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德克Haussecker（作者）是一个投资者，而不是乙肝病毒专家，他是RNAi专家
Thursday, August 6, 2015
Arrowhead Research Believes ARC520 Ready to Shine
On Tuesday, Arrowhead Research announced further pipeline expansion with ARC-F12 chosen to become its third DPC-based clinical RNAi candidate, this time for the treatment of hereditary angioedema.
Although this could have been used by the company as an opportunity to distract investor attention from the mechanistically riskier lead HBV program for which a much-anticipated Analyst Day is coming up on September 24, Arrowheadd chose to spend most of its earnings call on HBV-targeting ARC520.
To sum it up, the company said that it now believes that it has gathered sufficient insights into HBV biology and ARC520 action that it is ready to take on the functional cure challenge to be tested in a key upcoming phase IIb (multi-dose!) combination study of ARC520 with other HBV-agents, dubbed the MONARC(H) study.
Knockdown at low doses below expectations
To wit, early results from ARC520 in HBV patients late last year has caused much investor angst and anger triggering a couple of 'I-don't-take-reponsbility-for-my-investment-decisions' lawsuits alleging the company of having set expectations too high
Well, they accuse management of 'over-promising', but since when is this illegal anyway; would recommend paying attention to the forward-looking statement safe harbor once in while).
Accordingly, at 2mg/kg, there was ‘only’ a, albeit rapid and prolonged ~50% knockdown of the HBV surface antigen (HBsAg) following a single dose of ARC520.
This was also below my expectations not only based on the preclinical data, including data from a single chimpanzee in 2013, but also data from its other DPC-based development programs in what should otherwise be highly predictive monkey models.
Hepatitis e-antigen coming into focus
HBV biology is complex, and one of the attractions of an RNAi approach for HBV is that it can target the expression of not just one gene, but all of the gene products. This raises the hope that as more recent interferon-nuke combination studies show that HBV might be more vulnerable than previously thought when tackled in the proper sequence and in right combination that a pan-mRNA targeting agent might mess up HBV enough so that an effective T-cell response can be mounted against it.
Arrowhead has thus started to emphasize that it is not just targeting immune suppressive HBsAg, but also other HBV gene products. At the same time, the clinical development program has strongly shifted from e-antigen negative chronic HBV patients in the single-dose Hong Kong study (Heparc 2002 1-4mg/kg) to e-antigen positive HBV patients in the imminent multi-dose studies in the US, Europe, and Asia.
Since you would expect single-dose data in e-antigen positive patients to be desirable before multi-dose studies from a regulatory/safety and scientific point-of-view, it is my expectation that at least some of the newly added 3 cohorts in the HK 2002 study involve e-antigen positive patients (most likely single-dose).
Is it possible that the e-antigen is playing a more prominent role in immune evasion than previously thought and that the e-antigen positive state of the one chimpanzee (which also did not receive concomitant nukes) facilitated the chimpanzee apparently mount a desired immune response?
E-antigen a natural candidate for being immune suppressive
When considering the natural history of HBV infection, HBeAg stands out as the natural candidate for serving an immune suppressive role.
First of all, unlike HBsAg, HBeAg is not required for HBV replication and spread per se. In fact, most people lose it during the course of their infection and continued viral replication. Since immune evasion is the 3rd most important task of a successful virus next to replication and spread, this would be the expected task of HBeAg.
Also remember that the HBV population can be broadly divided into two buckets. In the first, young (typically Asian) people are infected around birth or early childhood. It is highly interesting that they are in an immune tolerant state for a number of years, meaning that the virus can replicate to high titers yet is not seen by the immune system.
They also happen to be e-antigen positive during this period.
As they, however, enter adulthood, most develop chronic hepatitis reflected by flares in liver enzymes. This is also the time when some of them either clear the virus or enter the e-antigen negative state.
