I really don't think it is going to come down to a non-inferiority trial. nm-283 at 24 weeks already has a viral undetectable rate of 68%, and there will be enough disparity in svr i am guessing to show superiority over soc (which lets remember in gen-1 is NOT 50% but rather 45%)
Overall, the nm-283 data is impressive, and based on toxicity alone (i.e. doing without ribavirin), is highly likely to make it through as gofish intimates, but I really think the data will bear out an improvement of 10% or so in svr as well
so it's not chance of approval per se that is really the question imo, but rather what role will nm-283 have in a treatment landscape if vx-950 achieves superior svr? That is the real question, and if it weren't for vx-950, nm-283 would be viewed as the next soc and an up and coming billion dollar drug and share price woudl be several multiples above today's value
so in my view the critical issue is the role (if any) of other antivirals with inferior activity to vx-950 (or any other best in class agent), assuming nm-283 is active but inferior (an assumption i am not quite ready to concede but realize is a distinct probability). this will depend on several factors, including
1. the impact on svr of combining more than one direct antiviral over monotherapy with a direct antiviral (with int-+/- riba)
2. the role of a second direct antiviral in the setting of resistance to soc
3. the role of antivirals in special populations (e.g. HIV/hepC coinfection, reinfection, flares following immunosuppression, etc.)
the answer to #1 will take some time, and certainly the superior monotherapy (with immne boosters) will be dominant in the marketplace pending outcome of such combination trials (which i would guess will also have non-inferiority arms to try and minimize interferon/riba toxicity)
the answer to #2 is going to be the most germane point with regard to the commercial potential of nm-283 IF it is found to be inferior to other direct antiviral(s)
#2 essentially hinges on the behavior of the hep C virus, namely is there some element of chronicity and emergence of drug-resistant strains demanding ongoig emergence of new agents with novel mechanisms and sites of action(e.g. HIV), or is it going to be like a common cold or other mroe traditional viruses that can be eliminated, and where drug resistance is really a non-factor. The VErtex mindset is the latter, and they feel the small degree of resistance that emerges can be "mopped up" by the immune system and drug resistance won't be a factor. Others feel resistence will inevitably emerge. no one really knows
Personally, i am guessing resistant strains will emerge and there will be a need for follow on agents, and they will play mroe than a minor "backup" role in this disease (perhaps not quite like HIV but close). I feel this way primarily because although Hep C does not integrate in the genome, and can certainly be held in check by the immune system post-therapy, it is never really eradicated. One need look no farther than data in immunosuppressed patients, in whom reactivation infections happen almost universally (e.g. post-liver transplantation)..so there must be some extrahepatic store of virus even after an svr is achieved. this tells me somewhere along the way, this virus will mutate and become reactivated and someone will get infected with a strain that has previously seen a first line agent and is now resistant, and we will need second-line agents (jsut like for bacteria) to manage the drug resistance.
#3 is also complicated, and no one really knows what regimen(s) will prove most effective, but it stands to reason svr will be much lower in HIV/HepC coinfection, and combinations will prove superior given the lack of immune support in these patients
that's my take..i'm sure there are flaws in my thinking/analysis, and please feel free to share if you've been able to get through this drivel;)
have a nice weekend everyone
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