Investigating RNAi therapies for rare and common diseases
We are developing a pipeline of RNAi therapies that aim to restore health by addressing the underlying causes of disease. We currently have three core programs in clinical development:
- PHYOX™ Clinical Program: evaluating nedosiran for the treatment of primary hyperoxaluria (PH)
- Hepatitis B Virus (HBV) Infection: in collaboration with Roche, evaluating RG6346 for the treatment of patients with non-cirrhotic chronic HBV infection
- SHINE Clinical Program: developing belcesiran for the treatment of patients with alpha-1 antitrypsin (AAT) deficiency-associated liver disease (AATLD)
- Alcohol Use Disorder: developing DCR-AUD for the treatment of alcohol use disorder (AUD)
PHYOX1 (NCT03392896) is a study of nedosiran in healthy volunteers (HVs) and patients with PH1 or PH2. Results from the PHYOX1 clinical trial showed favorable safety and tolerability profiles and normalization or near-normalization of urinary oxalate levels in a majority of participants with PH after a single dose of nedosiran.
PHYOX2 (NCT03847909) Dicerna’s global, multicenter, double-blind, randomized, placebo-controlled pivotal trial designed to evaluate the efficacy and safety of nedosiran delivered as a once-monthly subcutaneous injection over six months in 35 participants aged six years and older with PH1 or PH2. We announced positive top-line results in August 2021 and presented full results at the American Society of Nephrology Kidney Week 2021. Nedosiran achieved the primary and key secondary endpoints in the PHYOX2 trial. Urinary oxalate reductions were significant in participants with PH1 while participants with PH2 showed inconsistent results in this trial. Nedosiran was generally well tolerated in the study with an overall adverse event profile consistent with previously reported data from PHYOX trials. Patients administered nedosiran also showed a trend in urinary oxalate (Uox) reduction; however, these reductions did not meet prespecified secondary efficacy endpoint criteria.
PHYOX3
PHYOX3 (NCT04042402) is a long-term, multidose, open-label, extension trial designed to further evaluate the safety and efficacy of nedosiran. Participants who complete PHYOX trials, and their siblings with PH, are eligible to enroll in the PHYOX3 trial.
In October 2020, we announced positive interim data from the ongoing PHYOX3 trial, which showed normalization or near normalization of urinary oxalate levels in all 13 participants receiving nedosiran who had previously completed the PHYOX1 Phase 1 trial and had reached Day 180 in the ongoing PHYOX3 trial. Nedosiran was generally well tolerated, and no serious safety concerns were identified in this ongoing study. There were no treatment discontinuations or study withdrawals during the observation period.
PHYOX4 (NCT04555486) is a randomized, placebo-controlled, double-blind, multicenter study designed to evaluate the safety and tolerability of a single subcutaneous dose of nedosiran in patients with PH3 who have had at least one kidney stone event in the last 12 months. In October 2021, we announced nedosiran demonstrated safety and tolerability results in this trial consistent with previously reported studies in the PHYOX clinical development program.
PHYOX7 (NCT04580420) is an open-label, repeat-dose study of nedosiran in participants with PH1 or PH2 who have severe renal impairment, and who may or may not be undergoing dialysis.
PHYOX8 is an open-label, repeat-dose, study of nedosiran in participants 5 years of age or younger who have PH with relatively intact renal function.
RG6346
We are collaborating with Roche to develop RG6346 for the treatment of patients with chronic HBV. We initiated a randomized, placebo-controlled Phase 1 clinical trial designed to evaluate the safety and tolerability of RG6346 in healthy volunteers and in patients with non-cirrhotic chronic HBV, which is ongoing. Roche initiated RG6346 in a Roche-sponsored Phase 2 combination trial for the treatment of HBV in March 2021.
We are investigating belcesiran as part of the SHINE clinical development program. SHINE includes our Phase 2 study called ESTRELLA, which was initiated in 2021 to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of belcesiran in adults with AAT deficiency-associated liver disease (AATLD). Our Phase 1 trial of belcesiran is an ongoing placebo-controlled study designed to evaluate the safety and tolerability of single doses of belcesiran when administered to healthy adult participants. In October 2021, we presented Phase 1 results in a poster at The Liver Meeting® 2021, the annual meeting of the American Association for the Study of Liver Diseases (AASLD). These data expanded upon interim results announced in July 2021, demonstrating the safety and tolerability of single ascending doses of belcesiran in healthy volunteers (up to and including the final 12 mg/kg dose cohort) and further reaffirming the dosing regimen established for the ESTRELLA Phase 2 study of belcesiran.
DCR-AUD
We are investigating DCR-AUD for the treatment of alcohol use disorder (AUD). We initiated a randomized, double-blind, placebo-controlled Phase 1 trial in the third quarter of 2021 to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics of single ascending doses of DCR-AUD over a 24-week observation period in healthy volunteers.
