SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
PURSUANT TO SECTION 13 OR 15(d)
OF THE SECURITIES EXCHANGE ACT OF 1934
Date of Report (Date of earliest event reported): August 5, 2021
DICERNA PHARMACEUTICALS, INC.
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75 Hayden Avenue
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Item 7.01 Regulation FD Disclosure
On August 5, 2021, Dicerna Pharmaceuticals, Inc., a Delaware corporation (the “Company”), issued a press release titled “Dicerna Reports Positive Top-Line Results From PHYOX™2 Pivotal Clinical Trial of Nedosiran for the Treatment of Primary Hyperoxaluria.” A copy of the press release is furnished herewith as Exhibit 99.1.
Following issuance of the press release, the Company hosted a conference call and webcast to discuss the PHYOX2 top-line results. A copy of the presentation used on the conference call and webcast is furnished herewith as Exhibit 99.2.
The information in Item 7.01 of this Form 8-K (including Exhibits 99.1 and 99.2 attached hereto) are 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 9.01 Financial Statements and Exhibits
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 6, 2021||DICERNA PHARMACEUTICALS, INC.|
/s/ Douglas M. Fambrough, III
Douglas M. Fambrough, III, Ph.D.
Chief Executive Officer
Dicerna Reports Positive Top-Line Results From PHYOX™2 Pivotal Clinical Trial of Nedosiran for the Treatment of Primary Hyperoxaluria
– Nedosiran Achieved Primary Endpoint, Demonstrating Statistically and Clinically Significant Sustained Reduction in Urinary Oxalate Excretion; Key Secondary Endpoint Also Achieved; Robust Efficacy Seen in PH1 Participants –
– Nedosiran Was Generally Well Tolerated in PHYOX2 With a Safety Profile Similar to Previously Reported PHYOX Trial Results –
– Results Further Validate GalXC™ RNAi Technology Platform and its Ability to Silence Disease-Driving Genes –
– Management to Host Conference Call and Webcast Today at 4:30 p.m. ET –
LEXINGTON, Mass., Aug. 5, 2021 – Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA) (the “Company” or “Dicerna”), a leading developer of investigational ribonucleic acid interference (RNAi) therapeutics, today announced positive top-line results from the Company’s PHYOX™2 pivotal clinical trial of nedosiran, which is in development as a once-monthly treatment for primary hyperoxaluria (PH), a family of ultra-rare, life-threatening genetic disorders that initially manifest with complications in the kidneys. Nedosiran is Dicerna’s lead GalXC™ RNAi therapeutic candidate and is designed to inhibit the hepatic lactate dehydrogenase (LDH) enzyme – an enzyme that catalyzes the final step in the glyoxylate metabolism pathway that can lead to oxalate overproduction in patients with PH. The PHYOX2 clinical trial included participants with PH subtypes 1 and 2 (PH1 and PH2).
Nedosiran achieved the primary endpoint in the PHYOX2 trial, demonstrating a statistically significant reduction from baseline in urinary oxalate (Uox) excretion compared to placebo (p<0.0001). The study also achieved the key secondary endpoint, with a significantly higher proportion of patients given nedosiran achieving and sustaining normal or near-normal Uox at two or more consecutive visits after Day 90 compared to placebo (p=0.0025). Uox reductions were significant in participants with PH1 while participants with PH2 (5 nedosiran and 1 placebo) showed inconsistent results in this trial. Nedosiran was generally well tolerated in the study with an overall adverse event (AE) profile consistent with previously reported data from PHYOX trials.
“We believe the reduction in Uox excretion seen in patients with PH1 showed that nedosiran knocks down LDHA in the liver and reconfirms the ability of Dicerna’s GalXC RNAi technology to silence disease-driving genes, de-risking our growing pipeline of GalXC product candidates,” said Shreeram Aradhye, M.D., Executive Vice President and Chief Medical Officer at Dicerna. “The heterogeneity of Uox response seen in participants with PH2, despite LDHA inhibition in the liver and in contrast to prior clinical experience, suggests more complexity in the PH2 disease biology than has been previously understood and will require further evaluation.
