Dicerna Pharmaceuticals, Inc. operates as a biopharmaceutical company.
The company focuses on discovering, developing, and commercializing medicines that are designed to leverage ribonucleic acid (RNA) interference (RNAi) to silence selectively genes that cause or contribute to disease. Using its proprietary GalXC and GalXC-Plus RNAi technologies, the company is developing RNAi-based therapies with the potential to treat both rare and more prevalent diseases. By silencing disease-causing genes,...
Dicerna Pharmaceuticals, Inc. operates as a biopharmaceutical company.
The company focuses on discovering, developing, and commercializing medicines that are designed to leverage ribonucleic acid (RNA) interference (RNAi) to silence selectively genes that cause or contribute to disease. Using its proprietary GalXC and GalXC-Plus RNAi technologies, the company is developing RNAi-based therapies with the potential to treat both rare and more prevalent diseases. By silencing disease-causing genes, the company’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, the company has continued to innovate and is exploring new applications of its RNAi technology with GalXC-Plus, which expands on the functionality and application of its flagship liver-based GalXC technology, yet has the potential to treat diseases across multiple therapeutic areas.
In addition to the company’s own pipeline of core discovery and clinical candidates, it has established collaborative relationships with some of the major pharmaceutical companies, including Novo Nordisk A/S (Novo), F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc. (together, ‘Roche’), Eli Lilly, and Company (Lilly), Alexion Pharmaceuticals, Inc. (together with its affiliates, ‘Alexion’), Boehringer Ingelheim International GmbH (BI), and Alnylam Pharmaceuticals, Inc. (Alnylam). Between the company and its collaborative partners, the company has more than 20 active discovery, preclinical, or clinical programs focused on rare, cardiometabolic, viral, chronic liver, and complement-mediated diseases, as well as neurodegenerative diseases and pain.
Most of the company’s drug discovery and development efforts are based on the therapeutic modality of RNAi, a potent, natural, and specific mechanism that can be directed to reduce expression of a target gene. In this naturally occurring biological process, a short, synthetic, double-stranded RNA duplex induces the enzymatic destruction of the messenger RNA (mRNA) of a target gene that contains sequences complementary to one strand of a double-stranded RNA. The company’s approach is to design proprietary RNA molecules that have the potential to engage the enzyme Dicer and direct the endogenous cellular RNAi machinery to silence a specific therapeutic target gene. The company’s GalXC technology utilizes a proprietary N-acetyl-D-galactosamine (GalNAc)-mediated conjugate to cause the liver to internalize its synthetic RNA molecules. In contrast, its GalXC-Plus technology incorporates new chemistries and secondary structures to enable targeting of genes in tissues and cell types beyond the liver. Its clinical programs utilize the GalXC technology. The company’s GalXC-Plus technology utilizes modified RNA structures and various fully-synthetic conjugated ligands to deliver to non-liver tissues and is used in a number of its preclinical programs. Due to the enzymatic nature of RNAi, a single GalXC or GalXC-Plus molecule incorporated into the RNAi machinery can direct the cleavage and silencing of hundreds or thousands of mRNAs from the targeted gene.
Pipeline
Using the company’s GalXC RNAi technology, and applying the criteria of its development focus, it has created a pipeline of core liver-focused therapeutic programs for development by the company.
The company’s four core GalXC development programs are: nedosiran for the treatment of primary hyperoxaluria (PH); RG6346 for the treatment of chronic hepatitis B virus (HBV) infection; belcesiran for the treatment of alpha-1 antitrypsin (AAT) deficiency (AATD)-associated liver disease (AATLD); and DCR-AUD for the treatment of alcohol use disorder (AUD).
Nedosiran for PH
Nedosiran is the company’s lead investigational product candidate for the treatment of PH type 1 (PH1), PH type 2 (PH2), and PH type 3 (PH3) and is derived from its GalXC platform technology. PH is a family of rare, life-threatening genetic liver disorders characterized by the overproduction of oxalate, a highly insoluble metabolic end-product that is eliminated from the body mainly by the kidneys. PH1, PH2, and PH3 are each characterized by a specific enzyme deficiency. PH1 is caused by a deficiency of glyoxylate-aminotransferase, PH2 is caused by a deficiency of glyoxylate reductase/hydroxypyruvate reductase, and PH3 is caused by a deficiency of 4-hydroxy-2-oxoglutarate aldolase.
