: (i) Phase 1 proof-of-concept data for RG6346, an investigational GalXC™ RNAi treatment candidate for chronic hepatitis B virus (HBV) infection in development with Roche; (ii) multidose data from the PHYOX™3 trial of nedosiran, an investigational GalXC RNAi treatment candidate for primary hyperoxaluria (PH), (iii) first preclinical data on Dicerna’s RNAi technology in extrahepatic tissues; (iv) the therapeutic and commercial potential of nedosiran and (v) clinical development timelines and review related to nedosiran and continued alignment on the regulatory pathway to approval. The process by which investigational therapies, such as nedosiran, could potentially lead to an approved product is long and subject to highly significant risks. Applicable risks and uncertainties include those relating to Dicerna’s clinical research and other risks identified under the heading "Risk Factors" included in the Company’s most recent filings on Forms 10-K and 10-Q and in other future filings with the Securities and Exchange Commission. These risks and uncertainties include, among others, the cost, timing and results of preclinical studies and clinical trials and other development activities by us and our collaborative partners; the likelihood of Dicerna’s clinical programs being executed on timelines provided and reliance on the Company’s contract research organizations and predictability of timely enrollment of subjects and patients to advance Dicerna’s clinical trials; the reliance of Dicerna on contract manufacturers to supply its products for research and development and the risk of supply interruption from a contract manufacturer; the potential for future data to alter initial and preliminary results of early-stage clinical trials; the impact of the ongoing COVID-19 pandemic on our business operations, including the conduct of our research and development activities; the regulatory review and unpredictability of the duration and results of the regulatory review of Investigational New Drug applications (INDs) and Clinical Trial Applications (CTAs) that are necessary to continue to advance and progress the Company’s clinical programs; the timing, plans and reviews by regulatory authorities of marketing applications such as New Drug Applications (NDAs) and comparable foreign applications for one or more of Dicerna’s product candidates; the ability to secure, maintain and realize the intended benefits of collaborations with partners; market acceptance for approved products and innovative therapeutic treatments; competition; the possible impairment of, inability to obtain, and costs to obtain intellectual property rights; possible safety or efficacy concerns that could emerge as new data are generated in R&D; and general business, financial, and accounting risks and litigation. The forward-looking statements contained in this press release reflect Dicerna's current views with respect to future events, and Dicerna does not undertake and specifically disclaims any obligation to update any forward-looking statements. GalXC™ and PHYOX™ are trademarks of Dicerna Pharmaceuticals, Inc.


Slide 3

Today’s Speakers Man-Fung Yuen, M.D., Ph.D. Chair Professor and Endowed Professor in Medicine of the Li Shu Fan Medical Foundation, University of Hong Kong Douglas M. Fambrough, Ph.D. President and Chief Executive Officer Dicerna Pharmaceuticals Bob D. Brown, Ph.D. Chief Scientific Officer, Executive Vice President of R&D Dicerna Pharmaceuticals Rob Ciappenelli, M.B.A. Chief Commercial Officer Dicerna Pharmaceuticals Ralf Rosskamp, M.D. Chief Medical Officer Dicerna Pharmaceuticals Bernd Hoppe, M.D. Vice President, Global Medical Affairs Dicerna Pharmaceuticals


Slide 4

Program Agenda Corporate Vision and Strategy Douglas M. Fambrough, Ph.D. 10:00 – 10:10 a.m. RG6346 Phase 1 Data and Next Steps Bob D. Brown, Ph.D. Man-Fung Yuen, M.D., Ph.D. 10:10 – 10:50 a.m. Q&A All Presenters 10:50 – 11:00 a.m. Nedosiran PHYOX™3 Data and Commercial Planning Bernd Hoppe, M.D. Ralf Rosskamp, M.D. Rob Ciappenelli, M.B.A. 11:00 – 11:30 a.m. Going Beyond GalXC™ Bob D. Brown, Ph.D. 11:30 – 11:45 a.m. Q&A All Presenters 11:45 – 12:00 p.m.


Slide 5

Vision and Strategy Douglas M. Fambrough, Ph.D., President and Chief Executive Officer


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VISION Develop and commercialize our core high-probability-of-success programs either alone or in collaboration with partners Broadly enable the use of our GalXC technology by collaborating with therapeutic area leaders on non-core opportunities STRATEGY Maximize the impact of RNAi on medicine


Slide 7

Established safety in large population studies Multiple committed large pharmas Approved Products Multiple candidates in registration or pivotal development The RNAi Modality Has Come of Age Liver targets formed the foundation for RNAi’s early success. Today, RNAi technologies are exploring the vast opportunities outside the liver.


Slide 8

Expansive Opportunity for RNAi Throughout the Body Proprietary extended Dicerna structure provides unparalleled medicinal chemistry flexibility CNS collaboration with Lilly with multiple ongoing discovery programs Subcutaneous delivery for muscle and adipose tissue will be presented today Additional tissues under development


Slide 9

CANDIDATE / TARGET INDICATION DISCOVERY/ RESEARCH PRECLINICAL CLINICAL PROOF-OF-CONCEPT TRIALS REGISTRATION TRIALS DICERNA’S PRODUCT RIGHTS Nedosiran Primary Hyperoxaluria Types 1, 2, 3 100% RG6346 Hepatitis B Virus U.S. opt-in* DCR-A1AT ALN-AAT02 A1AT Liver Disease 100% U.S. Alnylam ex-U.S. opt-in DCR-proprietary Undisclosed 100% Core Pipeline Candidates *Under the Dicerna-Roche agreement, Dicerna has the option to co-fund pivotal development, which if exercised, entitles Dicerna to receive enhanced royalties and co-promotion rights in the U.S.


Slide 10

We Believe Dicerna Is Creating Best-In-Class Opportunities In Hepatitis B Dicerna’s X-sparing approach drives extended duration of effect that may lead to treatments that are both more convenient and more effective that non-X-sparing approaches In Primary Hyperoxaluria Dicerna conducted fundamental disease research to develop the LDHA mechanism seeking to treat multiple forms of PH and potentially generate the most effective approach to PH1 In Extending RNAi Throughout the Body Dicerna’s proprietary RNAi configuration provides unparalleled medicinal chemistry flexibility to potentially create molecules that transcend cell-type specificity and move toward general solutions to RNAi therapy in multiple cell types and tissues In A1AT Liver Disease Dicerna and Alnylam have joined forces to potentially develop the best A1AT RNAi therapy for patients with A1AT liver disease


Slide 11

Deep Collaboration Pipeline Over 15 Preclinical Targets In Process Across Multiple Therapeutic Categories Liver-Related Cardiometabolic Diseases Chronic HBV LY3561774 LY3819469 DCR-CM4 DCR-CM5 DCR-NEURO1 DCR-NEURO2 DCR-LLY9 DCR-PAIN1 DCR-PAIN2 DCR-LLY10 Cardiometabolic, Neurodegeneration, Pain, Undisclosed DCR-LIV2 DCR-COMP1 DCR-COMP2 DCR-COMP3 DCR-COMP4 DCR-RG1 Multiple potential targets 30+ potential targets Multiple targets selected NASH Complement-Mediated Rare Diseases Preclinical Discovery Stage Nov. 2017 Oct. 2018 Oct. 2018 Oct. 2019 Nov. 2019


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$175M upfront $75M total annuals $50M equity $200M upfront $100M upfront $100M equity 1 NASH Target $5M option exercised $10M upfront $22M upfront $15M equity Successfully Executing on High-Value Collaboration Strategy Nov. 2017 Oct. 2018 Oct. 2018 Oct. 2019 Nov. 2019 signed Dicerna retains opt-in rights 4 complement-mediated targets $20M option exercised Up to 8 cardiometabolic targets, liver and non-liver Neurodegeneration & pain targets DRNA retains rights to certain neuro orphan indications RG6346 and multiple potential HBV-related targets DRNA option to co-fund development and co-promote in U.S. 30+ potential targets for liver-related CM diseases 2 Novo programs: DRNA opt-in DRNA retains rights to 2 new orphan programs (Novo retains opt-in rights)


Slide 13

HBV HBsAg Reduction: The X-Sparing Hypothesis Bob D. Brown, Ph.D. Chief Scientific Officer, Executive Vice President Research & Development


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Hepatitis B: A Severe, Global Unmet Medical Need Significant worldwide prevalence: ~292 million infected Causes more than 887,000 deaths per year Current treatments are rarely effective in achieving functional cures Dicerna is collaborating with Roche to develop RG6346 and potentially other agents for the treatment of HBV Electron micrograph of HBV showing infectious viral particles (~42 nm) and non-infectious aviral “decoy” particles (~22 nm) and filaments Sources: Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. The Lancet Gastroenterology and Hepatology. Volume 3, Issue 6, June 2018, Pages 383-403. World Health Organization. Finding a cure for hepatitis B: are we close? https://www.who.int/hepatitis/news-events/hbv-cure-overview/en/. Accessed Aug. 4, 2020.


