Cogent Observations from the "Wolf" -- on Boceprevir production troubles at Schering

In the comment-box related to this post -- about Vertex's Telaprevir (a next generation Hep C treatment candidate) having taken a now-commanding lead over Schering's Boceprevir, in the race to reach Phase III trial-dosings, and eventual FDA approval, a poster called the "Wolf" offered some astoundingly helpful insights -- so I'll re-post them here, and now, for all to see [Emphasis supplied]. Knowledge is power. Do not hide yours under a bushel-basket (Thanks, Wolf!):

. . . .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 III trial batch sizes but rather one of scale up to commercial production which could be an even more significant problem for Schering-Plough (SP), especially in a race to market v. Telaprevir for the first oral small molecule inhibitor for HCV.

At Phase III it is important for SP to to work out their commercial production batch size process as batches that are produced for Phase III 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 III 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 Phase III 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 vest. On the other hand, Vertex has been much more forthcoming with their Phase II 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 three times a day and require close to 100 percent 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.

-- Wolf

Very well-turned. Spot on. And allow me to amplify one of Wolf's points, here: it is generally true that, at FDA, any change to method of manufacture must be pre- or re-approved by the agency. [Post-FDA approval, this process is abbreviated, and is a little less daunting, but pre-FDA-approval, it is more than a notion.] So, what Wolf wrote about needing to have full-scale commercial launch quantity-processes fully vetted, and running smoothing -- before dosing at Phase III even begins on Schering's Boceprevir -- is certainly correct.

Else, one faces the possibility of having to "start over" with FDA to prove the GMp process differences are entirely transparent -- as to the drug's efficacy and safety.

The upshot? Clearly, Vertex is in the driver's seat on next generation Hep C drugs, now.