The company’s nedosiran product candidate is designed to block production of the lactate dehydrogenase enzyme by silencing the lactate dehydrogenase A (LDHA) gene, which is the final common pathway of oxalate production in the liver.
The company has developed nedosiran as a once-monthly fixed-dose injection for the treatment of PH. This once-monthly formulation of nedosiran is designed to avoid the sudden oxalate spikes that could occur with less frequent administration or missed dosages, which could result in the formation of kidney stones and renal failure. To maximize patient convenience, it is developing pre-filled syringes to enable self-administration by most PH patients without the need for involvement of a healthcare provider for dosing.
In 2018, nedosiran received Orphan Drug Designation from the FDA, and the European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) designated nedosiran as an orphan medicinal product for the treatment of PH. In June 2020, the 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 on or before September 30, 2026. Subject to FDA approval of nedosiran for the treatment of PH, the company 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.
The broader PHYOX clinical trial program is designed to evaluate nedosiran in PH1, PH2, and PH3 patients of all ages and stages of renal health. Data from PHYOX1, PHYOX2, PHYOX4 clinical trials, the ongoing PHYOX3 open-label extension study, and the company’s PHYOX-OBX natural history study of PH3 participants are expected to support the initial nedosiran New Drug Application (NDA) submission.
RG6346 for Chronic HBV Infection
The company’s GalXC product candidate for the treatment of chronic HBV infection, RG6346, is being tested in a Phase 1 clinical trial. In order to be optimally positioned to develop and commercialize RG6346 in combination with other novel drugs, the company entered into a research collaboration and licensing agreement with Roche in October 2019. Under the terms of the agreement, the company is leading the development of RG6346 through the Phase 1 trial, and pending favorable results, Roche intends to further develop RG6346 with the overall goal of developing a combination regimen to achieve a functional cure of chronic HBV in combination with additional Roche product candidates. Roche will be responsible for initiating RG6346 in a Phase 2 combination trial, which is anticipated in the first quarter of 2021. The agreement also provides an option for the companies to collaborate in the discovery, development, and commercialization of oligonucleotide therapeutics intended for the treatment of chronic HBV.
The Phase 1 trial is a randomized, placebo-controlled, double-blind study designed to evaluate the safety and tolerability of RG6346 in healthy volunteers and in patients with non-cirrhotic chronic HBV. Secondary objectives are to characterize the pharmacokinetic profile of RG6346 and to evaluate preliminary pharmacodynamic effects on markers of HBV antiviral efficacy, including reductions of hepatitis B surface antigen (HBsAg) and HBV deoxyribonucleic acid levels in blood.
In agreement with Roche, the company is enrolling two additional, optional, open-label Group C cohorts, Cohort 4C and Cohort 5C, for which Roche will reimburse the company. Cohorts 4C and 5C will evaluate fixed dosing regimens and an extended conditional follow-up period. Cohort 4C is a single-dose cohort with a follow-up duration of up to 48 weeks. Cohort 5C is a multiple-dose cohort with a follow-up duration of up to 72 weeks.
In November 2020, the company expanded upon the interim results from both Group B and Group C presented in August 2020. In particular, top-line data from the Group C cohort demonstrated that four monthly doses of RG6346 treatment resulted in substantial and durable reductions in biomarkers of HBV disease activity as measured by reductions in HBsAg levels lasting up to one year following the last dose. RG6346 was also shown to have a favorable tolerability profile in the trial. In April 2020, Roche nominated the first of up to five targets under the research and development portion of the company’s collaboration agreement.
Belcesiran (DCR-A1AT) for AATLD
The company’s GalXC product candidate for the treatment of AATLD, belcesiran, is being tested in a Phase 1 clinical study. AATD is a rare, genetic, inherited condition that can lead to AATLD in children and adults and lung disease in adults. The condition is caused by mutations in the SERPINA1 gene.
In March 2020, the FDA granted orphan drug designation to belcesiran for the treatment of AATD. In December 2019, the European Commission granted orphan drug designation to belcesiran for the treatment of congenital AATD based on a positive opinion from the COMP of the EMA.
