At the 2018 European Association for the Study of the Liver (EASL) International Liver Congress (ILC), Arrowhead Pharmaceuticals presented positive results for its ribonucleic acid interference (RNAi) drug candidate ARC-520, which is being investigated for the treatment of chronic hepatitis B.

When co-administered with the antiviral entecavir, ARC-520 cleared the hepatitis B surface antigen (HBsAg) from one patient and substantially reduced its levels in the remaining participants of the eight-person study. Notably, ARC-520 was well-tolerated and produced sustained host responses. GlobalData believes that accumulating clinical evidence from Arrowhead and other RNAi companies like Alnylam is positioning RNAi as a strong future therapeutic strategy for hepatitis B and other infectious diseases.

Chronic hepatitis B is a serious liver disease that affects over 350 million people worldwide. There is no cure for chronic hepatitis B, which arises from acute hepatitis B virus (HBV) infection and becomes a lifelong affliction for most patients. According to key opinion leaders (KOLs) interviewed by GlobalData, currently available antivirals for HBV are substantially better at suppressing viral replication than older interferon-based regimens. However, experts maintain that eradication of HBV is the only means to prevent reactivation and remains a critical unmet need for current treatment options.

Arrowhead has been steadily advancing its RNAi technology in recent years, entering ARC-520 into a Phase II trial in 2014 and winning an FDA Orphan Drug Designation in 2015 for ARC-AAT, its alpha-1 antitrypsin deficiency drug. A major setback came in 2016 when several primate deaths in preclinical assessment of ARC-520 forced Arrowhead to pull its Phase II trial and drop the drug from its pipeline.

Accordingly, the results for ARC-520 presented at this year’s IRC were from an expansion to an earlier clinical trial (Heparc-2001), rather than an ongoing program. Arrowhead has since rebounded with a safer RNA delivery platform, and its revamped ARO-HBV vaccine for hepatitis B is now in Phase I/IIa clinical development. The company is banking on the possibility that ARO-HBV will replicate the success of ARC-520 in achieving HBsAg clearance, while minimising toxicity.

RNAi’s clinical potential

As a novel therapeutic technique, RNAi has the potential to address targets normally inaccessible to small molecules. Key opinion leaders interviewed by GlobalData expressed optimism about the future of RNAi as a clinical approach, tempered only by a desire for more clinical data.

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Unsurprisingly, Arrowhead is not alone in exploring this therapeutic space. Alnylam leads the field of RNAi, with several programs targeting genetic, cardio-metabolic and hepatic infectious diseases. Its most advanced product, patisiran, is expected to obtain a landmark FDA approval in the next year for treatment of hereditary ATTR amyloidosis, becoming the first commercialized RNAi therapeutic. Another player, Ionis Pharmaceuticals, has two antisense drugs (IONIS-HBVRx, IONIS-HBV-LRx) in Phase II clinical trials to target viral proteins associated with human papillomavirus (HPV).

In the face of stiff competition, Arrowhead has stocked its pipeline with diverse early-stage programs, including renal cell carcinoma therapy ARO-HIF2 and a pair of drugs for hypertriglyceridemia. The company has also partnered with Amgen in a $674m pact to develop therapies against genetically validated targets implicated in cardiovascular diseases. Regardless of which company ultimately emerges on top, GlobalData believes that the collective efforts of RNAi industry leaders are close to bringing a valuable new tool to the clinic, and with it a possible means to cure chronic infectious diseases like hepatitis B.

Related reports

GlobalData (2018). Conference Review: ILC 2018: NASH Therapeutics Dominate This Year’s International Liver Congress, April 2018, GDHC1714EI

GlobalData (2018). Expert Insight: VBI Vaccines Pursues Future Hepatitis B Vaccine Showdown with Dynavax, January 2018, GDHC1559EI

GlobalData (2016). Conference Review: While Challenges Remain, Treatment of Hepatitis B Advances Slowly Yet Surely, May 2016, GDHC1080EI

GlobalData (2016). PharmaPoint: Hepatitis B Virus (HBV) Therapeutics – Global Drug Forecast and Market Analysis to 2024, January 2016, GDHC117PIDR

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