Slide 15

The Promise of RNAi for the Treatment of Chronic HBV Organization of the HBV Genome Enables Effective RNAi Targeting of Multiple Viral Functions AAAAA P gene Polymerase. Involved in viral genome production S gene (HBsAg) Surface protein. Involved in viral coat and immune tolerizing agent X gene Involved in maintenance of cccDNA and viral gene regulation C gene Core protein. Involved in capsid assembly and viral gene regulation Overlapping mRNAs and protein-coding regions enable targeting multiple HBV genes with a single GalXC trigger AAAAA AAAAA AAAAA viral genome viral mRNA transcript Conserved S Region Silences S, P and C encoding mRNAs RG6346 targets this region Conserved X Region Silences S, P, C and X encoding mRNAs There are two conserved regions to target within the virus. Which is best? Or should you target both?


Slide 16

Superior HBsAg Reduction When Targeting Only the Conserved S Region Conserved S Region only: ≥3.9 log reduction, long duration of activity Conserved S & X Regions: 3.0 log reduction, shorter duration of activity Striking Differences Between Targeting S Region Alone vs. S and X Regions in a Preclinical Model Time (weeks) 3mg/kg qWx3 2/3 BLOQ 3/3 BLOQ Vehicle control HDI-HBV Plasmid Mouse Model (cccDNA-dependent) Only Conserved S Region targeted -1 0 1 2 3 4 5 6 7 8 9 0.001 0.01 0.1 1 10 100 10 11 12 %HBsAg +/- SEM (Normalized to d0) S and X Conserved Regions targeted The hydrodynamic injection (HDI) mouse model only introduces the HBV genome into mouse hepatocytes, so should reflect natural HBV gene regulation Targeting the Conserved X Region leads to more rapid HBsAg rebound Result is reproducible when different sequences within the regions are targeted These findings predict a longer duration of effect for candidate therapeutics that target solely the Conserved S Region


Slide 17

Known X Gene Function Supports Role as an S Gene Regulator Leaving X Gene Function Intact is Predicted to Give Better HBsAg Suppression Immunohistochemical staining of mouse liver sections for HBV Core protein reveals differential subcellular localization in the HDI-HBV plasmid model Silencing of X gene leads to nuclear localized Core protein likely driving additional S expression HBV Core Protein Vehicle Only S Region Targeted X and S Regions Targeted X present Core protein S transcription and HBsAg aviral particle production Core polymerization and encapsidation P P P X absent Nucleus cccDNA phosphorylated Model of How Presence or Absence of X Protein Impacts Core Protein HBV X protein has been characterized as a “rheostat” controlling the balance between active viral replication and cccDNA-mediated production of aviral particles (circulating HBsAg) Targeting the Conserved S Region with RG6346 leaves the X protein encoding mRNA intact Remaining X protein drives residual Core protein into the cytoplasm Cytoplasmic Core protein cannot act as a transcriptional activator Less HBsAg is produced


Slide 18

Phase 1 Trial: RG6346 for the Treatment of Hepatitis B Virus (HBV) Infection Man-Fung Yuen, D.Sc., M.D., Ph.D. Chair Professor & Endowed Professor in Medicine, Li Shu Fan Medical Foundation; Chief of the Division of Gastroenterology & Hepatology and Deputy Head of the Department of Medicine, Queen Mary Hospital, the University of Hong Kong


Slide 19

Man-Fung Yuen, D.Sc., M.D., Ph.D. A therapeutic expert and pioneering clinical researcher leading numerous studies on novel antiviral and immunomodulatory agents for the treatment of chronic hepatitis B virus infection Research includes prevention, natural history, molecular virology, treatment of chronic hepatitis B and C and hepatocellular carcinoma and is actively involved with cutting-edge research on novel markers for hepatitis B infection and occult hepatitis B infection One of the top internationally known researchers in the field of hepatitis B, with more than 430 papers published in world-renowned medical journals First bachelor’s degree of medicine in 1992; three doctoral degrees: Doctor of Medicine with Sir Patrick Manson Gold Medal in 2001 Doctor of Philosophy in 2005 Doctor of Science in 2017


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Disclosures Dr. Yuen is currently a principal investigator for Dicerna’s HBVS-101 study and was a member of our clinical advisory board that was held in 2019. Dr. Yuen has received compensation from Dicerna for both these activities. His role as an investigator in the HBVS-101 study and as a member of Dicerna’s clinical advisory board makes him uniquely qualified to present at today’s R&D event and share his perspective and experience. Dr. Yuen is receiving fair market value compensation from Dicerna for the services he is providing today on our behalf. Dicerna’s compensation to Dr. Yuen for his services today are not intended in any way to influence any future prescribing decision for any Dicerna compound in development or in return for any recommendation now or in the future to use any Dicerna product.


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Global Impact: Still Increasing HBV Disease Mortality Unlike HIV, tuberculosis, and malaria, mortality from viral hepatitis is increasing Putting it into context: mortality from HBV-related diseases each year is higher than current worldwide mortality from COVID-19 Source: WHO Global Health Estimates 2016 2,000,000 1,500,000 1,000,000 500,000 0 2000 2005 2010 2015 Year Number of Deaths Hepatitis Tuberculosis HIV Malaria Global Annual Mortality Due to Prevalent Infectious Diseases


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Present Treatment Aims/Goals The new treatment paradigm is to continue CHB treatment until HBsAg seroclearance is achieved for both HBeAg-positive and HBeAg-negative CHB patients, potentially resulting in functional cure Treatment guidelines from APASL, EASL and AASLD all agree that this is the optimal endpoint HBsAg Clearance Remains Key to Chronic Hepatitis B Virus Treatment Paradigm Source: WHO Global Health Estimates 2016 Yuen MF, et al. J Clin Gastroenterol 2016;50:286–294. Virologic response ↓ HBV DNA to undetectable ↓ cccDNA Biochemical and liver synthetic test improvement ALT, bilirubin, albumin Serologic responses HBeAg loss/seroconversion HBsAg loss/seroconversion Histologic improvement Aims: Prevent progression to cirrhosis, Hepatocellular Carcinoma and death


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Key Study Inclusion/Exclusion Criteria: HBeAg positive with HBsAg >1000 IU/mL or HBeAg negative with HBsAg >500 IU/mL; NUC naïve with screening serum HBV DNA >2000 IU/mL and ALT ≥35 U/L (males) or ≥30 U/L (females) Clinical history compatible with compensated liver disease, with no evidence of cirrhosis Group C: continuously on NUC therapy for at least 12 weeks prior to screening After completion of the treatment period, study participants with ≥1 log HBsAg reduction are followed in a conditional follow-up period (CFU) Group A Placebo-controlled (2:1 active vs placebo), single-ascending-dose study in healthy volunteers Completed n=30 RG6346 dose cohorts: 0.1, 1.5, 3.0, 6.0, 12.0 mg/kg Group B Placebo-controlled (5:3 active vs placebo), single-dose study in participants with no prior use of nucleoside or nucleotide analogue (NUC) therapy (NUC-naïve) with chronic HBV infection Ongoing n=9* RG6346 dose cohort: 3.0 mg/kg (NUCs initiated after 12 wks) Group C Placebo-controlled (2:1 active vs placebo), multiple-ascending-dose study in NUC-experienced participants with chronic HBV infection Ongoing n=18 Currently dosing 6.0 mg/kg cohort RG6346 dose cohorts: 1.5, 3.0, 6.0 mg/kg; 4 monthly doses RG6346 Phase 1: Three-Part Safety, Tolerability, PK/PD Study in Adult Healthy Volunteers and Participants With Chronic Hepatitis B Includes Placebo-Controlled Studies in Both NUC-Naïve and NUC-Experienced Participants * One additional subject was enrolled in Group B (total N=9) to replace a subject determined to be ineligible after the study dose had been administered.