“The results reinforce nedosiran’s potential to be a therapeutic option for patients with PH1, if approved,” Dr. Aradhye continued. “Our New Drug Application to the U.S. Food and Drug
Administration, expected to be submitted in the fourth quarter of 2021, will reflect the results reported today and a strategy to pursue approval of nedosiran for the treatment of PH1 for the near-term. We are extremely grateful to the patients, caregivers, physicians and healthcare professionals who participated in our trial and look forward to continuing to work with the PH community.”
PHYOX2 Top-Line Results and PHYOX Development Program
PHYOX2 (NCT03847909), a placebo-controlled, double-blind, multicenter, pivotal study, was designed to evaluate the efficacy, safety and tolerability of nedosiran over six months in participants aged six years and older across 11 countries, including the U.S., Japan and Europe, who have PH1 or PH2. Participants were randomized 2:1 to a fixed monthly dose of nedosiran or placebo administered once monthly by subcutaneous injection. Of the 35 patients randomized (23 nedosiran and 12 placebo; 29 with PH1 and 6 with PH2), 34 participants had at least one efficacy assessment after Day 90 (modified intent-to-treat population; mITT). Baseline mean estimated glomerular filtration rate (eGFR; a measure of kidney function) was 89.5 mL/min/1.73 m2 (SD=37.5) for participants given nedosiran and 82.0 mL/min/1.73 m2 (SD=30.0) for participants given placebo. Baseline mean Uox values were approximately 1.33 mmol/day (SD=0.47) and 1.96 mmol/day (SD=0.71) for the nedosiran and placebo groups, respectively.
The primary endpoint of the study was the percent change from baseline in 24-hour urinary oxalate excretion, as assessed by area under the curve (AUC) from Day 90 to Day 180. The primary endpoint of the study was met, with nedosiran resulting in a statistically significant reduction in Uox (p<0.0001). In the overall trial, nedosiran resulted in a 57.5% greater daily average reduction over Day 90 to Day 180 compared to placebo.
The key secondary endpoint was percentage of patients (PH1 and PH2) achieving normalization (defined as Uox level below 0.46 mmol adjusted per 1.73 m2 body surface area in participants younger than 18 years when collected over 24 hours) or near-normalization (defined as 1.3 times the upper limit of normal) on at least two consecutive visits from Day 90 to Day 180. Nedosiran achieved statistically significant results (p=0.0025) in the study, with 50% of nedosiran-treated patients reaching normal or near-normal Uox on at least two consecutive visits, compared to 0% for those receiving placebo.
Nedosiran was generally well tolerated in this study with an AE profile consistent with that observed in the PHYOX1 Phase 1 study and from previous interim analyses from the ongoing PHYOX3 open-label trial. The most common AEs in the trial were mild, self-resolving injection-site reactions (2 patients given nedosiran and zero given placebo). There were three reported kidney stone AEs in participants given nedosiran (13%) and five in participants given placebo (42%). Of the 35 participants enrolled in the trial, two discontinued, with one withdrawing from the study due to declining renal function (a participant who was receiving placebo) and one discontinuing due to self-resolving, benign palpitations considered to be unrelated to study drug by external experts.
Additional analyses of the Uox data for nedosiran-treated patients with PH1 demonstrated:
•59% greater reduction from baseline in 24-hour Uox averaged over Day 90 to Day 180 for nedosiran compared to placebo;
•68% (SD=14.6) mean maximum percent reduction in 24-hour Uox from baseline with nedosiran treatment at any time point;
•81% of participants achieved normal or near-normal Uox at Day 180;
•44% of participants had normal Uox at Day 180; and
•65% of participants had normal Uox on one or more visits during the 180-day period.
We expect the results from the PHYOX2 trial to support marketing authorization applications in the U.S. and other major markets.
