Benzinga | Aug 6, 2020 07:21AM EDT

Dicerna Reports Clinical Data For Investigational Treatments RG6346 For Chronic Hep B Virus, Nedosiran For Primary Hyperoxaluria

Dicerna 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(tm) 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 ?1.0 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 ?1.0 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 datashown 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."