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Patient Baseline Characteristics Well Balanced Across Cohorts COHORT C COHORT B 1.5 mg/kg (N=4) 3 mg/kg (N=4) 6 mg/kg (N=4) C (Placebo) (N=6) Total C Cohorts (N=18) 3 mg/kg (N=6) B (Placebo) (N=3) Total B Cohort (N=9) Age at Screening (years) Mean (SD) 37.8 (6.7) 46.5 (5.8) 51.8 (12.5) 45.2 (6.2) 45.3 (8.8) 37.7 (6.7) 40.0 (5.6) 38.4 (6.1) Gender n (%) Female 3 (75.0%) 2 (50.0%) 0 4 (66.7%) 9 (50.0%) 1 (16.7%) 0 1 (11.1%) Male 1 (25.0%) 2 (50.0%) 4 (100%) 2 (33.3%) 9 (50.0%) 5 (83.3%) 3 (100%) 8 (88.9%) Race n (%) Asian 4 (100%) 4 (100%) 4 (100%) 5 (83.3%) 17 (94.4%) 5 (83.3%) 2 (66.7%) 7 (77.8%) Native Hawaiian or Other Pacific Islander 0 0 0 1 (16.7%) 1 ( 5.6%) 1 (16.7%) 0 1 (11.1%) Other 0 0 0 0 0 0 1 (33.3%) 1 (11.1%) Weight (kg) Mean (SD) 59.9 (18.9) 63.2 (11.9) 70.0 (7.1) 66.5 (22.1) 65.1 (15.9) 85.3 (11.8) 72.1 (12.4) 80.9 (13.0) HBsAg Day 1 Predose Value (log10 IU/mL) Mean (SD) 3.48 (0.29) 3.62 (0.59) 3.45 (0.31) 3.71 (0.26) 3.58 (0.35) 4.16 (0.43) 3.82 (0.86) 4.05 (0.57) HBeAg Positive n (%) 2 (50.0%) 2 (50.0%) 2 (50.0%) 2 (33.3%) 8 (44.4%) 4 (66.7%) 1 (33.3%) 5 (55.6%) HBV DNA (log10 IU/mL) Mean (SD) 1.60 (1.04) 1.00 (0.00) 1.03 (0.05) 1.05 (0.12) 1.14 (0.45) 7.20 (2.06)     6.20 (2.69) 6.87 (2.17) ALT (U/L) Mean (SD) 12.75 (4.57)   14.25 (9.78) 22.25 (3.20) 22.83 (12.27) 18.56 (9.41) 78.00 (78.87)   89.00 (106.62) 81.67 (82.22)


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At Day 112 (end of treatment), mean HBsAg log10 IU/mL reduction from baseline in Group C was: 1.39 (SD 0.38) for 1.5 mg/kg cohort 1.80 (SD 0.57) for 3 mg/kg cohort 1.84 (SD 0.79) for 6 mg/kg cohort Mean max. HBsAg log10 IU/mL reduction was 1.88 (SD 0.52) for 3 mg/kg cohort; 1.84 (SD 0.79) for 6 mg/kg cohort 6 mg/kg cohort ongoing Only 2 of 4 participants had reached Day 112 as of data analysis cutoff Longest-treated participant in 1.5 mg/kg cohort had 2.21 log10 IU/mL reduction at Day 392 6 of 10 Group C participants who completed Day 112 had HBsAg <100 IU/mL at last reported visit RG6346 Showed Strong, Durable Reduction in HBsAg Levels at All Doses Lowest Dose Cohort Had Mean HBsAg Reduction Maintained Through Day 336 (Still Ongoing) Results shown as of June 25, 2020 data cutoff; 4 participants dosed with RG6346 in each dosing cohort at each time point unless otherwise noted Days Conditional Follow-Up * * n=3 (1.5 mg/kg) n=2 (1.5 mg/kg) n=2 (6 mg/kg) * * * * * n=3 (3 mg/kg) n=3 (6 mg/kg) Group C Dosing Cohorts


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Interim Results: Maximum HBsAg Change From Baseline for all Group C Participants Who Reached at Least Day 112 Data reflect participants who have completed the treatment period, i.e., Day 112 No Significant Difference in Max. HBsAg Change From Baseline for HBeAg+ vs. HBeAg- Participants 80% of subjects on active treatment had >1.5 log10 IU/mL reduction Greatest max reduction: 2.7 log10 IU/mL Maximum CBL Log10 IU/mL


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RG6346 Led to Reduction in HBV-DNA in NUC-Experienced Patient With Previously Incomplete Response Patient Experienced Drop to Levels Below the Limit of Quantification When RG6346 Added HBeAg+ Patient on NUC Therapy Had Persistent HBV-DNA Until RG6346 Initiated Results shown as of June 25, 2020 data cut Days <BLQ = Below Limit of Quantification for HBV DNA Conditional Follow-Up Patient taking 1.5 mg/kg


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Treatment With RG6346 + NUCs Resulted in Reductions in Key Viral Markers Across All Group C Dose Levels Mean HBcrAg Reductions Mean HBeAg Reductions Days Conditional Follow-Up Conditional Follow-Up Days HBeAg: minimum n=2 for each dose cohort; full data not collected for 1.5 mg/kg cohort HBrcAg: 1.5 mg/kg cohort n=4; 3 mg/kg cohort n=4; 6 mg/kg cohort n=3


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Two Additional Group B NUC-Naïve Patients Had Similar Responses Patient from Group B, 3 mg/kg cohort NUC-Naïve Patient With Transient ALT Elevation and Overall Preserved Liver Function Suggests Flare With Enhanced Host Immune Response Synthetic and Excretory Liver Function Preserved ALT Elevation Associated With Reductions in HBsAg, Other Viral Markers Days Days


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NUC-Naïve Patient With Transient ALT Elevation and Overall Preserved Liver Function Suggests Flare With Enhanced Host Immune Response Relationship of ALT Flare and Reduction in HBsAg and HBV-DNA Days ALT Elevation Coincides With Decline in HBV-DNA and HBsAg Reduction


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NUC-Experienced Patient Had Mild Serum ALT Elevation Associated With 2.5 Log10 IU/mL HBsAg Reduction Patient’s ALT Elevation Also Associated With Preserved Liver Synthetic and Excretory Function Days Synthetic and Excretory Liver Function Preserved All HBV-DNA and HBV-RNA values, at all time points, for this participant were BLQ Days BLQ Virologic Markers


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In the Phase 1 Patients, RG6346 Appeared To Be Safe and Generally Well Tolerated as of the Interim Analysis No serious adverse events (SAEs) associated with RG6346 observed as of June 25, 2020 in Groups B or C One participant in Group A (healthy volunteer on placebo) experienced one SAE not related to study drug No dose-limiting toxicities No safety-related discontinuations No dose/exposure dependent increase in frequency or severity of safety parameters: AEs, safety labs, ECG or vital signs In all participants with flares, or flare-like ALT/AST elevations, overall liver synthetic and excretory functions were preserved No cases of simultaneous elevations of ALT >3x ULN and total bilirubin >2x ULN The most commonly reported AEs were related to the injection site All injection site reactions (ISRs) were mild with exception of a single patient who had two moderate ISRs No Dose Effect on Liver Function Tests Observed in Healthy Volunteers at Dosages ≤12 mg/kg


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Preliminary Data Demonstrates RG6346 Was Generally Well Tolerated With Four Monthly Doses COHORT C COHORT B 1.5 mg/kg (N=4) 3 mg/kg (N=4) 6 mg/kg (N=4) C (Placebo) (N=6) Total C Cohorts (N=18) 3 mg/kg (N=6) B (Placebo) (N=3) Total B Cohort (N=9) Number of participants with at least 1 possibly-related AE 2 3 1 2 8 4 1 5 Number of participants with at least 2 AEs [1] Injection site erythema, Injection site vesicles, Injection site bruising, Injection site rash, Injection site pain [2] 2 Mild 3 Mild 1 Moderate 1 Mild 1 Mild 7 1 Mild 0 1 Fatigue 0 1 Mild 0 0 1 1 Mild 0 1 Headache 0 1 Mild 0 1 Moderate 2 0 0 0 ALT increased, AST increased, GGT increased[3] 0 0 0 0 0 2 Mild 2 Moderate 1 Severe 0 3 [1] MedDRA Preferred Term (PT) aggregated based on similarity. Possibly, Probably, or Definitely Drug-Related AEs in ≥ 2 participants [2] Inclusive of all ISRs regardless of onset time < 4 hours or ≥ 4 hours ( ≥ 4 hours case is defined as ISR by protocol) [3] May be associated with treatment-induced enhanced immune responses


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RG6346 Phase 1 Trial Interim Analysis Summary Participants treated with RG6346 and concomitant NUC therapy had meaningful and sustained reductions in HBsAg for all dose levels at end of treatment period 80% of subjects on active treatment had >1.5 log10 IU/mL reduction In the 3 mg/kg and 6 mg/kg cohorts the mean HBsAg reduction was ≥1.8 log10 IU/mL at Day 112 Mean maximal HBsAg log10 IU/mL reduction from baseline in Group C was*: 1.88 (SD 0.52) for 3 mg/kg cohort 1.84 (SD 0.79) for 6 mg/kg cohort Greatest max reduction: 2.7 log10 IU/mL First dosed patient in ongoing study has reached Day 392 with 2.21 log10 IU/ml reduction in HBsAg Several participants treated with RG6346 exhibited self-resolving ALT elevations with overall preserved liver function suggesting ALT flares potentially as a result of treatment-induced enhanced immune responses No differences in HBsAg reductions were noted between HBeAg+ and HBeAg- participants In the Phase 1 patients, RG6346 appeared to be safe and generally well tolerated as of the interim analysis Study ongoing; two of four participants treated with RG6346 6 mg/kg have not reached Day 112 *Mean max not included for Group C 1.5 mg/kg cohort due to patient replacement