Dicerna intends to present full results from PHYOX2 at an upcoming medical congress, subject to abstract acceptance.
PHYOX2 is part of the broader PHYOX clinical trial program designed to evaluate nedosiran in participants with PH1, PH2 and PH3. Data from PHYOX1, a single-dose Phase 1 trial in healthy volunteers and participants with PH1 or PH2; PHYOX2; PHYOX4, a single-dose safety and tolerability study in participants with PH3; and the ongoing PHYOX3 open-label extension study, are expected to support the nedosiran New Drug Application (NDA) submission, which is planned for the fourth quarter of 2021.
Conference Call and Webcast
Management will host a conference call and webcast at 4:30 p.m. ET today to discuss the PHYOX2 top-line results. The conference call can be accessed by dialing (855) 453-3834 or +1 (484) 756-4306 (international) and referencing conference ID 2845518 prior to the start of the call. A webcast presentation will also be available under the “Investors & Media” section of the Dicerna website, www.dicerna.com. A replay of the call will be available approximately two hours after the completion of the call. To access the replay, please dial (855) 859-2056 or +1 (404) 537-3406 and refer to conference ID 2845518. The webcast will also be archived on Dicerna’s website.
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 subtypes 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 an end-product of metabolism 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 eventually results in the accumulation of oxalate in a wide range of organs including the skin, bones, eyes and heart. In the most severe cases, symptoms start in the first year of life. A combined liver-kidney transplant may be undertaken to resolve PH1 or PH2, but it is an invasive solution with limited availability and high morbidity that requires lifelong immune suppression to prevent organ rejection. Genetic studies suggest approximately 8,500 people in the U.S. are affected by PH, and researchers estimate that more than 80% of patients remain undiagnosed.1 There is currently only one approved therapy available that is limited to the treatment of patients with PH1.
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 production of the hepatic lactate dehydrogenase (LDH) enzyme – an enzyme that catalyzes the final step in the glyoxylate metabolism pathway that can lead to oxalate overproduction in patients with PH1, PH2 or PH3. Dicerna is evaluating the safety and efficacy of nedosiran in patients with all known subtypes of PH as part of its PHYOX™ clinical development program.
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 silence selectively genes that cause or contribute to disease. Using our proprietary GalXC™ and GalXC-Plus™ RNAi technologies, 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 disease-causing genes in the liver, Dicerna has continued to innovate and is exploring new applications of its RNAi technology with GalXC-Plus, which expands on the functionality and application of our flagship liver-targeted GalXC technology to tissues and cell types outside the liver, and has the potential to treat diseases across multiple therapeutic areas. 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 cardiometabolic, viral, chronic liver and complement-mediated diseases, as well as neurodegenerative diseases and pain. At Dicerna, our mission is to interfere – to silence genes, to fight disease, to restore health. 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 our product candidates and the development thereof, such as the Company’s PHYOX clinical development program and potential impact of the results from the PHYOX2 trial of nedosiran as well as from the broader PHYOX clinical development program; the therapeutic potential of our product candidates, such as nedosiran; the Company’s regulatory plans and timelines for nedosiran, including our planned submission of a New Drug Application (NDA) for nedosiran and the indication(s) expected to be pursued in the near term; our business and operations, including the discovery, development and commercialization of our product candidates and technology platform, and the therapeutic potential thereof; our collaboration with partners and any potential future collaborations. 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; our reliance on the Company’s contract research organizations; the predictability of timely enrollment of subjects and patients to advance Dicerna’s clinical trials; positive data from preclinical studies and earlier clinical trials may not be predictive of results from subsequent preclinical studies and clinical trials; the reliance of Dicerna on contract manufacturers to supply its products for research, development and commercialization and the risk of supply interruption from one or more such contract manufacturers; the potential for additional or future data to alter initial, interim and preliminary results of clinical trials; the results of clinical trials may produce negative, inconclusive or uncompetitive results; 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 NDAs and comparable foreign applications for one or more of Dicerna’s product candidates; alignment with the FDA on the regulatory pathway to approval for nedosiran; 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 following commercialization; 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™, GalXC-Plus™ and PHYOX™ are trademarks of Dicerna Pharmaceuticals, Inc.