This is consistent with e-antigen serving an immune suppressive role, yet when it disappears or it becomes ineffective in serving such a role due to changes in the state of the ageing immune system, it becomes a liability and those viruses without it (e-antigen negative) take over (and HBsAg takes over in serving the main immune suppressive function).
It is interesting to speculate that an agent like ARC520 might be most successful in this young population.
In the Western world meanwhile it is in adulthood that people become infected with HBV. Although this is a surprisingly understudied area, it is my understanding from the literature that it is only HBeAg positive strains that can establish an infection. Although the vast majority (~90%) of those exposed to HBV in adulthood go through an acute (some fulminant) hepatitis episode and clear the virus, successful chronic infection persists in ~10%. Many of these will go on to seroconvert to e-antigen and become e-antigen negative.
The strict requirement for HBeAg in establishing an infection also in adulthood further strongly supports a key immune suppressive role for this protein.
Expectations for Analyst Day and beyond
With the above in mind, let’s speculate what might play out at Analyst Day and beyond.
On September 24, the company wants to present more or less complete data from the Heparc2002 HK study, including the unblinded results from the single-dose 3-4mg/kg cohorts and from 2 if not 3 of the newly added cohorts (note: one cohort is blinded so I am not sure whether there is enough time to gather the results for this event- hence two cohorts that are open-label).
As indicated above, I expect the new cohorts to involve e-antigen positive patients and to be single-dose.
For the 3-4mg/kg cohort, my hope is that they will reach an HBsAg knockdown of around 80%. Keep in mind, this is single-dose.
The much more important data, however, should come from the yearlong study in 8 chimpanzees the existence of which the company disclosed a quarter ago. Arrowhead Research is now saying that it has learned a lot from these to guide them in their crucial upcoming combination studies.
While I hate to set overly ambitious expectations for the chimpanzee results, also in light of the fact that functional cures (=s-antigen negative/seroconversion) are known to often occur long after interferon treatment (the only agent known to facilitate meaningful functional cure rates), it is my hope that they provide strong indications as to which treatment strategy, including combinations (nukes, interferons) e-antigen positive/negative state, immune tolerant/silent/active, will lead to functional cures.
It is worth keeping in mind that with 8 chimpanzees this is an ambitious task considering the potentially many variables, but when do you get the chance to test your drug in 8 chimpanzees anyway?
The tremendous upside, of course, is that if these studies indeed provide a clear path forward, the ‘theory risk’ of the ARC520 program will have been reduced tremendously given that HBV infection is essentially the same in chimpanzees and humans.
The final validation would then come from the multi-dose MONARC(H) study which should get underway in early 2016. Here, Arrowhead Research will test ARC520 (taking foot off immune brake) in combination with likely first either nukes or (immune booster) interferon. Arrowhead has also noted in the conference call that it has given ‘a lot of thought’ to combining ARC520 with other, likely investigational agents, but that given the early-stage nature of those, these might be few and far between.
The kicker is that these studies are open-label and flexible in their design so that the company can learn and adjust in real-time just as Pharmasset had done in developing fabled HCV blockbuster Sovaldi.
From a stock perspective, Arrowhead Research might be a year or so away from where comparable companies in the HCV space before (Vertex, Pharmasset) had been valued considerably higher before.
Disclosure: long ARWR. Here's why.
Market cap: $400M,
Growing pipeline (ARC520, ARC-AAT, ARC-F12)
RNAi delivery platform with broadest potential
Strong platform technology safety profile, including 6-9 month rat/monkey
Strong knockdown efficacy in non-human primates and apparently humans (à AAT)
Strong platform IP, including assets from Roche, Novartis, and others (àlow royalty
payments)
HBV and AAT first-mover (IP, including regarding combinations, and natural combo partner).
Hungry and capable management and scientific teams.
Invest at your own risk.
Posted by Dirk Haussecker at 4:12 AM Email |
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楼主: crystalandtiger
发表于 2015-8-5 17:22