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RG6346 Phase 1: Encouraging HBsAg Reduction and Duration of Response Phase 1 proof-of-concept study confirms X-sparing hypothesis and potential for best-in-class activity Innovative and thoughtfully designed development strategy provided additional insight to RG6346 effect HBsAg reduction and long duration of action indicate potential for best-in-class profile as part of potential HBV therapeutic cure regimen Trial ongoing; additional participants in Group C expected to complete treatment period in September May see additional dose response from two ongoing participants in 6 mg/kg dosing cohort ALT elevations consistent with enhanced immune responses (“flares”) observed in Group B and Group C participants Plan to present Phase 1 data at future scientific conference Under the agreement, Roche will be responsible for initiating Phase 2 development of RG6346


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Our Investigators & Site Teams Dr. Edward Gane Dr. Jung-Hwan Yoon Dr. Man-Fung Yuen Dr. Pisit Tangkijvanich Dr. Alexander Thompson Dr. Tien Huey Lim Dr. Wattana Sukeepaisarnjaroen Dr. Won Kim Dr. William Sievert Our Partners Innocent Clement Hardean Achneck Mark Pirner Wendy Cyr Jeremy Cronin Andrew Henderson Shuli Yu Mark Bercy Susan Griffin Jing Yu Dhruv Patel Bob Brown Jennifer Lockridge Jing Zhou Lara Curtin Thank You especially to our participants and all the people who care for them The Dicerna Team, particularly…


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HBV Q&A All Presenters


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Primary Hyperoxaluria: Unmet Need and Treatment Paradigm Bernd Hoppe, M.D. Vice President, Global Medical Affairs, Head of the German Hyperoxaluria Center and Professor of Pediatrics at University of Cologne


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PH: A Family of Rare Disorders Causing Hepatic Oxalate Overproduction Resulting in Life-Threatening Kidney Damage In all PH subtypes, LDH is Believed to Catalyze the Conversion of Glyoxylate to Oxalate Renal damage is caused by Calcium Oxalate crystals that primarily lead to nephrolithiasis and/or nephrocalcinosis, but also induces chronic inflammation, which results in progressive kidney damage, Chronic Kidney Disease, and later systemic oxalate deposition PH Liver enzyme deficiencies cause glyoxylate dysregulation. In PH LDH transforms some of the excess glyoxylate into oxalate. Oxalate accumulates in the kidneys in the form of CaOx crystals Glyoxylate Oxalate Hepatic LDH Abbreviations: CKD, chronic kidney disease; LDH, lactate dehydrogenase; CaOx, calcium oxalate PH1 PH2 Caused by the deficiency of the GRHPR enzyme Caused by the deficiency of the HOGA enzyme PH3 Caused by the deficiency of the AGT enzyme


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PH Is More Common Than Previously Thought, Affecting an Estimated 8,500 People in the U.S. Expected U.S. prevalence from genetic studies1,2: 1:58,000 or ~8,500 people >80% of patients currently undiagnosed1 Expected Prevalence* PH1 ~2,700 PH2 ~1,700 PH3 ~4,100 Expected Ratio* Approximately 11% of patients with a clinical phenotype consistent with PH have no known PH mutation detected *Prevalence based on PH mutant alleles found in the National Heart, Lung, and Blood Institute Exome Sequencing Project (NHLBI ESP) and calculated according to Hardy-Weinberg equilibrium for each PH type using the sum of all alternate PH1, PH2, or PH3 alleles (known, or known and scored as pathogenic) and all wild type alleles. 1. Hopp K, et al. J Am Soc Nephrol. 2015;26(10):2559-2570. 2. U.S. Census Bureau population on a date: February 20, 2020. United States Census Bureau website, 2020.


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Abbreviation: CaOx, calcium oxalate. 1. Milliner DS, et al. Kidney Int. 2001;59(1):31-36. 2. Soliman NA, et al. Nephrol Ther. 2017;13(3):176-182. 3. Takayama T, et al. Clin Genet. 2014;86(4):342-348. 4. Johnson SA, et al. Pediatr Nephrol. 2002;17(8):597-601. 5. Garrelfs SF, et al. Kidney Int. 2019;96(6):1389-1399. 6. Fang X, et al. Pediatr Nephrol. 2019;34(10):1785-1790. 7. Williams EL, et al. Nephrol Dial Transplant. 2012;27(8):3191-3195. 8. Allard L, et al. Pediatr Nephrol. 2015;30(10):1807-1813. 9. Monico CG, et al. Clin J Am Soc Nephrol. 2011;6(9):2289-2295. 10. Hoppe B. Nat Rev Nephrol. 2012;8(8):467-475. 11. Jacob DE, et al. PLoS One. 2013;8(8):e70617. 12. Daudon M, et al. N Engl J Med. 2008;359(1):100-102. 13. Carrasco A Jr, et al. Urology. 2015;85(3):522-526. Kidney Stones Are a Hallmark of All PH Subtypes Appearance before treatment 11-13  Light whitish or pale yellow surface color Loose aggregations of different-sized crystals Median size: 1.6 cm (range, 0.5-4.5 cm) PH 1 73%-100% of patients have stones1,2 PH 2 83%-100% of patients have stones,3-5 many before age 4 years PH 3 Nearly 100% of patients have stones,6-9 most before age 4 years CaOx Stones10 Stone Burden


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A Single Kidney Stone in Children and Recurrent Stones in Adults Can Be Signs of PH Warning signs can include one or a combination of the following symptoms1-11: Family history of kidney or bladder stones CKD with no known etiology Recurrent UTIs, flank pain, hematuria Severe infantile form: Failure to thrive, ESRD, severe retinal abnormalities Nephro-calcinosis ESRD Systemic oxalosis Plasma Oxalate13 Kidney Function12 GFR (mL/min/1.73 m2) ≥90 60-89 30-59 15-29 <15 CKD Stage 1 Mild renal impairment CKD Stage 2 Kidney damage, mild loss of kidney function CKD Stage 3 CKD Stage 4 CKD Stage 5 End-stage renal disease (ESRD) Moderate to severe loss of kidney function Recurrent stones in adults A single kidney stone in children Abbreviations: CKD, chronic kidney disease; ESRD, end-stage renal disease; UTIs, urinary tract infections. 1. Edvardsson VO, et al. Pediatr Nephrol. 2013;28(10):1923-1942. 2. Bhasin B, et al. World J Nephrol. 2015;4(2):235-244. 3. van Woerden CS, et al. Nephrol Dial Transplant. 2003;18(2):273-279. 4. Soliman NA, et al. Nephrol Ther. 2017;13(3):176-182. 5. Frishberg Y, et al. Am J Nephrol. 2005;25(3):269-275. 6. Johnson SA, et al. Pediatr Nephrol. 2002;17(8):597-601. 7. Garrelfs SF, et al. Kidney Int. 2019;96(6): 1389-1399. 8. Belostotsky R, et al. Am J Hum Genet. 2010;87(3):392-399. 9. Harambat J, et al. Kidney Int. 2010;77(5):443-449. 10. Birtel J, et al. Am J Ophthalmol. 2019;206:184-191. 11. Mandrile G, et al. Kidney Int. 2014;86(6):1197-1204. 12. Estimated glomerular filtration rate (eGFR). National Kidney Foundation website, 2018. 13. Milliner DS. Am J Nephrol. 2005;25(2):154-160.


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Abbreviations: CKD, chronic kidney disease; ESRD, end-stage renal disease. *Limited data, N=4 patients. 1. Hopp K, et al. J Am Soc Nephrol. 2015;26(10):2559-2570. 2. Mandrile G, et al. Kidney Int. 2014;86(6):1197-1204. 3. Garrelfs SF. Kidney Int. 2019;96(6):1389-1399. 4. Allard L, et al. Pediatr Nephrol. 2015;30(10):1807-1813. 5. Beck BB, et al. Eur J Hum Genet. 2013;21(2):162-172. 6. Jacob DE, et al. PLoS One. 2013;8(8):e70617. 7. Harambat J, et al. Kidney Int. 2010;77(5):443-449. 8. Martin-Higueras C, Hoppe B. Chronic kidney disease in patients with primary hyperoxaluria type 3 (PH3) - a meta-analysis from literature. Accepted for oral presentation at: GPN 51st Annual Meeting; 2020. 9. Hoppe B, Langman C. Pediatr Nephrol. 2003;18(10):986-991. PH Often Has Early Onset, But Patients Can Vary in Symptom Timing and Kidney Function Diagnosis often only follows years after symptoms begin9 Symptom Onset1-5 Median (age) Age at Diagnosis2,3,6 Median (range) Kidney Function1-4,7,8 PH Type 1 3.9 - 5.2 years (0-66 years) 8.1 years (0-72 years) 10% have ESRD by age 1 year 19% have ESRD by age 10 years 24%-41% have ESRD by age 20 years 57% have ESRD by age 40 years PH Type 2 3.2 years (1.0-11 years) 9 years (2-32 years) >50% have CKD stage 2+ 25% have ESRD by age 40 years PH Type 3 0.75 - 2.6 years (0.1-31 years) 1.5 years* (0.7-13 years) 1 report of ESRD 14%-30% with CKD