1 Hopp K, et al. J Am Soc Nephrol. 2015;26(10):2559-2570 and U.S. Census Bureau population on a date: February 20, 2020. United States Census Bureau website, 2020.
Topline Data Presentation Investigation of Nedosiran for the Treatment of Primary Hyperoxaluria Type 1 and Type 2 August 5, 2021
Forward-Looking Statements This presentation has been prepared by Dicerna Pharmaceuticals, Inc. (“we,” “us,” “our,” “Dicerna,” or the “Company”) and includes forward-looking statements. 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) the therapeutic and commercial potential of nedosiran as well as those of RG6346, belcesiran (formerly DCR-A1AT), DCR-AUD and our GalXC™ and GalXC Plus™ RNAi technology; (ii) our research and development plans and timelines for nedosiran as well as those for RG6346, belcesiran, DCR-AUD, GalXC and GalXC-Plus; (iii) our regulatory pathways, plans and timelines for nedosiran as well as those for RG6346, belcesiran, DCR-AUD, GalXC and GalXC-Plus; (iv) the Company’s strategy, business plans and focus; (v) the Company’s expectations about our cash, cash equivalents and marketable securities; (vi) the potential of Dicerna’s technology and drug candidates, including our pipeline expansion efforts and expectations; and (vii) the Company’s collaborations with Novo Nordisk A/S; Roche; Eli Lilly and Company; Alexion Pharmaceuticals, Inc.; Boehringer Ingelheim International GmbH; and Alnylam Pharmaceuticals, Inc. The process by which an early-stage investigational therapy such as nedosiran and an early-stage platform such as GalXC could potentially lead to an approved product is long and subject to significant risks. Applicable risks and uncertainties include, but are not limited to, those risks identified under the heading "Risk Factors" included in the Company’s most recent Form 10-K filing and in subsequent filings with the Securities and Exchange Commission. These risks and uncertainties include, among others, the potential for additional or future data to alter initial, interim and preliminary results of clinical trials; positive data from preclinical studies and earlier clinical trials may not be predictive of results from subsequent preclinical studies and clinical trials; the results of clinical trials may produce negative, inconclusive or uncompetitive results; possible safety, efficacy concerns could emerge as new data are generated in R&D and/or clinical trials; the impact to, and potential for delays in, the current and future conduct of the business of the Company, its clinical programs and operations as a result of the COVID-19 pandemic; the cost, timing and results of preclinical studies and clinical trials and other development activities; the likelihood of Dicerna’s clinical programs being executed within timelines provided; our reliance on the Company’s contract research and manufacturing organizations; the unpredictability of timely enrollment of subjects and patients to advance Dicerna’s clinical trials; the unpredictability of the duration and results of the regulatory review of Investigational New Drug (IND) applications and Clinical Trial Applications necessary to continue to advance and progress the Company’s clinical programs and the regulatory review of submissions relevant to regulatory agencies for marketing approvals, including New Drug Applications (NDAs); market acceptance for approved products and innovative therapeutic treatments; competition; the possible impairment of, inability to obtain and costs of obtaining needed intellectual property rights; that the Company may not realize the intended benefits of its collaborations; general business, financial and accounting risks; and the risks and potential outcomes from litigation. Dicerna is providing this information as of this date and does not undertake any obligation to update or revise it, whether as a result of new information, future events or circumstances or otherwise. Additional information concerning Dicerna and its business may be available in press releases or other public announcements and public filings made after the date of this information. 2 Dicerna™, GalXC™, GalXC-Plus™ and PHYOX™ are trademarks of Dicerna Pharmaceuticals, Inc.
