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.
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?|
|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|
|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|
|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)|
|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.