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Abbreviations: CaOx, calcium oxalate; ESRD, end-stage renal disease. *Case courtesy of Dr Ian Bickle, Radiopaedia.org, rID: 45927. 1. Lai C, et al. Mol Ther. 2018;26(8):1983-1995. 2. Harambat J, et al. Int J Nephrol. 2011;2011:864580. 3. Cochat P, Rumsby G. N Engl J Med. 2013;369(7):649-658. 4. Salido E, et al. Biochim Biophys Acta. 2012;1822(9):1453-1464. 5. Sas DJ, et al. Urolithiasis. 2019;47(1):79-89. 6. Hoppe B, et al. Kidney Int. 2009;75(12):1264-1271. Renal Damage Caused by Oxalate May Not Be Reversible and Progresses to Systemic Oxalosis Progressive CaOx crystal deposition, recurrent stones, but especially inflammation, and interstitial fibrosis lead to ESRD1,2,* CaOx crystals are deposited in tissue throughout the body, especially the skeleton3 As glomerular filtration rate declines, oxalate is inadequately filtered by the kidneys, resulting in increased plasma oxalate values and then systemic oxalosis2 Crystal deposits at finger tip6 CaOx deposits in the heart6 1 2 CaOx deposits in the bone6 Retinal CaOx deposits6 Cardiomyopathy, conduction disturbances4,5 Skin ulcers, nodules4,5 Bone fractures, bone deformation, inhibited bone growth, anemia, severe pain4,5 Retinopathy4,5


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Multiple Studies Show That Earlier Diagnosis Is Needed to Improve Patient Outcomes and Preserve Renal Function A separate study found that3 ~5% are diagnosed after kidney transplant 19% of those diagnosed after transplant are not diagnosed until after first transplant failure of patients with PH experience a significant delay in diagnosis1 Patients experience 3.4 ± 5.4 years between first symptom presentation and diagnosis Abbreviations: ESRD, end-stage renal disease. 1. Hoppe B, Langman C. Pediatr Nephrol. 2003;18(10):986-991. 2. Zhao F, et al. Clin J Am Soc Nephrol. 2016;11(1):119-126. 3. Bergstralh EJ, et al. Am J Transplant. 2010;10(11):2493-2501. One study reported that2 27% of patients are diagnosed at ESRD, with delay of 3.5 years after symptom onset 42%


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Current Treatments for PH Do Not Stop Disease Progression and Can Contribute to Patient Burden Kidney Stone Management1-4 Percutaneous nephrolithotomy (PCNL) or ureteroscopy Renal Replacement Therapy1 Intermittent hemodialysis (HD), additional peritoneal dialysis (PD) in some patients Organ Transplant Simultaneous liver/kidney transplant for PH 1 Isolated kidney transplantation for PH 2 patients Oxalate Reduction Aggressive hydration1 2-3 liters water/per 1m2 BSA/day Gastrostomy tube for infants or adults struggling with water intake Pyridoxine (vitamin B6) For a subset of patients with PH1 only1 Multiple tablets per day Crystallization inhibition1 Alkaline citrate or orthophosphate 3-4 times daily application Dietary changes1 B6 Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate. 1. Sas DJ, et al. Urolithiasis. 2019;47(1):79-89. 2. Danese D, et al. Poster presented at: IPNA 18th Congress, 2019. 3. Harambat J, et al. Kidney Int. 2010;77(5):443-449. 4. Bergstralh EJ, et al. Am J Transplant. 2010;10(11):2493-2501. 5. Neuberger JM, et al. Transplantation. 2017;101(4S)(suppl 2):S1‐S56. Avoidance of oxalate-rich foods recommended


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Nedosiran for the Treatment of Primary Hyperoxaluria Ralf Rosskamp, M.D. Chief Medical Officer


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Nedosiran Is Designed to Inhibit the Final Common Step in Oxalate Production GO = glycolate oxidase LDHA = lactate dehydrogenase A Kidney function preservation Kidney stones Impacted by ESRD and systemic oxalosis Targeting GO blocks glyoxylate in PH1 only Known Types of Primary Hyperoxaluria PH1 Genetic mutation AGXT PH2 Genetic mutation GRHPR PH3 Genetic mutation HOGA1 GO Glyoxylate Glyoxylate Glyoxylate Nedosiran blocks final common pathway of oxalate production by silencing LDHA Oxalate Oxalate Oxalate Calcium oxalate crystallization GO


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Human Genetic Deficiency Supports Safety of Liver LDHA Inhibition LDHA is involved in the inter-conversion of lactate to pyruvate Human data in PHYOX1 in HVs up to 12mg/kg of nedosiran show no changes in plasma lactate and pyruvate concentrations over placebo Preclinical studies of nedosiran in mice do not show changes in plasma lactate and pyruvate concentrations over placebo, in both resting and exercised mice1 14 Case Reports of Humans Naturally Deficient for LDHA, With No Liver Dysfunction Reported 1Lai C et al. Specific Inhibition of Hepatic Lactate Dehydrogenase Reduces Oxalate Production in Mouse Models of Primary Hyperoxaluria. Mol Ther  2018 Aug 1;26(8):1983-1995 * Of the 14 case reports, six were women Muscle Skin 14 Case Reports of Humans Naturally Deficient for LDHA, With No Liver-Related Abnormalities Reported *


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Final Results From PHYOX1 Single-Dose Phase 1 Study of Nedosiran in Participants With PH1 or PH2 PHYOX1: Mean Urinary Oxalate Levels by Dose* PH Type Dose (mg/kg) Pts. Reaching Normalization or Near-Normalization (%) Max Reduction Uox (%) Mean (range) PH1 1.5 (n=5) 3 (60) 51 (28-72) 3.0 (n=6) 5 (83) 73 (62-80) 6.0 (n=4) 4 (100) 78 (35-100) PH2 1.5 (n=1) 0 (0) 39 3.0 (n=2) 2 (100) 54 (42-66) *Days with at least two values in both dosing groups ClinicalTrials.gov: NCT03392896 Abbreviation: BSA=body surface area 24 hr Urinary Oxalate Corrected for BSA (mmol/1.73m2 BSA/24hr) Mean±SEM Days After Single Dose ≥0.46 and <0.6 Near normal <0.46 Normal 2.0 2.5 1.0 1.5 0.0 0.5 29 0 8 71 113 15 43 57 85 99 141 169 197 239 253 281 3.0 mg/kg 6.0 mg/kg


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1Cowan R et al. Physician and patient preferences for dosing options in migraine prevention. J Headache Pain 20, 50 (2019). Monthly Dosing is a Simple Choice for Participants and May Safeguard Against Sudden Oxalate Spikes Consistency - Based on modeling and simulation of PK and PD data from the PHYOX1 Study Modeling shows that highest percentage of participants reach normal Uox levels with monthly dosing Monthly dosing was superior compared to a loading-dose regimen with nedosiran after 6 months of treatment Simple and Convenient - Monthly dosing will be at home with pre-filled syringes for adults and adolescents Monthly dosing is easy to remember and may lead to better adherence Facilitates establishment of treatment routine and provides consistent protection Patient and physician preference study in migraine show no difference between monthly and quarterly regimen1 Monthly Dosing Supports Comprehensive Coverage, Convenience and Safety Advantage Urine Without Hyperhydration Safety Advantage - A missed dose in a monthly regimen is unlikely to lead to sudden spike in Uox When reaching normal Uox concentrations, participants may be weaned off their supportive therapy including hyperhydration and potassium citrate PH participants are vulnerable to sudden increases in Uox, which may lead to renal failure within days Abbreviations: PK, pharmacokinetics; PD, pharmacodynamics


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PHYOX3 Clinical Trial Design 3-Year Open-Label Extension Study for Participants With PH1, PH2 or PH3 From Another PHYOX Study Key evaluation objectives: Effect on estimated glomerular filtration rate (eGFR) Effect on new stone formation and nephrocalcinosis Effect on Uox levels Safety and tolerability when administered monthly Nedosiran once-monthly dosing regimen: Fixed-dose regimen in participants 12 years and older Participants weighing ≥50 kg, receive dose of 170 mg (1 mL) Participants weighing <50 kg, receive dose of 136 mg (0.8 mL) Initially, weight-based dose in participants 11 years and younger For single-dose studies, after Uox rebound enrollment For PHYOX2, immediate rollover = At-home dosing = Office visit for dosing and safety assessment year 1 year 2 year 3 Siblings of enrolled participants are also eligible to enroll pending genetic diagnosis of PH.