Douglas M. Fambrough, Ph.D. President and Chief Executive Officer Introduction GalXC RNAi Technology Pipeline Rob Ciappenelli Chief Commercial Officer Disease and Patient Journey Shreeram Aradhye, M.D. Executive Vice President, Chief Medical Officer PHYOX2 Data Trial design Demographics Efficacy Endpoints Safety Douglas M. Fambrough, Ph.D. Summary and Conclusions Speakers and Agenda 3
• Sequence-specificity to silence only the targeted gene in the delivery tissues • Long duration of action – weeks to months – enables convenient dosing regimens • Off-target activity is generally not observed • Ability to address previously “undruggable” target classes Dicerna’s & RNAi Platform Offering Compelling Pharmacological Properties to De-Risk Development GalNAc liver delivery 4 Including alternative nucleic acid structures Various ligands Adipose Tumor-Associated Immune Cells Additional Tissues Muscle Central Nervous System Liver Our RNAi Platform creates broad opportunities for Dicerna and our partners Neurodegeneration, rare disease, spinal cord injury, etc. Immuno-oncology Diabetes, obesity, rare diseases, etc. Diseases of the eye, lung, etc. Myotonic dystrophy, other rare diseases Rare diseases, HBV, NASH, cardiometabolic diseases, AUD, etc.
With 20+ discovery-stage programs in multiple tissues Core and Collaborative Development-Stage Programs Fifteen Programs Have Entered Development, Many More Are in Discovery Stage TARGET INDICATION COMPOUND (GENE TARGET) PRECLINICAL PHASE 1 PHASE 2 PHASE 3 DICERNA PRODUCT RIGHTS PARTNER Primary Hyperoxaluria 1, 2 & 3 100% global Chronic Hepatitis B U.S. opt-in AAT Liver Disease 100% U.S. (Alnylam ex-U.S. opt-in) Alcohol Use Disorder 100% global Cardiometabolic Milestone/royalty Cardiometabolic Milestone/royalty Cardiometabolic Milestone/royalty Cardiometabolic Milestone/royalty Complement-mediated Milestone/royalty Complement-mediated Milestone/royalty Cardiometabolic Opt-in to co-dev. and co-comm. Cardiometabolic Opt-in to co-dev. and co-comm. Nonalcoholic Steatohepatitis Milestone/royalty Undisclosed GalXC-Plus 100% global Undisclosed GalXC-Plus 100% global Anticipated Timing: IND/CTA filings for DCR-CM4 and DCR-CM3 are the responsibility of Lilly and are at their discretion. Dicerna estimates IND timing for DCR-CM4 in Q1’22. Dicerna intends to deliver IND-supporting packages to Alexion for DCR-COMP1 and DCR-COMP2 in Q4’21 and Q1’22, respectively; IND/CTA filings are the responsibility of Alexion and are at their discretion. Belcesiran (SERPINA1) RG6346 (HBV) DCR-COMP1 (C3) DCR-COMP2 (CFB) DCR-CM3 DCR-NOVO1 5 DCR-NOVO2 DCR-CM4 DCR-LIV2 LY3561774 (ANGPTL3) LY3819469 (LPA) Nedosiran (LDHA) DCR-AUD (ALDH2)
Disease and Patient Journey Chief Commercial Officer Rob Ciappenelli
The Primary Hyperoxalurias • A family of three closely-related ultra-rare genetic diseases ‒ PH type 1 ‒ PH type 2 ‒ PH type 3 • All subtypes of PH are associated with high urinary oxalate levels, resulting in potentially severe health and quality-of-life consequences ‒ Frequent kidney stones ‒ Progression to end-stage renal disease 7 Estimated PH Diagnosis Rates PH1 PH2 PH3 Current Diagnosis Projections^ ~40% – 50% ~10% ~7% Expected U.S. Prevalence1,2 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. Analysts’ projections Similar numbers for major EU markets An Ultra-Rare Disease With an Evolving State of the Science
Patient Journey Demonstrates Challenges in PH Awareness, Disease Education and Diagnosis Majority of PH Patients Across Subtypes Remain Undiagnosed 8 Emergency Department Nephrologist Pt/Caregiver Renal Impairment PH Diagnosis Genetic Testing 24hr UoxKidney Stones Heterogenous Symptoms (e.g., Pain, Large Stones, Renal Impairment) Renal transplant Renal Impairment CKD / Kidney Stones Urologist Graft Failure Systemic Oxalosis Liver-Kidney Transplant Diagnostic delay Legend experience significant delay in diagnosis 1 diagnosed at ESRD2 diagnosed after kidney transplant3 (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. Typical PH Patient Journey (3 to 9 yrs. after symptoms)1
PHYOX2 Data Executive Vice President, Chief Medical Officer Shreeram Aradhye, M.D.
