Defending and Dogging the FDA

I know.  You're asking, "Who is writing this blog?"  Its still me.  I'm not schizophrenic yet! But I ran across several news articles regarding the fact that the FDA is insisting that Basilea run two trials to get approval of ceftobiprole, an anti-MRSA cephalsoporin that retains some activity vs. Pseudomonas, for the treatment of hospital-acquired pneumonia instead of the single trial they have submitted.  But that result was entirely predictable as far as I can tell.  The original two trials conducted by J&J and Basilea for complicated skin infection were rejected by the FDA as having been of inadequate quality - essentially - too many mistakes in enrollment and even possible fraud among investigators.  J&J argued that even removing all the questionable enrolling sites, the trial still demonstrated the efficacy and safety of the drug for skin infections, but the FDA stood its ground.  Now - I'm not defending the FDA on this aspect of things. I don't know which argument should prevail here - but a number of really smart people think that J&J proved that ceftobiprole works for skin infections.

But the FDA has said that they will accept a single trial in pneumonia - but it needs to be large - or a single standard (smaller) sized trial when backed by data in another indication.  With the rejection of the data on treatment of skin infections, there are no data to support the single trial in pneumonia presented by Basilea. Also - how big is the safety database?  Can the rejected trials be used to show safety? So where is the surprise here? What were they thinking?  Maybe I'm missing some key information that Basilea can supply. . . .

Now - back to dogging the FDA.  We're still waiting for the FDA to rescind previous infeasible guidance documents,  especially those in both community acquired and hospital acquired pneumonia. I have covered this multiple times in this blog, most recently here.  They are struggling with how to deal with early endpoints that were concocted to conform to their guidance on justifying non-inferiority margins where they had to turn to 80 year old literature that is completely inadequate to determine the treatment effect of sulfonamide antibiotics or penicillin such that our new antibiotics might have a standard for comparison.  But these endpoints are probably not valid, the scientific basis for using the endpoints is questionable at best, and there is no reason to go to these lengths. The FDA has a treasure trove of data on the development of previous antibiotics that can be mined.  They have pharmacokinetic data, the susceptibilities of the pathogens involved and the ultimate clinical outcome of interest - cure at test of cure.  These data can be put together using pharmacometrics to provide a no-treatment level of response and therefore a treatment effect level that can be used to establish a robust justification for non-inferioirty margins using cure as the endpoint. So - where are we?  So far - nowhere.  But I am assured by the FDA that they "are on the case!"  We are all waiting . . . .

Cubist Rocks!

I got a call from a reporter the other day asking me what I thought about the Cubist acquisitions of Optimer and Trius (See the link for the Cubist website).  My response was – Cubist Rocks!  These acquisitions are probably going to be good for Cubist in many ways – but they are a sorely needed shot in the arm for the future of antibiotic research and development around the world.  These acquisitions validate the investments in academia and biotech aimed at identifying new antibiotics against resistant pathogens and even antibiotics that are not particularly members of new classes of antibiotic – an extremely rare bird.  They will provide impetus for future investors and investments. They should inspire large pharma to think twice about their current lack of vision in the antibiotic space and to rectify this obvious financially attractive blind spot.

So – the basics.  Cubist is a small pharmaceutical company with revenues of about $1B almost entirely from sales of Cubicin (daptomycin), an IV antibiotic only active against Gram positive pathogens.  95% of sales are in the US.  Cubist’s ability to leverage markets outside for the US still leaves something to be desired (obviously). The original patent on daptomycin will expire in 2016, but patents on methods of administration and on the more pure form of daptomycin expire around 2020. Sooner or later, Cubist must find a way to replace Cubicin.  They have a promising antibiotic for Pseudomonas infections, ceftolozane (+ tazobactam) in phase III development, but nothing to addresss the Gram positive market represented by Cubicin.  The addition of Trius’ tedizolid will provide a strong alternative to linezolid as an oral (and IV) therapy for Gram positive infections. This compound has clear advantages over linezolid (which will become generic in 2015) and should do well in the marketplace – especially in the US and especially with Cubist’s experienced marketers behind it.

Cubist will pay up to $818MM including milestones for Trius (with $700MM being the purchase of Trius from its shareholders).  This also includes the interesting early stage clinical and preclinical programs at Trius.  It will be interesting to see how all that is merged into Cubist over the next year or two.

Trius had to go through FDA hell and partnering oblivion to emerge victorious in the end. They had to deal with changing FDA endpoints, a generally confused and inconsistent FDA overall and with an extremely skeptical group of potential large pharma partners. They were forced to raise money privately, with an important licensing deal with Bayer for Asian rights and through an IPO to get through two phase III trials for tedizolid, one trial at a time, cautiously raising money at each step of the way. This tortoise has finally won the race.  The fit with Cubist is a good one.  Tedizolid is a solid inheritor of the Cubicin franchise, and can complement Cubicin during Cubicin’s phase out (if that ever happens) as an oral follow-on to Cubicin therapy.  I think the Trius pipeline is also a good fit for Cubist.

So Cubist-Trius is a win-win for the world!  The world gets a badly needed additional choice for oral therapy of Gram positive pathogens, and IV choice beyond linezolid. The pharmaceutical industry gets a shot in the arm (and a kick in the head) for antibiotic R&D. And I get to feed the optimistic side of my view on the future of antibiotics and resistance.

On the Optimer purchase – I have little to say. Cubist was forced to choose to extend its contract with Optimer or not last month – obviously they chose an interesting path forward. Of course, lets not forget that Cubist has its own candidate for the treatment of C. difficile diarrhea (Surotomycin) already in phase III trials.  Optimer’s Difficid is already approved for that indication, although sales are not great ($23MM in 2012).  To my view, that molecule has definite advantages over oral vancomycin but may have been priced too high for the advantages it does offer.  Nevertheless, Cubist is paying up to $800MM for Optimer as well.  But how Difficid fits with Surotomycin and how Cubist will handle this I couldn’t say.  All in all –this seems like not a bad problem to have.  Hey – I have two good products for the same disease – what do I do?

So – Cudos to Cubist.  Congratulations to both Trius and Optimer. And good health to all those of us who are going to need new antibiotics as we yield to the inevitable passage of time.