A GalXC far, far away

Collaboration to explore RNA interference therapeutics for liver disease

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INGELHEIM, Germany & CAMBRIDGE, Mass.—Global research-driven pharmaceutical company Boehringer Ingelheim (BI) has announced a research collaboration and license agreement with Dicerna Pharmaceuticals, a developer of investigational RNA interference (RNAi) therapeutics and inventor of the GalXC technology platform. The partnership will allow a joint effort to develop novel GalXC RNAi therapeutics for the treatment of chronic liver diseases, with an initial focus on nonalcoholic steatohepatitis (NASH).
The collaboration combines BI’s capabilities in drug discovery, expertise in the cardiometabolic space and proven commercial experience with Dicerna’s GalXC technology platform and scientific approach focused on the development of investigational RNA interference (RNAi) therapeutics. RNAi therapies carry the potential to treat many diseases—including rare diseases, chronic liver diseases, cardiovascular disease and viral infectious diseases—by silencing some of the most well-validated drug targets that have nevertheless remained inaccessible with conventional therapies.
“Boehringer is a natural partner to speed the development of the first GalXC RNAi program targeting chronic liver disease,” says Jim Weissman, chief business officer of Dicerna Pharmaceuticals. “The collaboration combines the strong capabilities of both companies to pursue the full potential of our GalXC technology to bring valuable and differentiated RNAi therapies to patients with liver diseases.”
GalXC is a proprietary technology platform of Dicerna’s invention. The platform facilitates the development of subcutaneously administered RNAi-based therapies designed to silence disease-driving genes in the liver across multiple therapeutic areas, including rare diseases, chronic liver diseases, cardiovascular disease and viral infectious diseases.
“Each GalXC molecule is a chemically optimized, double-stranded RNA designed to potently induce RNAi,” explains Weissman. “We attach N-acetyl galactosamine sugars to one or more points on GalXC compounds, yielding multiple effective and proprietary conjugate delivery configurations. These molecules specifically bind to highly expressed asialoglycoprotein (ASGPR) receptors on the target cells, leading to internalization via endosomes and access to the RNAi machinery within the cells. Within the endosome, the ASGPR releases the GalXC and recycles to the cell surface, enabling delivery of the GalXC into the cytoplasm of the cell (hepatocytes in the liver).”
According to Weissman, in preclinical studies GalXC compounds have demonstrated potency on par with or better than comparable platforms, high specificity to their gene targets and long duration of action. They also offer a convenient subcutaneous route of administration.
Under the terms of the agreement, BI agreed to make an upfront payment of $10 million to Dicerna. Dicerna is eligible to receive up to $191 million in potential development and commercial milestone payments, and research and development reimbursement for a GalXC candidate product addressing an undisclosed NASH target. Dicerna also stands to receive royalty payments on potential global net sales, subject to certain adjustments, tiered from high-single-digits up to low-double-digits. BI retains an option to add a second target in exchange for additional payments to Dicerna, including an option fee payment, success-based development and commercialization milestones and royalties.
The collaboration will initially focus on investigating RNAi therapeutic options for NASH, a chronic liver disease caused by buildup of fat in the liver, for which there is no approved treatment. Weissman estimates that about 20 percent of all people with nonalcoholic fatty liver disease (NAFLD)—one of the most common causes of liver disease in the United States—have NASH. It has an especially high prevalence among obese and diabetic patients, and is an area of high unmet medical need. NASH is among the most common causes of advanced liver disorders including liver fibrosis and cirrhosis, and the disease often necessitates liver transplantation.
“Boehringer Ingelheim has a long history of excellence in the discovery and development of medicines for cardiometabolic diseases,” says Michael Mark, head of research for cardiometabolism at Boehringer Ingelheim. “The cardiometabolic diseases pipeline and discovery focus extends beyond type 2 diabetes and anticoagulation. We focus on innovative drugs for the treatment of the devastating consequences of diabetes or on concomitant diseases like NASH/liver diseases. Furthermore, obesity is an important underlying reason for the development of diabetes and is also part of our research and development efforts.”
“As the opportunity to work together advanced through the deal-making process, [Boehringer Ingelheim] demonstrated keen collaborative spirit and teamwork and impressed upon Dicerna their ability to be a great partner,” Weissman tells DDNews. “This partnership complements both companies’ existing research efforts and expertise.”
Dicerna is building a portfolio of research and development programs to advance the treatment of diseases involving the liver, leveraging its proprietary GalXC technology to develop innovative RNAi therapeutics. Dicerna filed a clinical trial application (CTA) for its lead GalXC product candidate, DCR-PHXC, in October 2017, which is currently in Phase 1 trials. According to Weissman, the company expects to file additional CTAs and/or IND applications in 2018 and 2019. Dicerna currently has three priority therapeutic programs and a series of programs in the clinical candidate selection stage.
“Our three priority programs are: DCR-PHXC for the treatment of primary hyperoxaluria (PH); a program against an undisclosed rare disease; and DCR-HBVS for the treatment of chronic hepatitis B virus (HBV) infection,” Weissman reports. “Our programs in clinical candidate selection include DCR-PCSK9 for the treatment of hypercholesterolemia, for which a provisional clinical candidate has been selected, and multiple programs targeting undisclosed targets in chronic liver diseases, cardiovascular diseases and additional rare diseases.
“At Dicerna, we believe that strategic partnerships, research collaborations and licensing arrangements should add value to both parties, assisting each in attaining goals beyond those that could be achieved individually.”

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