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Demographics and Baseline Uox Values for PHYOX3 Data Reflect 11 Participants Who Rolled Over From PHYOX1 and Have Reached Day 120 (5 Doses) PHYOX3 BSA corrected baseline values are lower compared to PHYOX1 BSA corrected baseline values Average 0.926 mmol/1.73m2 BSA/24hr for PHYOX3, versus 1.323 mmol/1.73m2 BSA/24hr for PHYOX1 Some PHYOX1 participants had not returned to 80% of baseline PHYOX1 baseline (mean of 2 screening values) used for comparison as this is the only real pre-treatment value For reference, the pivotal PHYOX2 BSA corrected baseline is currently at 1.409 mmol/1.73m2 BSA/24hr 301 participants (101 rollover) (N=11) Age (years) Mean (SD) 27.0 (8.57) Median 26 Min, Max 16, 46 6 - 11 years 0 12 - 17 years 1 (9.1%) >18 years 10 (90.9) Gender Male 7 (63.6%) Female 4 (36.4%) Race Asian 1 (9.1%) White 5 (45.5%) Not recorded 5 (45.5%) Ethnicity Not Hispanic or Latino 10 (90.9%) Not recorded 1 (9.1%) Baseline eGFR (mL/min/BSA) (n=9) Mean (SD) 75.3 (22.86) Median 82 Min, Max 36, 102 ≥ 30 and < 45 mL/min/BSA 2 (22.2%) ≥ 45 mL/min/BSA 7 (77.8%) Baseline 24Hr Urinary Oxalate (mmol/24Hr/BSA) Mean (SD) 0.926 (0.272) Median 0.922 Min, Max 0.557, 1.448 PH Type Type 1 8 (72.7%) Type 2 3 (27.3%) Time since PH Diagnosis (months) Mean (SD) 222.29 (109.656) Median 197.27 Min, Max 50.2, 475.9 Based on availability of data as of July 10, 2020 Abbreviation: BSA=body surface area


Slide 54

PHYOX3 BSA Corrected Mean 24-Hour Uox Absolute Values for Participants With 5 Doses of 170 mg of Nedosiran Day 120 BSA corrected mean value for all participants (n=11): 0.524 mmol/1.73m2 BSA/24hr 24 hr Urinary Oxalate Corrected for BSA (mmol/1.73m2 BSA/24hr) Mean±SEM 2.0 2.5 1.0 1.5 0.0 0.5 BL (101) BL (301) 30 60 90 120 Days ≥0.460 and <0.600 Near normal <0.460 Normal For both PHYOX1 and PHYOX3 the first dose was administrated Day 1 after baseline (BL= Day 0)


Slide 55

PHYOX3 Mean Percent Reduction of Uox Values for Participants With 5 Doses of 170 mg of Nedosiran Mean Reduction From PHYOX1 Pre-Treatment Baseline Day 120 mean reduction value for all participants (n=11): 54.3% Mean % reduction in urinary oxalate from baseline (±SEM) 0 20 -40 -20 -100 -60 0 30 60 90 120 -80 Days For PHYOX3 the first dose was administrated Day 1 after baseline (BL= Day 0)


Slide 56

Normalization and Near-Normalization of Uox Levels As of interim analysis, five participants have reached normal Uox concentrations at 3 consecutive visits and are eligible for weaning off disease management, including hyperhydration For PH1 participants, the average Uox level achieved is in the normal range (mean Uox= 0.404 mmol/1.73m2 BSA/24 hr, 66% reduction) Normalization: Uox at or below 0.460 mmol/1.73m2 BSA/24 hr Near Normalization: Uox between 0.460 and 0.600 mmol/1.73m2 BSA/24 hr (~130% of normal) PH Type Pts. Reaching Normalization at Day 120 (%) Pts. Reaching Normalization or Near-Normalization at Day 120 (%) PH1 (n=8) 5 (63) 8 (100) PH2 (n=3) 1 (33) 1 (33) PH1+PH2 (n=11) 6 (55) 9 (82)


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Similarities and Differences Between PHYOX3 Open-Label Extension Study and PHYOX2 Pivotal Registration Study Patient Population PH1 and PH2 participants Ages 6 and above PH1, PH2 and PH3 participants PHYOX1 rollover participants are 12 and above, younger ages may enroll from other trials; siblings of participants may also enroll Evaluation Period 180-days 3-years Primary Endpoint Uox AUC from Day 90-180 eGFR Uox Completeness Criteria Strict rules Initially guidelines, now consistent with PHYOX2 Uox Measurements Monthly Monthly measurements for PHYOX1 rollover participants; others quarterly Study Design Double-blind, placebo controlled Randomized 2:1 drug:placebo Open-label


Slide 58

PHYOX3 Interim Safety Data Favorable risk/benefit profile in this study AEs mostly related to SC injection Drug-related ISRs in 3/16 participants ALT elevations <2.5 ULN; both participants started study with elevated ALT One SAE of nephrolithiasis No other clinically significant laboratory abnormalities, ECG findings and vital signs Treatment-emergent adverse event (TEAE) is defined as any adverse event that begins on or after the first dose of study intervention. Safety population n= 16; [1] The severity shown is the greatest severity reported for a particular subject (Severe > Moderate > Mild) Abbreviations: SC, subcutaneous; BL, baseline, ALT, alanine transaminase; ULN, upper level of normal, ECG, electrocardiograph Based on availability of data as of July 10, 2020 Category 301 Study n (%) Total TEAEs 16 (94.1) TEAEs occurring in >=10% of participants in group (n, %)   Injection site discomfort 6 (35.3) Injection site pain 6 (35.3) Injection site erythema 4 (23.5) Flank pain 3 (17.6) Injection site discoloration 3 (17.6) Aspartate aminotransferase increased 2 (11.8) Headache 2 (11.8) Injection site atrophy 2 (11.8) Injection site hematoma 2 (11.8) Pyrexia 2 (11.8) ISRs (n, %) 3 (17.6) TEAEs leading to discontinuation of study treatment (n, %) 0 TEAEs leading to study withdrawal (n, %) 0 Death (n, %) 0 Serious TEAEs (n, %) 1 (5.9) Severity of TEAEs (n, %) [1]   Mild 12 (70.6) Moderate 3 (17.6) Severe 1 (5.9)


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Nedosiran Clinical Trial Program to NDA Filing Coordinated Program of Clinical Trials to Support a Broad Label in PH Trial Description/Details Status PH Type Study 201: Pivotal, double-blind, randomized, placebo-controlled trial (2:1 randomization) Monthly fixed-dose, enabling prefilled syringes at launch Enrolling n=~36 1,2 Study 301: Long-term, multidose, open-label extension study open to all participants in PHYOX trials and siblings Enrolling 1,2,3 Study 104: Double-blind, randomized, placebo-controlled study in participants with primary hyperoxaluria type 3 (PH3) Enrollment Q3 2020 3 Study 204: Multidose trial in participants (birth to adult) with PH and end-stage renal disease (ESRD) Enrollment Q4 2020 1,2 Study 203: Open-label study in children 0-5 yrs Enrollment Q1 2021 1,2 Study 502: Natural history study to evaluate association between Uox and stone formation rate Initiation Q3 2020 3 Pivotal Study Package Additional Supportive Studies


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Nedosiran Summary PHYOX3 Day 120 results in line with expectations from single-dose PHYOX1 study Already a high percentage of participants with normalization/near-normalization at Day 120 High Uox percent reduction despite low baseline Average Uox for PH1 participants at Day 120 was in the normal range (Uox = 0.404 mmol/1.73m2 BSA/24 hr) Five participants have reached normal Uox concentrations at 3 consecutive visits and are eligible for gradual fluid reduction Monthly nedosiran administration appears safe and generally well tolerated Low rate of injection-site reactions No evidence of changes to blood lactate or pyruvate levels Expect comprehensive label including all ages in participants with relatively intact renal function (GFR ≥ 30mL/min/BSA) at time of launch Nedosiran fixed dose monthly dosing regimen for participants 12 years and above is simple and will avoid oxalate spikes We expect monthly weight-based dosing regimen for children <12 years of age Agreement with FDA on path to full approval for PH1 and PH2 Safety data from participants with severe renal impairment (GFR <30 mL/min/BSA) will be included with the NDA Currently 6 compassionate-use cases in young participants undergoing hemodialysis


Slide 61

Our Investigators & Site Teams Screening and Enrolling Participants


Slide 62

Nedosiran Business Planning Rob Ciappenelli Chief Commercial Officer


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Nedosiran: The Only RNAi Drug Candidate in Development for All PH Types Limited Disease Awareness, Education and Resources to Efficiently Diagnose PH Nedosiran’s target profile provides a comprehensive treatment option for all PH patients with convenient once monthly dosing, including self administration Nedosiran Availability Education Estimated PH Diagnosis Rates PH1 PH2 PH3 Current Diagnosis Projections^ ~40% – 50% ~10% ~7% Diagnostic Testing Patient & Caregiver Support Dicerna estimates nedosiran global sales > $500M Expected Prevalence* *Prevalence based on PH mutant alleles found in the National Heart, Lung, and Blood Institute Exome Sequencing Project (NHLBI ESP) and calculated according to Hardy-Weinberg equilibrium for each PH type using the sum of all alternate PH1, PH2, or PH3 alleles (known, or known and scored as pathogenic) and all wild type alleles. 1. Hopp K, et al. J Am Soc Nephrol. 2015;26(10):2559-2570. 2. U.S. Census Bureau population on a date: February 20, 2020. United States Census Bureau website, 2020. ^Sources: Dicerna internal estimates PH claims/registry analysis and scientific advisors. Analyst Projections.