The company’s 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. Secondary objectives of the trial are to characterize the pharmacokinetic profile of belcesiran and to evaluate the preliminary pharmacodynamic effects on serum AAT protein concentrations. The company expects to advance belcesiran into Phase 2 development in the first half of 2021 and it expects to present data from the Phase 1 trial in healthy volunteers in 2021.
In April 2020, the company entered into a collaboration agreement with Alnylam. Under the collaboration agreement, Alnylam’s ALN-AAT02 and the company’s belcesiran would be explored for the treatment of AATLD at its cost, and it had the option to progress one or both of these investigational medicines through clinical development. The company selected belcesiran to advance in development for the treatment of patients with AATLD.
At the completion of Phase 3, Alnylam has the no-cost opportunity to opt in to commercialize belcesiran in countries outside the U.S. where it already has a commercialization infrastructure in place (the Commercialization Option).
DCR-AUD for AUD
The company is pursuing the development of DCR-AUD for the treatment of AUD. DCR-AUD is an investigational therapy based on its GalXC technology for the treatment of AUD. DCR-AUD specifically knocks down ALDH2 gene expression in the liver, which plays a key role in alcohol metabolism. Inhibition of ALDH2 may help individuals with AUD avoid harmful levels of alcohol use.
The company’s goal is to submit an Investigational New Drug (IND) or Clinical Trial Application filing in mid-2021 and initiate a subsequent Phase 1 single-ascending-dose trial in healthy volunteers in the third quarter of 2021.
Non-core Partner Development Programs
Novo Collaboration
In November 2019, the company entered into a Collaboration and License Agreement with Novo (the Novo Collaboration Agreement). Under the terms of the Novo Collaboration Agreement, the company and Novo will seek to use GalXC to explore more than 30 gene targets associated with liver disease with the goal of delivering multiple clinical candidates for disorders, including chronic liver disease, non-alcoholic steatohepatitis, type 2 diabetes, obesity, and rare diseases. The company will conduct and fund discovery and preclinical development to clinical candidate selection for each liver cell target. Novo will be responsible for all further development and commercialization of each candidate selected for development, with the company manufacturing clinical candidates selected for Phase 1-related clinical development, subject to reimbursement for its manufacturing costs. In addition, it will assist Novo with the IND filing for the first development candidate. The company also retains the ability to opt in to co-development of a total of two programs during clinical development in Phases 1-3, subject to limitations in the event of a change in control.
The company is working exclusively with Novo during the research collaboration period on the discovery, research, development, and commercialization of hepatocyte targets subject to certain exclusions, including those targets subject to its existing partnerships and Novo is, during a specified discovery period, working exclusively with the company in any new research and development of compounds and products directed to collaboration targets using small interfering RNA conjugated to the sugar GalNAc to reduce the expression of specific target genes in the liver. Under the Novo Collaboration Agreement, the company is providing Novo with exclusive and non-exclusive licenses and manufacturing support to enable Novo to commercialize products derived from or containing compounds developed pursuant to such agreement.
Roche Collaboration
As part of the terms of the company’s collaboration agreement with Roche, Roche had until receipt of interim Phase 1 data from the RG6346 Phase 1 study (but no later than December 31, 2020) to initiate a research and development collaboration with the company to pursue up to five targets selected by Roche, which are intended primarily to treat HBV. Under an amendment to the collaboration agreement with Roche, in June 2020, the company and Roche agreed to extend the date for nomination of targets from December 31, 2020 to January 15, 2021, subject to further potential extension by the parties due to the coronavirus disease global pandemic shutdowns. Under the terms of the Roche Collaboration Agreement, the goal of such research and development collaboration will be to select compounds developed by the company or Roche for Roche’s continued development and commercialization.
Lilly Collaboration
In October 2018, the company entered into a Collaboration and License Agreement with Lilly (the Lilly Collaboration Agreement) for the discovery, development, and commercialization of potential new medicines in the areas of cardiometabolic disease, neurodegenerative diseases, and pain. Under the terms of the Lilly Collaboration Agreement, the company and Lilly will use its proprietary GalXC RNAi technology to progress new drug targets toward clinical development and commercialization. In addition, the company will collaborate with Lilly on non-liver (i.e., extrahepatic) tissues, including neural tissues.