Primary Hyperoxaluria Disease Biology A Family of Ultra-Rare, Life-Threatening Genetic Disorders Resulting in Renal Complications 10 PEROXISOME Oxalate GO Primary hyperoxaluria 1 Glycolate Glyoxylate Primary hyperoxaluria 2 & 3 Glycine LDH nedosiran AGT HEPATOCYTE GRHPR Glyoxylate Glycolate MITOCHONDRIA Pathway Inputs HOGA 1 2 3 • Standard published PH biochemical models link the three types of PH to the same liver metabolic pathway • In each case, the glyoxylate intermediate is believed to be converted to oxalate by LDH • Published animal model data, and early clinical results, are supportive of this model for PH1 and PH2 • Abnormal production and accumulation of oxalate leads to: ⁻ Recurrent kidney stones ⁻ Nephrocalcinosis ⁻ Chronic kidney disease that may progress to end- stage renal disease ⁻ Systemic oxalosis, impacting diverse tissues • Nedosiran silences LDHA, believed to be the ultimate step in the oxalate production pathway
Study Design 11 Key Eligibility Criteria Adults and children (>6 yo) Genetically confirmed PH1/PH2 (AGXT/GRHPR mutations) eGFR >30 ml/min/1.73m2 Urinary Oxalate (Uox) excretion >0.7 mmol/24hr/1.73m2 2:1 Randomization Nedosiran Placebo Intent to Treat (ITT) Population 6-Month Double-Blind Treatment Period 36-Month Open-Label Extension 6 total doses (1 per month) Subcutaneous dosing Ages >12+ weighing >50kg 170mg Ages >12+ weighing <50kg 136mg Ages >6 to <12 3.5mg/kg (not exceeding 136mg) Nedosiran 36 total doses (1 per month) Subcutaneous dosing (same fixed dosing for >12+ & 3.5mg/kg for <12yo) NCT04042402 * NCT03847909 * Primary Endpoint: Percent change from baseline in 24-hour Uox as measured by AUC from Day 90 to Day 180 Key Secondary Endpoint: The proportion of participants reaching normalization or near-normalization of 24-hour Uox on at least 2 consecutive visits, starting from Day 90
Subject Disposition All Screened Participants 12 57 participants were screened 22 were not enrolled • Most common reasons for screen failure were Uox <0.7 mmol/24hr or baseline urine creatinine variability >20% 35 participants enrolled and randomized 23 participants assigned to receive nedosiran 12 participants assigned to receive placebo 23 participants included in safety analysis (safety population)* 12 participants included in safety analysis (safety population)* 22 participants included in efficacy analysis (mITT population)** 12 participants included in efficacy analysis (mITT population)** 1 discontinuation due to AE 1 discontinuation due to AE occurring after D90 *Safety Population = participants randomly assigned to study intervention and who take at least 1 partial or full dose of study intervention. ** MITT Population = participants randomized and at least one efficacy assessment after Day 90 dosing visit.