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Multiple Important Clinical, Regulatory and Infrastructure Milestones Projected Over Next Two Years 2020 2021 2022 Launch Readiness Preparations Stand Up Commercial Build Enterprise Infrastructure PHYOX Clinical Trial Results Expected Establish Medical Group Target Regulatory Filings Potential Approvals


Slide 65

Establishing Product Strategy and Business Infrastructure to Drive Nedosiran Global Commercialization U.S. Launch Readiness Outside the U.S. Launch Preparations Teams / Infrastructure: Commercial: Patient Advocacy, Patient Services, Marketing, Market Access, Insights/Analytics and Commercial Operations Enterprise: Medical Affairs, Regulatory, Compliance, Legal, Technical Operations, IT and Finance Partnering: Active partner discussions with regional and multi-national pharma/biotech commercial groups Planning: Strategic Product Plan (e.g. positioning, branding…etc.) Product Launch Infrastructure Market Engagement: Market Assessments EMA and PMDA discussions Patient: Patient advocacy grant - “FDA Voice of the Patient” event led by the Oxalosis and Hyperoxaluria Foundation October 5, 2020 European Primary Hyperoxaluria Patient Advocacy Sept 19, 2020 Annual Patient Meeting Building foundation to support patients through Dicerna’s growing portfolio Operations Overview


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Nedosiran: Setting the Stage for Commercial Success Nedosiran has potential to address all patients with PH, regardless of type Mechanism: Nedosiran silences LDHA, the ultimate step in the oxalate production pathway Development Plan: Comprehensive PHYOX development program to evaluate all types of PH Dosing Format: Simple, once-monthly, self-administered subcutaneous injections in patients ≥12 years Data from PHYOX3 present competitive product profile Achievement of 100% normal or near-normal response in participants with PH1 Five of the 17 participants enrolled in the trial achieved normal Uox at three consecutive visits, making them eligible for gradual reduction in fluid intake Commercial preparations underway, with key infrastructure in place and fit-to-purpose as key development and regulatory milestones are achieved Target NDA submission: Q3 2021


Slide 67

Extrahepatic Platform Bob D. Brown, Ph.D. Chief Scientific Officer, Executive Vice President Research & Development


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Platform Expansion to Achieve Effective Extrahepatic Delivery Including Central and Peripheral Nervous Tissues and Other Extrahepatic Tissues Novel nucleic acid constructs with variable secondary structures and chemical compositions ± Non-GalNAc ligands (e.g. small molecules, peptides, Fabs, etc.) 1st Generation GalXC 5′ 3′ GalNAc Sugars to bind hepatocyte ASGPR GalXC New NA Platforms Abbreviations: NA, nucleic acid; SAR, structure-activity relationship Our RNAi platform provides remarkable flexibility for medicinal chemistry optimization and expansion We are modifying the fundamental nucleic acid composition of oligonucleotides to enhance drug-like properties Optimization of nucleic acid composition alone can drive significant extrahepatic delivery function We are utilizing a broad range of molecular weights, secondary structures and chemistries Targeting moieties are not required for effective extrahepatic delivery Targeting moieties can enhance delivery efficiency after medchem optimization, if needed We are testing potent hits against multiple neurological and systemic extrahepatic targets These platform advancements can deliver nucleic acid therapeutics with non-RNAi mechanisms of action Enables potential expansion into new target/indication opportunities


Slide 69

Accessing Multiple Cell Types: Delivery to Neurons, Astrocytes and Oligodendrocytes in the Central Nervous System Many neurological disorders are not cell type specific, highlighting the need for a platform that enables delivery and potency in a variety of cell types Modified siRNA payloads have been designed against cell type-specific mRNAs to enable specific cell-type challenges to be identified and overcome: Astrocytes Oligodendrocytes Neurons Our modified platforms are capable of dose-dependent and durable target mRNA suppression after intrathecal injection CNS platforms can be tuned to enhance activity and durability in distinct cell types to treat a variety of neurological diseases Broad mRNA Suppression in the Central Nervous System After Intrathecal Delivery Cell-Type Specific mRNA Silencing in Rodent CNS (7 days) % Target mRNA Remaining [Target mRNA/Ppib mRNA]±SEM Abbreviation: CNS, central nervous system


Slide 70

Medchem/SAR Activity in Mouse CNS After Intrathecal Administration One 300 µg Dose (≈10 mg/kg equivalent), Target Knockdown at Day 7 vs. Day 28 CNS Target Knockdown at Day 28 CNS Target Knockdown at Day 7 % Target mRNA Remaining [Target mRNA/Ppib mRNA]±SEM % Target mRNA Remaining [Target mRNA/Ppib mRNA]±SEM RNAi Test Articles Sense (passenger) strand modifications alone can increase RNAi potency and duration of action Initial SAR characterizations in the CNS includes potency, duration and tolerability CD68 and other CNS markers of inflammation demonstrate tolerability in both rodents and NHP


Slide 71

Delivery of Novel Constructs via I.T. versus I.C.M. Administration in Rats Yields Consistent CNS-Wide Target mRNA Knockdown Efficient mRNA Target Reduction Independent of Route of Administration Intrathecal Lumbar vs. Intrathecal Cisterna Magna Administration of in Rats % Target mRNA Remaining [Target mRNA/Ppib mRNA]±SEM CNS Tissue Sample Location i.t. i.c.m. Administration Routes


Slide 72

CNS Tissue Distribution After Intracisternal and Intrathecal Administration Bulk Distribution of RNAi Payload Throughout Rat CNS by in situ Hybridization (ISH) Detection aCSF, brain i.c.m., brain i.t., brain aCSF, spinal cord i.c.m., spinal cord i.t. , spinal cord RNAi Test Article Exposure by ISH (Day 7 After a 1 mg Dose) In situ hybridization visualization of bulk test article tissue distribution in the CNS vs the route of administration Exposure by Administration Route (Day 7 After a 1 mg Dose) Effective target knockdown from the forebrain to the lumbar region and in DRG over a two order of magnitude difference in drug exposure Abbreviation: aCSF, artificial cerebrospinal fluid; DRG, dorsal root ganglia


Slide 73

Durable CNS Target mRNA Knockdown After a Single Dose in Rats 1 mg Dose, i.t. Time (Days) Ongoing mRNA Reduction 160 Days After a Single Lumbar Intrathecal Dose % Target mRNA Remaining [Target mRNA/Ppib mRNA]±SEM Sustained control of target mRNA reduction for at least 160 days (ongoing) The duration of target knockdown is not dependent on the magnitude of initial knock down


Slide 74

Widespread Therapeutic Target mRNA Reduction in Nonhuman Primate (NHP) CNS by RNAi in the Absence of Complex Conjugation Broad Distribution and Target mRNA Reduction 28 Days After a Single 45 mg i.c.m. Dose Target mRNA Reduction Throughout Primate CNS at Day 28 % Target mRNA Remaining [Target mRNA/(GAPDH/RPL23)±SEM % Target mRNA Remaining [Target mRNA/(GAPDH/RPL23)±SEM


Slide 75

Cellular Uptake in NHP CNS After Intracisternal Administration High Resolution Images Reveal Delivery and Intracellular Accumulation in Multiple Cell Types In situ hybridization (ISH) visualization of test article at 20x magnification RT-PCR of target mRNAs confirms intracellular delivery and target knockdown Frontal Cortex aCSF i.c.m. RNAi Parietal Cortex Occipital Cortex Cerebellum Brainstem Lumbar SC aCSF i.c.m. RNAi


Slide 76

New Indications Are Enabled by Delivery To Extrahepatic Non-Neural Tissues Using Nucleic Acid Platforms Without GalNAc Optimized chemistries enables delivery to multiple tissues beyond the liver Delivery to multiple tissues expands the range of important cardiovascular and metabolic targets to access Peripheral tissue delivery is independent of Apolipoprotein E, including muscle 10 mg/kg Subcutaneous Dose in Mice, Target Silencing Measured 14 Days Post-Dose Liver WT ApoE-/- Skeletal Muscle WT ApoE-/- Adipose WT ApoE-/- % Target mRNA Remaining (rel to PBS, Mean±SEM)


Slide 77

Flexible Subcutaneous Dosing Regimens Yield Equivalent Extrahepatic Target Knockdown Multiple effective dosing regimens support flexible subcutaneous clinical development strategies Mice, 15 mg/kg Total Exposure, Subcutaneous Administration Skeletal Muscle Adipose % Target mRNA Remaining (rel to PBS, Mean±SEM)