The company will work exclusively with Lilly in the neurodegenerative disease and pain fields with the exception of mutually agreed upon orphan indications. Additionally, it will work exclusively with Lilly on select targets in the cardiometabolic field. Under the Lilly Collaboration Agreement, the company will provide Lilly with exclusive and non-exclusive licenses to support the companies’ activities and to enable Lilly to commercialize products derived from or containing compounds developed pursuant to such agreement. The Lilly Collaboration Agreement provides for three initially named hepatocyte targets, and the company and Lilly developed research programs with the goal of researching and developing multiple lead candidates directed to each of these initial targets. The Lilly Collaboration Agreement contemplates in excess of ten targets.
During the first quarter of 2020, Lilly selected LY3819469, a GalXC molecule for the second collaboration target in cardiometabolic disease that targets the LPA gene, for advancement into preclinical development. The company expects Lilly to file an IND for LY3819469 in the second quarter of 2021. Another GalXC molecule, LY3849889, is in preclinical development, and the company expects Lilly to file an IND for LY3849889 in the first quarter of 2022.
Lilly filed an IND and initiated a Phase 1 study of LY3561774, a GalXC molecule for the first collaboration target in cardiometabolic disease that targets the ANGPTL3 gene for the treatment of dyslipidemia, in the fourth quarter of 2020.
In February 2021, Lilly notified the company of their decision to extend for an additional year the initial research collaboration term for the extrahepatic targets subject to the Lilly Collaboration Agreement. Under the agreement between the companies, Lilly has the option to extend the three-year initial research collaboration term for these extrahepatic targets for up to three consecutive one-year periods. This first extension allows the research program for these extrahepatic targets under the collaboration between the two companies to continue through October 2022.
Alexion Collaboration
In October 2018, the company entered into a Collaborative Research and License Agreement (the Alexion Collaboration Agreement) with Alexion for the joint discovery and development of RNAi therapies for complement-mediated diseases. The company will collaborate with Alexion on the discovery and development of two subcutaneously delivered GalXC candidates, in preclinical development, for the treatment of complement-mediated diseases with potential global commercialization by Alexion. It will lead the joint discovery and research efforts through the preclinical stage, and Alexion will lead development efforts beginning with Phase 1 studies. The company will be responsible for manufacturing of the GalXC candidates for use through the completion of Phase 1, and certain related costs will be paid by Alexion. Alexion will be solely responsible for the manufacturing of any product candidate subsequent to the completion of Phase 1. The Alexion Collaboration Agreement provides Alexion with exclusive worldwide licenses, as well as development and commercial rights to the GalXC RNAi molecules developed in the collaboration in exchange for development and approval-related milestones, sales milestones, and royalties on future product sales.
In November 2019, the company and Alexion amended the Alexion Collaboration Agreement to clarify funding of certain manufacturing costs for each of the two initial targets and increased milestone payments for the additional targets if Alexion exercised its options for the two additional targets.
In December 2019, Alexion exercised its options for the exclusive rights to two additional targets within the complement pathway for the discovery and development of GalXC molecules. These exercises expanded the companies’ existing research collaboration and license agreement to encompass four targets within the complement pathway.
Two GalXC molecules targeted for complement-mediated indications are in preclinical development under the Alexion Collaboration Agreement. The company expects to supply an IND-supporting package for DCR-COMP1, which targets the C3 gene, in the fourth quarter of 2021. The company expects to supply an IND-supporting package related to DCR-COMP2, which targets the CFB gene, in the first quarter of 2022.
BI Collaboration
In October 2017, the company entered into a collaborative research and license agreement with BI (the BI Agreement), pursuant to which the company and BI jointly research and develop product candidates for the treatment of chronic liver disease using GalXC. The BI Agreement is for the development of product candidates against one target gene with an option for BI to add the development of product candidates that target a second gene (the Second Target). Pursuant to the BI Agreement, the company granted BI a worldwide license in connection with the research and development of such candidates and transferred certain intellectual property rights of the selected product candidates to BI for clinical development and commercialization. The company also may provide assistance to BI in order to help BI further develop selected product candidates.
Under the terms of the Additional Target Agreement, BI is responsible for future clinical development and commercialization of candidate products for the Second Target.
Cross-License Program
Alnylam
In April 2020, the company and Alnylam entered into a Patent Cross License Agreement (the PH Agreement). Pursuant to the PH Agreement, the parties completed a cross-license of their respective intellectual property for Alnylam’s lumasiran and the company’s nedosiran investigational programs for the treatment of PH.
