Benzinga | Aug 5, 2021 04:23PM EDT

Dicerna Reports Top-Line REsults From PHYOX 2 Trial Of Nedosiran For Treatment Of Primary Hyperoxaluria Met Primary Endpoint

-- 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(tm) 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.--(BUSINESS WIRE)-- 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(tm)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(tm) 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.