Dicerna president and CEO Douglas M. Fambrough III, PhD.

Roche will partner with Dicerna to develop and commercialize the Phase I chronic hepatitis B virus (HBV) candidate DCR-HBVS, as well as discover and develop additional HBV treatments, through a collaboration that could generate more than $1.67 billion for Dicerna.

DCR-HBVS is designed to function by using RNA interference to selectively knockdown specific genes involved in the creation of HBV messenger RNA (mRNA) and the entry of the virus into liver cells.

“Preclinical studies with a standard mouse model of HBV infection showed DCR-HBVS led to greater than 99.9% reduction in circulating HBV surface antigen (HBsAg), suggesting superior HBsAg suppression—both in magnitude and duration of suppression—compared to targeting within the X gene sequence region,” Dicerna president and CEO Douglas M. Fambrough III, PhD, told GEN. “With existing therapies, specifically nucleoside-based viral polymerase inhibitors combined with interferon, the depth of HBsAg suppression correlates with likelihood of functional cure.”

Dicerna has said DCR-HBVS is likely to work better than current therapies for HBV, such as nucleoside analogs, which can provide long-term viral suppression upon continuous use but rarely lead to long-term functional cures, as measured by the clearance of HBV surface antigen (HBsAg) and sustained HBV deoxyribonucleic acid (DNA) suppression in patient plasma or blood.

DCR-HBVS is being studied in a Phase I trial (NCT03772249) designed to study the drug’s safety and tolerability compared with placebo in healthy volunteers and patients with non-cirrhotic chronic HBV infection. The study has an estimated enrollment of 56 participants, with an estimated primary completion date of May 2020.

Dicerna discovered DCR-HBVS through its proprietary GalXC™ RNAi platform technology, which uses liver-targeted GalXC-based compounds to enable subcutaneous delivery of RNAi therapies designed to specifically bind to receptors on liver cells, leading to internalization and access to the RNAi machinery within the cells.

The companies have agreed to use GalXC and other platform technologies to discover and develop additional HBV treatments that targeting “multiple” additional human and viral genes.

“The collaboration brings together Dicerna’s DCR-HBVS already in Phase I development, and Roche’s deep expertise in HBV, best-in-class pipeline of other HBV modalities, and proven development and commercial capabilities, creating an opportunity to develop and deliver a best-in-class combination therapy and potential cure for chronic HBV infection to patients on a global scale,” Fambrough said.

Two-prong approach to HBV “cure”

Fambrough cited Roche’s expertise in HBV and established global infrastructure: “Roche is ideally suited to help us accelerate the development and commercialization of DCR-HBVS, pursue a cure for chronic HBV infection, and address this serious global threat to public health.”

HBV and other infectious diseases are one of Roche’s therapeutic areas of focus: “Roche’s strategy to achieve a cure with finite, short-term treatment involves combining two very different approaches to eliminating the virus. The first targets the HBV life cycle (direct antivirals), while the second boosts the immune system’s ability to clear HBV (immune enhancers).”

Roche’s pipeline lists five treatment candidates, all in Phase I development. In addition to RG6084 and RG6217, which are not detailed on the company’s website, Roche’s HBV candidates include:

  • RG6004, which incorporates HBV LNA, a liver-targeted locked nucleic acid oligonucleotide designed to inhibit hepatitis virus gene expression by specifically targeting viral mRNAs.
  • RG7854, a toll-like receptor (TLR) 7 agonist oral, small molecule immuno-modulator designed to work by activating TLR7, and to a lesser extent TLR8.
  • RG7907, a CpAM oral small molecule, class I HBV core protein allosteric modulator designed to disrupt HBV nucleocapsids assembly and induce the depletion of functional core proteins, thereby effectively inhibiting HBV replication.

Roche agreed to pay Dicerna $200 million upfront and an additional up to $1.47 billion tied to achieving development, regulatory, and commercial milestones. Dicerna may also be eligible to receive royalties from Roche based on potential product sales of DCR-HBVS.

Dicerna has retained an option to co-fund pivotal development of DCR-HBVS worldwide. Should that option be exercised, Dicerna would be entitled to receive enhanced royalties and co-promote products including DCR-HBVS in the United States.

“The collaboration provides additional cash resources to expand and advance our pipeline of GalXC therapies across a growing number of targets and therapeutic areas,” Fambrough said.

He added that the agreement also supports and fulfills Dicerna’s long-term business strategy.

“For more complex diseases with multiple gene dysfunctions and larger patient populations, the company plans to pursue partnerships that can provide the enhanced scale, resources, and commercial infrastructure required to maximize these prospects,” Fambrough explained. “For diseases with focused patient populations, such as certain rare diseases, as we retain a full or substantial ownership stake and invest internally.”

Separate from the Roche collaboration, Dicerna continues to develop its proprietary pipeline. The company’s lead product candidate, DCR-PHXC for the treatment of all forms of primary hyperoxaluria, is in a Phase II pivotal trial. The company is also developing DCR-A1AT for the treatment of alpha-1 antitrypsin (A1AT) deficiency-associated liver disease, which is in a Phase I/II trial.

Advancing RNA-based HBV candidates

Roche is not the only pharma giant seeking to develop an RNA-based HBV treatment. In October 2018, Johnson & Johnson’s Janssen Pharmaceuticals and Arrowhead Pharmaceuticals launched a potentially more than $3.7 billion collaboration to develop an RNA interference (RNAi) treatment candidate for hep B, plus up to three other RNAi therapies against targets to be selected by Janssen, through a collaboration Arrowhead said could generate for it more than $3.7 billion.

At the International Liver Congress™ 2019, the annual meeting of the European Association for the Study of the Liver (EASL) in April, Arrowhead presented Positive Phase I/II clinical data for JNJ-3989 (ARO-HBV). The data showed JNJ-3989 rapidly reducing HBsAg in patients that had 24 weeks or more of HBsAg assay results to thresholds possibly associated with improved chances of HBsAg seroclearance in many patients, after only three doses. JNJ-3989 was also shown to reduce all measurable viral products, including HBsAg in hepatitis B e-antigen (HBeAg) positive or HBeAg negative patients.

Arrowhead has since expanded the Phase I/II study to include a new triple combination cohort that includes: JNJ-3989, as well as JNJ-6379, Janssen’s investigational orally administered capsid assembly modulator of the class that forms normal capsid structures; and, a nucleos(t)ide analog, or NUC. In connection with the start of dosing of the cohort, Arrowhead earned a $25 million milestone payment from Janssen.

And on August 27, GlaxoSmithKline (GSK) exercised its option to license Ionis Pharmaceuticals’ RNA-targeting antisense treatments for people with chronic HBV infection—IONIS-HBV-LRx and IONIS-HBVRx—following positive Phase II results. GSK agreed to pay Ionis license fees and milestone payments up to $262 million, including a $25 million license fee. Ionis is also eligible to receive tiered royalties in the low double digits on net sales. GSK is now responsible for all development, regulatory, and commercialization activities and costs.