Baseline Characteristics 13 Category or Statistic Nedosiran (n = 23) Placebo (n = 12) Mean Age (years) / 6-11 (years) 23.7 / 3 (13.0%) 23.6 / 2 (16.7%) PH Type 1 / 2 18 (78.3%)/5 (21.7%) 11 (91.7%)/ 1 (8.3%) White 15 (65.2%) 10 (83.3%) Weight (kg), Mean(SD) 64.93 (19.3) 72.75 (27.3) Baseline eGFR (mL/min/1.73 m2), Mean(SD) 89.5 (37.5) 82.0 (30.0) Chronic Kidney Disease Stage Stage 1 12 (52.2%) 5 (41.7%) Stage 2 8 (34.8%) 2 (16.7%) Stage 3A 0 2 (16.7%) Stage 3B 3 (13.0%) 2 (16.7%) Missing 0 1 (8.3%) 24-Hr Urinary Oxalate (mmol/day), Mean(SD) 1.330 (0.465) 1.965 (0.706) High Baseline Urinary Oxalate* 7 (30.4%) 10 (83.3%) Baseline Plasma Oxalate (µmol/L), Mean(SD) 7.9 (5.1) 8.8 (5.1) Mean Time Since PH Diagnosis (years) 7.089 7.351 *High baseline Uox defined as ≥1.6 mmol/24h on at least one baseline value
PHYOX2 Met Primary Endpoint Achieving a Significant Reduction in Uox Mean AUC24-hour Uox (Day 90 to Day 180) 14 Standardized AUC24-hour Uox from Day 90 to Day 180** Nedosiran (n=22) Placebo (n=12) n 22 12 LS Mean (SE) 3507.4 (788.49) -1664.4 (1189.96) 95% CI for LS Mean (1961.7, 5053.1) (-3997.2, 668.4) LS Mean Difference from Placebo (SE) 5171.7 (1144.07) 95% CI for Difference from Placebo (2929.3, 7414.2) P-value for Difference from Placebo  <0.0001  mITT Population = All participants in the ITT population who have at least one efficacy assessment after the Day 90 dosing visit.  P-value for testing difference from placebo Overall mITT Population1 (PH1 + PH2) Baseline 30 60 90 120 150 180 (EOS) *LS means from MMRM model using time point estimates ** Multiple imputation (MI) under the missing at random (MAR) assumption was used to handle missing 24-hr Uox data -60 -50 -40 -30 -20 -10 0 10 20 30 40 *M ea n % C ha ng e fr om B as el in e ± SE M Day of Treatment Nedosiran Placebo AUC placebo AUC nedosiran
Significant Reduction From Baseline in 24h Uox Between Day 90-180 in PH1, But Not PH2 15 * Overall and PH1 data based on restricted maximum likelihood based MMRM approach ** PH2 analysis based on observed data given small n Average % Change From Baseline in 24-Hr Uox Between Day 90 to 180 -51% -59% 43% -80 -60 -40 -20 0 20 40 60 Av er ag e % C ha ng e Fr om B as el in e Nedosiran Placebo Net Change p<0.0001 p<0.0001 n = 1 n = 5 n = 22 n = 12 n = 17 n = 11 Overall (PH1+PH2)* PH1* PH2 **
0 10 20 30 40 50 60 70 Nedosiran (n=22) Placebo (n = 12) 0% 50% PHYOX2 Met Key Secondary Endpoint: Proportion of Participants Reaching Normalization/Near-Normalization ≥2 Consecutive Visits ≥D90 16 *24-hour Uox values are considered normalized if the value <0.46 mmol/24 hours (upper limit of assay normal-ULN), and near-normalized if the value is (1.3XULN) ≥0.46 to <0.6 mmol/24 hours ** p-value for one-sided test p = 0.0025** % o f P ar tic ip an ts A ch ie vi ng N or m al iza tio n/ N ea r- N or m al iza tio n* 50%
0 10 20 30 40 50 60 70 Nedosiran (n=22) Placebo (n = 12) 0% 59% Positive Responder Analysis: Proportion of Participants Meeting Normalization/Near- Normalization Criteria OR ≥70% Reduction in Uox on ≥2 Consecutive Visits ≥D90 17 24-hour Uox values are considered normalized if the value <0.46 mmol/24 hours (upper limit of assay normal-ULN), and near-normalized if the value is (1.3XULN) ≥0.46 to <0.6 mmol/24 hours * p-value for one-sided test p = 0.0005* % o f P ar tic ip an ts M ee tin g Re sp on de r C rit er ia
