Tuesday, June 24, 2008

Some More Detail on the "Horse Race" to Phase III for Next-Gen Hep C Drug candidates. . . .

[UPDATED 11:00 AM EDT -- Adam Feurstein at The Street has gotten this story exactly backwards. Exactly. That is my view; that is also the view of several of the more-learned Wall Street analysts, as well (from Feurstein's piece, at the end):
". . . .Cowen & Co. analyst Rachel McMinn views Monday's [Vertex] selloff as an overreaction to expected news. She reiterated her outperform raring [sic] on Vertex.

"We believe that yesterday's [Vertex] sell off was driven by an over-reaction to two-week old information. Timelines for commercial launch of. . . . telaprevir (late 2010/early 2010) are unchanged, and we see 50% upside relative to the market on the basis of this timeframe. While probability of an early 2009 FDA approval is low, we see 100% upside relative to the market under this scenario over the next 6-12 months. . . ."


Some mindless stock-boosters, over at Yahoo!, set me to digging more deeply (background, from my earlier post on Vertex's candidate, here) into what Schering has actually disclosed about its next generation Hep C Drug candidate -- and, what I found is actually rather comical:
". . . .A phase III protocol has been submitted to the FDA and the company is waiting for concurrence from the FDA prior to beginning phase III clinical trials. . . . Schering-Plough is also working through the complex chemical synthetic process to build additional qualified clinical supplies for the phase III clinical trials. . . ."

That was from Schering-Plough's April 21, 2008 Investor FAQs (from the bottom of page 1, to top of page 2, of the PDF file).

Next, in June 2008 (no exact date available), Schering updated its "Product Pipeline Chart" (PDF file), adding this text:

". . . .Phase II

. . . .Boceprevir

In May 2008, Schering-Plough announced that it is initiating two Phase III studies with boceprevir in patients chronically infected with hepatitis C virus (HCV) genotype 1. The compound will remain in Phase II until patient dosing commences in the Phase III trial. . . .

That quote comes from the top of page 2, first column of text, of the "Pipeline" PDF file.

Read together, it is very-likely that FDA has not yet signed off on the SGP Phase III study design. I mean, seriously -- if FDA had cleared Schering's Phase III study designs, wouldn't Schering have very-directly said so?

Perhaps more importantly, it is also increasingly clear that Schering-Plough is having some difficulty (as a matter of physical chemistry) manufacturing adequate supplies of this drug candidate to even begin dosing the Phase III patients -- re-read this, from April 2008: ". . .working through the complex chemical synthetic process to build additional qualified clinical supplies for the phase III clinical trials. . ."

And, that line would actually dove-tail with the odd "asterisked" disclosure on page 1 of the June 2008 "Pipeline" sheet -- about staying in Phase II, until "dosing commences" for the Phase III group.

It is almost humorous: the oft' befuddling-fog -- over at Schering Plough Resaerch Institute -- of only-positive-information. . . . magically becomes as clear as a crisp mountain morning, if one reads about, around, over and through its myriad, disparate disclosures on any given topic. . . . long enough, hard enough and with a truly independent eye.


Anonymous said...

First Schering doesn't need FDA approval to start Phase III trials it's just dumb if you do.

Second when they used the term qualified with regards to drug supply it means they've probably got a toxic contaminant in the mix. Typically this is worked out and it's not a problem from batch to batch. A batch to batch variability might as you say indicate a physicochemical problem, e.g. a toxic enantiomer that's being formed.

Third I've got to complement you on your blog and your comments I've seen elsewhere, very astute.

Condor said...

Thanks for your thoughts, Anon. No. 1 -- You are right, the prudent course is to be sure FDA agrees with one's study design -- to avoid costly reworking, mid-stream.

You are the expert here, but couldn't "qualified" refer to batch-size related problems?

I would think it might mean that going up in batch-scale by a couple orders of magnitude has revealed chemical effects not detectable in the very small scale batching used for Phases I and II.

It could be something as simple as using a new set of stainless steel vats/tubing/connections (impurities in the tubes?), to deliver an active ingredient -- as opposed to glass-piping/beakers used on a bench-top lab set-up, during Phases I and II, given how small the runs needed to be.

In either case, I suspect Schering's disclosures add up to Adam Feurstein getting this story exactly backwards.

Thanks for stopping by -- do check in on us, from time to time -- as we'll always have much more to say. (Heh!)


Anonymous said...

Condor, I enjoy reading your blog.

I agree that it seems the issues are of scaling up to larger batch sizes. Boceprevir formulation and process is likely very complicated with a multitude of steps. However, the issue is less likely one of scale-up to Phase 3 trial batch sizes but rather one of scale up to commercial production which could be an even more significant problem for SP especially in a race to market vs telaprevir for the first oral small molecule inhibitor for HCV.

At Phase 3 it is important for SP to to work out their commercial production batch size process as batches that are produced for Phase 3 trials must be set aside for stability testing in order that data to support commercial product shelf-life as well as data on drug quality are available at time of filing to FDA and other regulatory authorities.

As you can imagine, it would be difficult after Phase 3 trials to change equipment and process for commercial production sized batches as these changes may impact the formulation and level of impurities that could potentially impact on release and shelf-life specifications and putting into question Phase III trial results. Many regulatory authorities require this info as part of their drug application review process. For an oral product that will likely be produced centrally, it is desirable to have a minimum of 24 months shelf-life at time of launch to ensure that there is smooth introduction into the trade.

Of note, I am surprised to hear reports of anticipated commercial availability of these small molecule inhibitors as early as 2010. I think these reports are overly optimistic. There was anticipation a couple of years back that they would be able to get away with 6 months treatment and 6 months follow-up with these inhibitors in combination with standard of care when the current standard treatment duration is 12 months and 6 months follow-up. This may be true, however if we assume the comparative arm in the PIII trials will be 12 months standard of care (as most regulatory authorities would require) and that the trials are yet to be started, one could easily work out the timelines:

Assuming the trial starts today with a 6 month enrollment phase ending in 2008, 12 months treatment, 6 month follow-up and 3 months for database lock and analysis, final results would not be available until 4Q2010 earliest. Add on another 6 months to develop the regulatory filing and minimum 12 months regulatory review, it is unlikely that molecules like boceprevir will likely see the commercial light until end of 2012, beginning of 2013 at the very earliest (possibly just in time for vytorin hard clinical endpoints to arrive???)

That being said, SP is keeping their boceprevir results very close to the chest. On the other hand, Vertex has been much more forthcoming with their Phase 2 clinical data. One must wonder if there are other issues with the product. We know from our HIV experience that resistance is always of concern especially with products that must be taken 3X a day and require close to 100% compliance to avoid emergence of resistant variants. As with anything else, what is not said or shown is probably much more important than what is disclosed or released. time will tell.