Great post. Approvals based on subsets are rare, and there are usually sound reasons for this. Approval without a confirmatory study, or addition to a label, does occur when the overall study is positive and the subset is plausible. The problem is that even with pre-hoc identification there are many possible subsets and this raises issues of multiplicity. And if the overall study is not significant, one has to see what removing a "positive" subset does to the comparison with the remaining population. It can occur that that remaining population then looks worse than control. It's too bad this study was designed as it was, seems underpowered or poorly anticipating the activity of the control arm.
Much depends on what was actually inked, and if that level of detail is ever revealed. The NVS announcement is sort of coy about if this was a strategic decision - ie we like this approach but want to focus elsewhere with our resources but keep a hand in- or a technical one - ie we have data suggesting for whatever reason this stuff isnt worth much.
All that said big Pharma often make mistakes this way, and just as well ARWR has the rights.
I agree that ALNY seemed to be taken off-guard on this one. I just wish ARWR could have been a little classier and a little less promotional. Why rise to any bait if you think you came out ahead?
They could have avoided lots of problems by saying this in conjunction with release of the primary EP for efficacy at 27 weeks. That said, for AODM they will need to show a durable effect on HBA1C, and long-term tolerability. It looks like they can, but the explanation you got and their behavior seems amatuerish. "Top-line" by definition means the pre-hoc endpoints specified in the protocol, and they did not release those, only post-hoc. The clintrials posting makes it clear the prespecified efficacy EP was at 27 weeks. What makes this a bit more dicey is that if in fact your post reflects what was said to you, to suggest the 38 week efficacy endoint is meaningful they now have to show a steady response post-week 27, otherwise 38 weeks will be considered a cherry-picked finding. All IMO, but this could have been handled so much better.
Agree as well. I think the question will be what happens at the higher dose and longer duration. If what we hear is accurate, tox due to basic molecular chemistry of the agent and accumulation is not an issue, so assuming there are no inducible or blocked pathways at higher doses there should not be an issue. Hopefully there will be no off-target or downstream effects either. Hoping the company communictes well on this!
Posters are conflating PK with PD. Duration of tox requirements for filing will be based on the the duration of effect. 7x of T1/2 is applicable for orthosteric agents, but has long been abandoned for biologics, RNA agents etc., as the PD duration is typically longer, often not reversible, and one needs to test for downstream consequences of the MOA. It is simply inaccurate to state that if the drug is gone but the effect persists, that there is no chance of toxicity.
IMO - this is an exercise between two classless organizations. But it's grow-up time. No capable CEO launches a highly touted lawsuit and then says "oops," too busy right now. Compete BS IMO- that's why you pay lawyers. And anyone can google what happens with DOJ investigations. They NEVER go away, and they never help a company. These are truths readily accessible via a Lexis search. Regardless of what one thinks of the product merits, IMO the management here have been ham-handed.
FDA holds will come with a communication about the nature and concern for the hold. The company can decide I suppose, if the reasons are material beyond the communication. More transparency would be nice, but likely with their new lawyer they are getting expert advice.
The Agency does not issue partial holds unless there is concrete cause for action, either clinical or preclinical. The Company release I think was far less than transparent in communicating the issues. Why leave us guessing? IMO poor form.
The facts are going to come out at some point or the company will settle with the government. Their civil claim however, will likely have only downside for them as documents become available. One had to wonder why the leadership want to engage in this sort of distraction if the product is so good. The hiring from other companies the CEO now blames for his woes is documented. Just seems like a mess of their own making. IMO
It is an amateur attempt to distract people from the news, along with his petulant self-righteous remarks about Organogenesis. This is a company that needs professional leadership.