Additional Subgroup Analysis: Normalization/Near-Normalization and Uox Changes in PH1 Participants Nedosiran (n = 17) Placebo (n = 11) p-value*** Normalized* (at Day 180) 43.8% ** 0% ** 0.0174 Near-Normalized + Normalized* (at Day 180) 81.3%** 0%** <0.0001 Normalized* (≥1 visit) 65% 9% 0.0047 Maximal Uox % Reduction (at any time point), Mean (SD) 68% (14.6) 31% (30.2) 0.0004 18 * 24-hour Uox values are considered normalized if the value <0.46 mmol/24 hours (upper limit of assay normal-ULN), and near-normalized if the value is (1.3XULN) ≥0.46 to <0.6 mmol/24 hours ** Excludes 1 participant in each arm who did not complete the trial *** p-values for one-sided test
Treatment-Emergent Adverse Events and Laboratory Findings • Two discontinuations, both due to SAEs (1 nedosiran and 1 placebo) • Three total SAEs were reported (1 nedosiran and 2 placebo): ‒ One participant with fluctuating tachycardia on nedosiran (considered not to be related to study drug by two external cardiology experts) ‒ Two participants on placebo with SAEs related to underlying PH (elevated creatinine and renal colic/kidney stone) • Injection-site reactions (ISR): ‒ 2 participants (8.7%) with 11 events of mild protocol-defined ISR * ‒ Erythema at injection site was most common AE, 5 participants on nedosiran (21.7%) and 0 participants on placebo • Two reported AEs of CK elevation (1 nedosiran and 1 placebo) • No other clinically significant laboratory findings • Kidney stone-related adverse events reported in 3 participants on nedosiran (13%) and 5 participants on placebo (41.7%) 19 AE term Nedosiran n, (%) n = 23 Placebo n, (%) n = 12 Erythema at injection site 5 (21.7%) 0 Kidney stone- related events 3 (13%) 5 (41.7%) Nausea 4 (17.4%) 1 (8.3%) Headache 4 (17.4%) 3 (25%) Abdominal cramp 3 (13%) 2 (16.7%) Most Common Treatment-Emergent Adverse Events (>3 participants) * Signs or symptoms at the injection site with a time to onset of 4 or more hours from the time of study intervention administration
• Nedosiran achieved the primary and key secondary endpoints with a statistically significant reduction in Uox • Robust Uox reduction seen in the PH1 subpopulation • PH2 results inconsistent with prior experience • Nedosiran was generally well tolerated, and its AE profile was consistent with previous studies • We expect these results to support marketing authorization applications for PH1 in the U.S. and other major markets 20 PHYOX2 Summary of Top-Line Data Nedosiran Demonstrated Robust Uox Reduction in PH1 and Was Well Tolerated in This Study
Doug Fambrough, Ph.D. President and Chief Executive Officer Summary and Conclusions
Summary and Conclusions • Nedosiran decisively hit the primary and key secondary endpoints in PHYOX2 • Nedosiran showed an AE profile similar to previously reported PHYOX trial results • The success of nedosiran in PH1 validates the GalXC technology at the foundation of our proprietary and partnered pipeline • We will seek the optimal commercialization path for nedosiran • Planned next steps: ‒ Complete PHYOX4 in PH3 and announce results in October ‒ Submit NDA for nedosiran in Q4 2021 ‒ Continue PHYOX7 and PHYOX8 to support label expansion ‒ Continue to evaluate PH2 data to determine next steps 22