Developing next-generation RNAi therapies.
Dicerna has a growing pipeline of product candidates to address unmet medical needs in diseases involving the liver, including rare diseases, viral infectious diseases, chronic liver diseases, and cardiovascular diseases. Our optimized, subcutaneously administered GalXCTM molecules are designed to potently and selectively silence genes that are implicated in these disorders. We have qualified dozens of disease-associated genes in clinical indications where we believe an RNAi-based inhibitor may provide substantial benefit to patients, providing expansive therapeutic opportunities. In addition, Dicerna has developed hits and/or optimized GalXC conjugate inhibitors against dozens of these qualified targets.
We choose to attack disease targets where we have high confidence that successful silencing of the target gene will provide substantial benefit to patients, and for which we can move rapidly through the drug approval process. Whether focusing on our core area of rare diseases or on serious, life-threatening, chronic diseases, the common threads are the expression of faulty genes in the liver and a substantial need for new treatment options. In making these choices, we are working to improve the lives of patients suffering from potentially debilitating conditions.
Primary Hyperoxaluria (PH)
Dicerna is developing DCR-PHXC, a subcutaneously delivered GalXCTM candidate for the treatment of patients with all forms of primary hyperoxaluria (PH). DCR-PHXC is currently being tested in a Phase 1 trial, called PHYOX, comprised of healthy volunteers and patients with PH types 1 and 2. Proof-of-concept data from this trial are expected in the second half of 2018.
PH is a family of severe, rare, genetic liver disorders characterized by overproduction of oxalate, a natural chemical in the body that is normally eliminated as waste through the kidneys. In patients with PH, the kidneys are unable to eliminate the large amount of oxalate that is produced, and the accumulation of oxalate can result in severe damage to the kidneys (nephrocalcinosis) and other organs (systemic oxalosis). Currently, there are no approved therapies for the treatment of PH. In preclinical studies, DCR-PHXC mediates near complete silencing (>90%) of the oxalate-generating enzyme LDHA when dosed monthly in non-human primates at 4 mg/kg, an easily tolerated dose. Comparable dosing in the mouse genetic model of PH type 1 blocks the production of excess oxalate and prevents the induced nephrocalcinosis symptoms.
Chronic Hepatitis B Virus Infection
We have declared a GalXC RNAi platform-based product candidate for the treatment of HBV, DCR-HBVS, and are conducting formal non-clinical development studies. Current therapies for HBV rarely lead to a long-term immunological cure as measured by the clearance of HBV surface antigen (HBsAg) and sustained HBV deoxyribonucleic acid (DNA) suppression in patient plasma or blood. We expect to file regulatory clearances to initiate a clinical trial during the fourth quarter of 2018. DCR-HBVS targets HBV messenger RNA and leads to greater than 99% reduction in circulated HBsAg in mouse models of HBV infection. Based on preclinical studies, and only if we receive appropriate regulatory approval to begin human clinical trials, we hope to determine the potential of DCR-HBVS to reduce HBsAg and HBV DNA levels in the blood of HBV patients in a commercially attractive subcutaneous dosing paradigm.
GalXC™ Program Partnering Opportunities
Cardiometabolic and Chronic Liver Disease
Dicerna is investigating potential pharmaceutical therapeutic options with the GalXC RNAi platform for the treatment of cardiometabolic and chronic liver diseases such as hypocholesteremia, hypertriglyceridemia, other forms of dyslipidemias, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and multiple additional liver diseases less
frequently diagnosed. Based on preclinical studies, Dicerna believes that its GalXC RNAi platform enables exquisite targeting of hepatocytes and the silencing of injury-responsive mRNAs for the potential treatment of cardiometabolic and chronic liver diseases. In October 2017, Dicerna announced a collaboration with Boehringer Ingelheim to generate a potential therapeutic for NASH using the GalXC RNAi platform.
