The hepatitis B market is expected to generate $3.5 billion in global revenues by 2021. Estimates suggest that two billion people worldwide have been infected with the hepatitis B virus, and that more than 360 million have chronic (long-term) liver infections. Each year, the virus (and its associated infection) kills around 620,000 people (source). There's no cure, but a market for treatment exists right now, and it's dominated by Gilead Sciences, Inc. (NASDAQ:GILD). The company's most recent approval in the space, a prodrug formulation of its already approved asset Viread called Vemlidy, is the first hepatitis B asset to pick up FDA approval in ten years.
There currently exists a strong market for hepatitis B vaccines, but the currently available options fall down in a number of key areas. The administration schedule is taxing, and often goes uncompleted. There are subsectors of the population (immunocompromised, elderly, diabetic) for which said alternatives just don't generate the immunogenicity required to be considered effective.
The space is in dire need of an upgrade, and this (of course) has not gone unnoticed. A number of companies are working on bringing new generation hepatitis B assets to market, and for the one (or more) that succeeds, there's a large potential reward in gaining access to the above mentioned multi billion dollar sales pot.
Here's a look at four that are leading the pack right now, what the assets underlying the programs in question are, and where each of them is along the development pathway.
Dynavax Technologies Corporation (NASDAQ:DVAX)
Dynavax is probably the most well known of the bunch. The company has been making headlines for its hepatitis B vaccine Heplisav-B since it first submitted for approval back in 2012, but for the most part, these headlines haven't been great. The way hepatitis B vaccines work is by exposing the immune system to an antigen that the hepatitis B virus expresses. In doing this, they trick the immune system into gearing up a response, and this response results in the creation of antibodies that act as a sort of chemical memory - they are ready to attack if the actual virus shows itself in the future. Current generation vaccines express an antigen called the S Antigen and an adjuvant which serves to amplify the immune response. In most cases, the adjuvant is alum (aluminum). Dynavax has stuck with the S Antigen, but has changes the adjuvant to what's called 1018 ISS. The idea is that this adjuvant can generate an amplified response over the alum adjuvant, and data from the company's trial set supports this hypothesis. The numbers show that Heplisav-B generates seroprotection in 95% of patients treated, whereas the current SOC, called Engerix-B, does so in just 81%. It also improves over the latter in the above mentioned sub populations, inducing seroprotection in circa 20% more of said patients that Engerix-B.
But it keeps getting knocked back by the FDA, and the agency - why?
Because there are concerns over its safety. The adjuvant used is, perhaps, so powerful that it can induce the onset of rare autoimmune diseases in patients. There are additional cardiovascular concerns. There's an advisory panel set to convene on July 28, 2017, to discuss efficacy and safety (and no doubt the autoimmune concern will form a major a part of this discussion) and this panel will advise the FDA ahead of a PDUFA of August 10, 2017.
So will the FDA green light the drug?
Probably. It's been a long time coming, and there may be some safety concerns associated with administration, but Dynavax has a strong (and very large) dataset in hand, and the FDA is aware that new alternatives are required in the space right now.
ContraVir Pharmaceuticals, Inc. (NASDAQ:CTRV)
For the second addition to this list, we're shifting from vaccine to treatment. This is the space in which Gilead currently dominates. As a brief introduction to the underlying science here, HBV is much more similar to HIV than it is HCV. That's why Gilead has been able to (for all intents and purposes) cure hepatitis-C, but it's not had a similar success with hepatitis-B. The current standard of care treatment regimen for chronic hepatitis B sufferers is a combination of antivirals, just as is the case with HIV sufferers. And again, just as with HIV sufferers, there are a number of said antivirals that have a different impact, and to a different degree, in different combinations, in different patients. The above noted Viread is by far and away the market leader in this antiviral group, and a common belief in the chronic treatment community is that any cure, or near cure, is going to derive from a combination that revolves around Viread.
ContraVir has taken Viread, and reformulated it to allow for the utilization of polymeraze, which (or so the company hypothesizes) should result in increased bioavailability, and by proxy, reduced systemic exposure (through a reduction in circulating active compound). Reduced systemic exposure should translate to a reduced toxicity, and help to alleviate some of the tolerability issues associated with Viread - specifically, renal toxicity.
The drug, called TXL, is currently under investigation as part of a phase II dose escalation study, which consists of 40 patients spread across four cohorts, receiving four weeks of a once-daily dose of 5, 10, 25, 50, 100, 150 and 200 mg, respectively. The latest update saw the 100 mg dose level reached safely (and green lighted by an independent data safety monitoring board (DSMB)), and the next step is the 150 mg dose. The 150 mg dose is of particular interest as the previous study, a phase Ib, only dosed up to 100 mg.
ContraVir is currently doing the rounds on the conference circuit, so there's plenty of awareness now and to come, and according to its study protocol on clinicaltrials.gov, the trial should have wrapped up by now, meaning we should see some report on the drug's impact in the target population very near term. Safety is the primary on the study, but there's an antiviral activity co-primary, and a number of secondaries should serve up some insight into whether the drug can actually outperform Viread, and if so, can it do so without bringing about some of the toxicity issues associated with the latter.
VBI Vaccines Inc. (NASDAQ:VBIV)
To close out the list, we're heading back to the vaccine side of the space. VBI is working on a similar asset to that of Dynavax, but with a couple of key differences. The drug is a hepatitis B vaccine called Sci-B-Vac, and it's already commercially available in a number of countries across the globe. It's one of two market leading hepatitis B vaccines in Israel, administered to circa 50% of newborns, with the above discussed Engerix-B accounting for the majority of the remaining 50%.
It's not approved in the US, Europe or Canada, however, and that's severly limiting its market potential right now. VBI is working on these regions, and more on that shortly, but first, a quick look at the asset.
Whereas Dynavax's Heplisav-B is a second generation vaccine, VBI's Sci-B-Vac is what's termed a third generation vaccine. VBI has figured out a way to use mammalian cells to encapsulate the antigens that vaccines present to the immune system (as opposed to yeast cells), and this translates to a couple of core benefits over second generation vaccines - all rooted in immunogenicity (which is just another way of saying how quick, and to what degree, the immune system responds to a vaccine).
The first is that the immune system is far more responsive to the mammalian cells, as they mimic the pathogenic nature of the virus that the vaccine is attempting to replicate to a far higher degree. An increased similarity (from the perspective of the immune system) between vaccine and virus translates to an increased immunogenicity, and in turn, an increased degree of seroprotection.
The second is that the company has designed Sci-B-Vac to include three separate antigens (i.e. not just the S Antigen that Heplisav-B presents) in its presentation to the immune system. More antigens increase similarity, and that results in the outcome just detailed in the above paragraph.
All this, in turn, results in the ability to improve immunogenicity in the immunocompromised, elderly and other groups in which Engerix-B falls down, and do so in as little as two doses across the entire patient population, something that neither Engerix-B or Heplisav-B look like they can achieve.
As things stand, VBI has nailed down protocol for a phase III study with the EMA in Europe and Health Canada that should serve to underpin registration in both regions once conducted. The company is reportedly working right now to get to the same position with the FDA, and once it does, we should see phase III initiation.
There's a wealth of safety and efficacy data already available from the administrations in Israel and the other already approved regions, so combined with data collected from what will likely prove a large scale phase III, there should be plenty of evidence to support approval - assuming, of course, the data collected falls in line with legacy numbers.
For VBI, it's this phase III that's going to serve up the major near term catalysts.
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I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.