Pursuant to the PH Agreement, the parties granted to each other a perpetual non-exclusive cross-license to their respective intellectual property related to their respective PH treatment investigational programs to ensure that each party has the freedom to develop and commercialize its respective product with Alnylam’s lumasiran targeting glycolate oxidase for the treatment of PH1 and its nedosiran targeting LDHA for the treatment of PH1, PH2, and PH3. Each party will have sole discretion concerning the research and development of its products in the field.
Research
The company continues to advance its GalXC RNAi platform as it is applied to therapeutic targets expressed in hepatocytes using GalNAc conjugates for both its collaborative research and development programs and its internal liver-targeted programs. All existing collaborative programs include one or more liver-targeted applications of the GalXC RNAi platform.
In addition, the company is exploring applications of its GalXC-Plus RNAi technology against therapeutic gene targets expressed in tissues other than the liver, including targets expressed in the central nervous system (CNS), muscle tissue, adipose tissue, tumor-associated immune cells, and other tissues. The company has achieved significant gene target knockdown in multiple cell types and regions of the CNS and these other tissues, in both rodents and nonhuman primates. These extrahepatic applications are based on proprietary modifications to its clinical-stage GalXC platform that enable extrahepatic delivery and pharmacological activity. In August 2020, the company presented for the first time preclinical data related to its GalXC-Plus RNAi technology in CNS, skeletal muscle, and adipose tissues.
Strategy
The key elements of the company’s strategy are to create new programs in disease indications with high unmet medical need; validate its product candidates and its platform in clinical proof-of-concept studies; retain significant portions of the commercial rights for select disease programs; lead the United States (U.S.) commercialization efforts for select programs; enter into strategic collaborations with pharmaceutical companies with either GalXC or GalXC-Plus RNAi technologies for specific indications or therapeutic areas; and expand the reach of its RNAi technology to therapeutic targets beyond the liver.
Intellectual Property
Patents and Proprietary Rights
The company owns U.S. patents and pending patent applications with claims to methods and compositions of matter that cover various aspects of its RNAi technology and its discovery technologies, including its proprietary GalXC technology and the newly developed GalXC-Plus technology. These U.S. patents include various platform patents that protect its ability to make its structures: the U.S. 8,349,809 (issued in January 2013, with a projected expiration date of January 2030); the U.S. 10,131,912 (issued in November 2018, with a projected expiration date of January 2030); the U.S. 8,513,207 (issued in August 2013, with a projected expiration date of May 2030); and the U.S. 8,927,705 (issued in January 2015, with a projected expiration date of July 2030). These patents are from the same family of patents and constitute the core patents for the company’s GalXC technology. The company also owns numerous patents and patent applications covering other elements of its platform technology, as well as patents to specific RNAi sequences that drive activity against a substantial number of high-value disease targets, including targets for its disclosed core and non-core programs. The company has issued or pending claims to RNAi molecules, pharmaceutical compositions/formulations, methods of use, including in vitro and in vivo methods of reducing target gene expression, methods of treatment, methods of inhibiting cell growth, and methods of synthesis.
Research and Development
The company’s research and development costs were $205.4 million for the year ended December 31, 2020.
Regulation
The company’s product candidates must be approved by the U.S. Food and Drug Administration (FDA) through the NDA process before they may be legally marketed in the U.S. and will be subject to similar requirements in other countries prior to marketing in those countries.
In the U.S., the company’s activities are potentially subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare and Medicaid Services, other divisions of the Department of Health and Human Services (such as the Office of Inspector General and the Health Resources and Service Administration), the U.S. Department of Justice (the DOJ) and individual U.S. Attorney offices within the DOJ, and state and local governments.
The company’s third-party manufacturers are subject to inspections by the FDA for compliance with current good manufacturing practices and other U.S. regulatory requirements, including the U.S. federal, state, and local regulations regarding environmental protection and hazardous and controlled substance controls, among others.
Competition
The company competes with companies working to develop antisense and other RNA-based drugs, including Ionis Pharmaceuticals, Inc.; Moderna, Inc.; and Wave Life Sciences Ltd.
History
Dicerna Pharmaceuticals, Inc. was founded in 2006. The company was incorporated in Delaware in 2006.
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