We are using our GalXC RNAi platform to develop a therapeutic that targets the PCSK9 gene for the treatment of hypercholesterolemia. Based on the Company’s candidate development work during the fourth quarter of 2016, Dicerna is positioned to advance DCR-PCSK9, which targets the PCSK9 gene and will be evaluated for the treatment of statin-refractory patients with hypercholesterolemia, into formal preclinical development. PCSK9 is a validated target for hypercholesterolemia, and there are FDA-approved therapies targeting PCSK9 that are based on monoclonal antibody technology. Based on preclinical studies, we believe that our GalXC RNAi platform can produce a PCSK9-targeted therapy with attractive commercial properties, such as small subcutaneous injection volumes and less frequent dosing.
An Undisclosed Rare Disease Involving the Liver
We are developing a GalXC-based therapeutic, targeting a liver-expressed gene involved in a serious rare disease. For competitive reasons, we have not yet publicly disclosed the target gene or disease. We have selected this target gene and disease based on criteria that include having a strong therapeutic hypothesis, a readily-identifiable patient population, the availability of a potentially predictive biomarker, high unmet medical need, favorable competitive positioning and what we believe is a rapid projected path to approval. The disease is a genetic disorder, where mutations in the disease gene lead to the production of an abnormal protein. The protein causes progressive liver damage and fibrosis, in some cases leading to cirrhosis and liver failure, and we believe that silencing of the disease gene will prevent production of the abnormal protein and thereby slow or stop progression of the liver fibrosis. Greater than 100,000 people in the U.S. are believed to be homozygous (i.e. having identical pairs of genes for any given pair of hereditary characteristics) for the mutation that causes the liver disease, and at least 20% of those people, and potentially a significantly higher fraction, are believed to have liver-associated disease as a consequence. We plan to seek a risk-sharing collaborator for this program before we file regulatory clearances to initiate a clinical trial, likely in the second half of 2018. For competitive reasons, the Company has not yet publicly disclosed the target gene or disease.
Hypercholesterolemia (PCSK9-targeted therapy)
We are using our GalXC RNAi platform to develop a therapeutic that targets the PCSK9 gene for the treatment of hypercholesterolemia. The Company has selected a provisional clinical candidate for the program but is continuing to explore ways to further optimize the program. PCSK9 is a validated target for hypercholesterolemia, and there are U.S. Food and Drug Administration (FDA)-approved therapies targeting PCSK9 that are based on monoclonal antibody technology. Based on preclinical studies, we believe that our GalXC RNAi platform has the potential to produce a PCSK9-targeted therapy with attractive commercial properties, such as small subcutaneous injection volumes and less frequent dosing.
Additional Pipeline Programs
We have developed a robust portfolio of additional targets and diseases that we plan to pursue either on our own or in collaboration with partners. We have applied our GalXC technology to multiple gene targets across our disease focus areas of chronic liver diseases, cardiovascular diseases and rare diseases. Pursuant to our strategy, we are seeking collaborations with larger pharmaceutical companies to advance our programs in the areas of chronic liver diseases and cardiovascular diseases. Both these disease areas represent large and diverse patient populations, requiring complex clinical development and commercialization paths that we believe can be more effectively pursued in collaboration with larger pharmaceutical companies. For our additional rare diseases, we are continuing to assess their potential for clinical success and market opportunity while optimizing our GalXC molecules. For our additional pipeline programs (including PCSK9), we utilize more advanced versions of our GalXC technology, that further improve pharmaceutical properties of the GalXC molecules, including enhancing the duration of action and potency. We have further optimized our GalXC technology platform, enabling the development of next generation GalXC molecules. Improvements to our GalXC compound include modification of the tetraloop end of the molecule, which can be applied to any target gene and program, resulting in a substantially longer duration of action and higher potency of target gene silencing in animal models across multiple targets. Modification of the tetraloop only impacts the passenger strand and does not impact the guide strand. These modifications are unique to our GalXC molecules and, we believe, provide a competitive advantage for the Company.