Therapy focus – Hepatitis B developers try to repeat Gilead’s hep C trick

When Roche pulled out of an alliance with Inovio two weeks ago to develop a hepatitis B treatment, it might have seemed like the Swiss giant was calling time on a disease that already had approved therapies in addition to a 95%-effective vaccine.

Nothing could be further from the truth, and a search of EvaluatePharma reveals Roche to be one of the most prominent developers of hepatitis B therapeutics (see table below). It is not the only big gun that sees potential here – Gilead and Johnson & Johnson are also active, as are several small biotechs whose investors will be keenly awaiting the outcome of mid-stage trials.

Undoubtedly the reason behind this excitement is the market’s desire to find the next disease similar to hepatitis C. Development of a functional hep C cure with the drugs Sovaldi and Harvoni turned Gilead from a big biotech into a huge one whose market cap now outstrips that of Lilly and AstraZeneca.

While clearly there are similarities between hep B and C, the former has vaccines, and many infected patients are in the developing world. Acutely infected patients often recover spontaneously, but chronic infection can cause liver cirrhosis, and hep B is actually seen as harder to treat than hep C.

Approved current treatments for hep B comprise interferon and old HIV antivirals, implying side effects and no curative efficacy – viral replication can be suppressed but patients must be treated chronically. Several companies are working on novel prophylactic hep B vaccines, but this analysis looks only at treatments for already infected patients.

Mechanisms

Unfortunately Roche has not disclosed the mechanisms behind its three clinical-stage hep B antivirals, RO6864018, RO7020322 and RG7834.

Presumably it saw more promise in these than in Inovio’s INO-1800, a DNA vaccine aiming to stimulate an immune response against surface and core antigens (Inovio gets the final farewell from Roche, August 4, 2016). Therapeutic vaccines are also being pursued by Transgene – with a large fusion protein comprising a core, polymerase and envelope domains – Altimmune and Aicuris.

However, the most important contender in hep B therapeutic vaccines is Gilead itself, with GS-4774, a project licensed from Globeimmune and in phase II in treatment-naive patients. A phase II study in virally suppressed subjects failed last year.

In phase II Gilead also has GS-9620, one of several small molecules in development. This agonises toll-like receptor 7, based on the theory that this stimulates an interferon response critical to developing broad, protective immunity; Roche also had a TLR7 agonist, ANA773/RG7795, but this completed phase II and has not appeared in the Swiss group’s pipeline since 2012.

Hepatitis B therapy pipeline
Project Company Pharmacology Trial ID Data due?
Phase II
GS-9620 Gilead Sciences TLR7 agonist NCT02166047 & NCT02579382 Imminent & Dec 2016
GS-4774 Gilead Sciences/Globeimmune Therapeutic vaccine NCT02174276 Imminent
Myrcludex B Hepatera Viral entry inhibitor NCT02637999 Imminent
REP 2139 Replicor HBsAg release inhibitor NCT02726789 Sep 2016
ARC-520 Arrowhead Pharmaceuticals RNAi therapeutic NCT02604199 and 4 others Oct 2016
ARB-1467 Arbutus Biopharma RNAi therapeutic NCT02631096 Oct 2016
CMX157 Chimerix/Contravir NNRTI NCT02710604 Oct 2016
GC1102 Green Cross (Korea) Recombinant hep B immunoglobulin NCT02569372 May 2017
RO6864018 Roche Not disclosed NCT02391805 Sep 2017
SB 9200 Spring Bank Pharmaceuticals RIG-I & NOD2 activator NCT02751996 Dec 2017
REP 2165 Replicor HBsAg release inhibitor NCT02565719 Sep 2018
Phase I
NVR 3-778 Johnson & Johnson Capsid inhibitor NCT02401737 Imminent
JNJ-56136379 Johnson & Johnson Not disclosed NCT02662712 Nov 2016
IONIS-HBV-LRx GlaxoSmithKline/Ionis Hepatitis B antisense NCT02647281 Nov 2016
HepTcell (FP-02.2) Altimmune Therapeutic vaccine NCT02496897 Feb 2017
RO7020322 Roche Not disclosed NCT02604355 Apr 2017
ARC-521 Arrowhead Pharmaceuticals ccc DNA-targeting RNAi NCT02797522 Jun 2017
TG1050 Transgene Therapeutic vaccine NCT02428400 Mar 2018
INO-1800/RG7944 Inovio Pharmaceuticals Therapeutic vaccine NCT02431312 Dec 2018
RG7834 Roche Not disclosed (1st pt in Q4 2015)
AIC649 Aicuris Therapeutic vaccine
EYP001 Enyo Pharma Farnesoid X receptor agonist
GSK3228836 GlaxoSmithKline/Ionis Hepatitis B antisense
Source: EvaluatePharma and Clinicaltrials.gov.

Hep B might be a tough nut to crack, but it actually presents many different targets, which explains the variety of mechanistic approaches being employed against it. Either the host can be targeted – this is the goal of TLR7 agonists and therapeutic vaccines – or the virus itself.

Hepatera’s Myrcludex B, for instance, aims to prevent entry of the virus into the host cell, while other approaches attempt to hit viral processing such as encapsidation or replication, or secretion of HBsAg, a viral protein detectable in the blood of acute and chronic hep B patients; Replicor’s REP 2139 and REP 2165, and Spring Bank’s SB 9200 all ultimately target HBsAg.

J&J last year bought Novira, a private US biotech whose small molecule NVR 3-778 is a capsid inhibitor. Meanwhile another private biotech, Enyo Pharma, is developing EYP001, a farnesoid X receptor agonist aiming to hit another aspect of viral processing – the formation of covalently closed circular DNA (cccDNA), which is thought to act as a reservoir of infection.

Also targeting cccDNA is Arrowhead’s ARC-521, though like Arbutus’s ARB-1467 this is an RNA interference project. For small company watchers these and the related approach of RNA-targeted antisense, where Ionis has two phase I assets over which GlaxoSmithKline has an option, might be a particular focus.

Arrowhead recently started Monarch, one of six phase II trials of its lead asset, ARC-520, which it says interferes at the mRNA level upstream of the reverse transcription process. Interestingly, it was Roche that, for next to nothing, sold Arrowhead its RNAi technology back in 2011 (EP Vantage interview – Arrowhead looks to evolve beyond the chimp, November 1, 2013).

The Swiss group might have given up on RNAi and on Inovio’s vaccines, but it certainly has not given up on hep B.

To contact the writers of this story email Jacob Plieth or Amy Brown in London at news@epvantage.com or follow @JacobPlieth or @AmyEPVantage on Twitter

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