Slide 78

Rodents Are Predictive of Extrahepatic Activity in NHPs SAR and medchem screening in rodents enables rapid, reliable translation into monkeys Mouse Sampled at Two Weeks; NHP Samples at Four Weeks Skeletal Muscle Monkey, Week 4 Mouse, Week 2 Adipose Monkey, Week 4 Mouse, Week 2 % Target mRNA Remaining (rel to PBS, Mean±SEM)


Slide 79

Broadly Distributed Activity Is Observed Within Individual Tissue Types in Nonhuman Primates Target mRNA Measured 4 Weeks After a Single Subcutaneous Dose Soleus Gastrocnemius Bicep Tricep Skeletal Muscles Adipose Tissues Gonadal Subcutaneous Mesenteric Up to 85% target reduction detected in both peripheral tissue types in cynomolgus monkeys Onset of RNAi activity was 1-2 weeks post-dose No adverse effects observed at either dose level % Target mRNA Remaining (rel to PBS, Mean±SEM) Quadricep % Target mRNA Remaining (rel to PBS, Mean±SEM)


Slide 80

Expansion of Dicerna’s Therapeutic Nucleic Acid Platforms and Programs We are developing nucleic acid technologies independent of the hepatic GalNAc/ASGPR system Chemical and structural modifications of our clinical-stage GalXC platform have: Increased the intrinsic drug-like properties of our RNAi and non-RNAi nucleic acid platforms Lowered barriers to intracellular delivery beyond hepatocytes, including systemic and CNS applications Enabled additional mechanisms of action to expand our target/indication spaces beyond RNAi applications We are applying these advances to a range of indications beyond the liver Indications in the CNS, peripheral nervous system and muscle Indications requiring simultaneous liver and adipose tissue targeting, such as cardiometabolic diseases Going Beyond GalXC


Slide 81

Closing Remarks Douglas M. Fambrough, Ph.D., President and Chief Executive Officer


Slide 82

Dicerna: Well Positioned for Near- and Long-Term Success Core pipeline of early and late-stage assets with multiple development milestones over next year+ Nedosiran: A potential best-in-class therapeutic for PH1, PH2 and PH3 RG6346: A Potential best-in-class therapeutic for the treatment of chronic HBV A1AT: Dicerna/Alnylam collaboration to bring forward best A1AT program Collaborations with leading global pharmaceutical and biotech companies expected to yield multiple clinical programs over the coming years and have the potential to provide significant financial upside Unparalleled medicinal chemistry flexibility has enabled us to expand beyond GalNAc mediated delivery to the liver and allows us to create nucleic acid molecules that may address additional tissues and indications Strong balance sheet with cash into 2023 provides runway through projected nedosiran commercialization Diversified Core & Collaborative Pipelines Plus Expanding Technology Platforms to Drive Growth


Slide 83

Q&A Dicerna Management Team

EX-99.4

Exhibit 99.4

 

LOGO

Dicerna Announces Appointment of Shreeram Aradhye, M.D., as

Executive Vice President and Chief Medical Officer

– Dr. Aradhye Brings to Dicerna More Than 20 Years of Successfully Leading Global Teams in Developing Diverse Portfolios of Innovative Medicines–

LEXINGTON, Mass., Aug. 5, 2020 — Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA) (the “Company” or “Dicerna”), a leading developer of investigational ribonucleic acid interference (RNAi) therapeutics, today announced that Shreeram Aradhye, M.D., will become Dicerna’s executive vice president and chief medical officer (CMO) and a member of the Company’s executive leadership team, effective Sept. 8, 2020. Dr. Aradhye’s appointment follows the previously announced retirement of Ralf Rosskamp, M.D., who will continue with the Company in a consulting capacity at least through the end of June 2021.

“We are pleased to welcome Dr. Aradhye to succeed Ralf Rosskamp, M.D. who has made important contributions to advancing our pipeline of clinical programs, including our lead asset, nedosiran,” said Douglas Fambrough, Ph.D., president and chief executive officer of Dicerna. “Dr. Aradhye’s success in leading global teams and developing products across multiple therapeutic areas perfectly match Dicerna’s needs as we continue to advance and grow our RNAi development pipeline and our business. His previous experience as a practicing nephrologist paired with his clinical, regulatory and medical affairs experience across a wide range of therapeutic categories make Shreeram an ideal fit as we continue to broaden the reach of our RNAi technology, first in the liver and then into new tissues. We look forward to Shreeram’s contributions as a proven business leader, clinician and researcher in our continued evolution toward becoming a fully integrated, commercial-stage biopharmaceutical company with a maturing clinical pipeline and new opportunities emerging from our proprietary technology platform.”

“Dicerna is increasingly being recognized for its scientifically rigorous and patient-centric approach to drug development – a combination that, together, has produced a pipeline of therapeutic candidates for rare and more common diseases,” commented Dr. Aradhye. “There is a profound desire among the team at Dicerna to not only ensure new therapies reach patients quickly, but to continually innovate and apply unique scientific expertise and excellence in clinical execution to enable as many patients as possible to benefit from its RNAi technology – all of which create an attractive patient-focused, entrepreneurial culture. With nedosiran now in late-stage clinical development and commercial preparations underway, it’s an exciting time to be joining Dicerna, and I am looking forward to contributing to the success of nedosiran and other current and future clinical programs.”

Dr. Aradhye joins Dicerna from Axcella Health, where he has served as executive vice president and chief development officer and a member of the executive team with direct oversight of clinical development, regulatory affairs, QA and scientific communications.


Prior to Axcella, Dr. Aradhye spent 20 years in various leadership roles in development and medical affairs at Novartis Pharmaceuticals and its global affiliates. Dr. Aradhye served as Novartis’ global head of medical affairs and chief medical officer – pharmaceuticals, and was a member of the global pharmaceuticals executive team. His leadership covered teams working in diverse disease areas including cardiometabolic, respiratory, immunology, neuroscience and ophthalmology, and included direct operational oversight of Novartis’ global medical affairs team. Prior to this role, Dr. Aradhye served as the development head for Novartis’ neuroscience portfolio with innovative programs in multiple sclerosis, Alzheimer’s disease, migraine, neuropathic pain and muscle disease.

Prior to joining the life science industry, Dr. Aradhye was an attending physician, assistant professor of medicine and a transplant nephrologist at the University of Pennsylvania for a large tertiary-care, multi-organ transplant program performing more than 150 renal transplants, 100 liver transplants and 25 kidney-pancreas transplants per year. He also provided expert consultation for cases with a wide variety of renal and electrolyte disorders and was co-investigator for industry-sponsored clinical trials. Dr. Aradhye also served as an attending nephrologist and instructor in medicine at the Overton Brooks VA Medical Center.

Dr. Aradhye received his medical education at the All India Institute of Medical Sciences in New Delhi, India, and trained in Internal Medicine at Newton Wellesley Hospital in Newton, Mass. and in Nephrology at St. Luke’s-Roosevelt Medical Center in New York.

About Dicerna Pharmaceuticals, Inc.

Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA) is a biopharmaceutical company focused on discovering, developing and commercializing medicines that are designed to leverage ribonucleic acid interference (RNAi) to selectively silence genes that cause or contribute to disease. Using our proprietary RNAi technology platform called GalXC, Dicerna is committed to developing RNAi-based therapies with the potential to treat both rare and more prevalent diseases. By silencing disease-causing genes, Dicerna’s GalXC platform has the potential to address conditions that are difficult to treat with other modalities. Initially focused on hepatocytes, Dicerna has continued to innovate and is exploring new applications of its RNAi technology beyond the liver, targeting additional tissues and enabling new therapeutic applications. In addition to our own pipeline of core discovery and clinical candidates, Dicerna has established collaborative relationships with some of the world’s leading pharmaceutical companies, including Novo Nordisk A/S, Roche, Eli Lilly and Company, Alexion Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH and Alnylam Pharmaceuticals, Inc. Between Dicerna and our collaborative partners, we currently have more than 20 active discovery, preclinical or clinical programs focused on rare, cardiometabolic, viral, chronic liver and complement-mediated diseases, as well as neurodegeneration and pain. At Dicerna, our mission is to interfere – to silence genes, to fight disease, to restore heath. For more information, please visit www.dicerna.com.

Cautionary Note on Forward-Looking Statements

This press release includes forward-looking statements relating to the Company’s business, its plans and strategies, its product candidates, their clinical development and therapeutic potential, as well as the Company’s technology platform. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Applicable risks and uncertainties include those relating to our preclinical research and clinical programs and other risks identified under the heading “Risk Factors” included in our most recent Form 10-Q filing and in other future filings with the Securities and Exchange Commission. The forward-looking


statements contained in this press release reflect Dicerna’s current views with respect to future events, and Dicerna does not undertake and specifically disclaims any obligation to update any forward-looking statements.

GalXC is a trademark of Dicerna Pharmaceuticals, Inc.

Media:

Amy Trevvett

+1 617-612-6253

atrevvett@dicerna.com

Investors:

Lauren Stival

+1 617-514-0461

lstival@dicerna.com