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Three Updates

When I last wrote about Catalyst Pharmaceuticals, they were pursuing their plan to charge a lot of patients money for an existing drug, currently being provided without cost, which plan was somehow to everyone’s benefit. The FDA, though, sent them a refusal-to-file letter, and the agency has now clarified their position: Catalyst has to run another Phase III trial, as well as several toxicology studies, so this could take a while. This sounds, from the outside, like a case of very poor coordination with the agency, at the very least – being told to go run another Phase III is never a good sign, and this for a drug that people are already taking.

I also wanted to update the lesinurad story. Back in 2012, AstraZeneca bought Ardea to get this gout drug candidate, but things have apparently not gone very well since then. The drug was recently approved as Zurampic, but AZ has now sold off the US rights to the drug to Ironwood for “up to 265 million” in payments, plus single-digit royalties. That does not sound like a very good return on the roughly one billion dollars they spent to acquire it and the money they’ve spent since then to get it to market. There’s another Ardea gout drug from the original deal, but apparently Ironwood is getting some rights to that one, too.

Finally, many will remember the disastrous first-in-man trial of TGN1412 (a drug that is in the process of making what would be the most unlikely comeback since thalidomide). I remember wondering at the time what it must have been like to be one of the clinicians involved, and now we get to find out. It was just as horrible as you might have imagined:

After I’d given the dose to the seventh man, a nurse told me one of the men had a headache, which is common. While dosing the eighth, the nurse returned and told me that the first man was feeling worse and that a second was throwing up. Then they tumbled like dominoes. One man tried to walk to the toilet and collapsed. The wards became chaotic, with blood, vomit, and staff and patients shouting. It was clear which two had been given the placebos.

Yeah, that one was unblinded pretty quickly. Everyone survived, barely, and the physician involved says he’s never done another first-in-man trial since (which I can well believe). He also says that he has wondered since then about how the participants in this trial have been doing, but doesn’t think that they would want to hear from them. He may be wrong about that, actually – I hope he does hear from some of them after his article, and that it helps him with coming to terms with what happened.

8 comments on “Three Updates”

  1. A Nonny Mouse says:

    I recently read an interview with one of the people on the trial who seems to have recovered pretty well (apart from a few fingers). He has been told that there is a increased risk of cancer, but is regularly monitored.

  2. formerly at AZ Waltham says:

    Speaking as one of those caught in the big 2012 AZ layoff, it’s so nice to know that AZ put my salary to such good use.

  3. Dr. Manhattan says:

    ” Back in 2012, AstraZeneca bought Ardea to get this gout drug candidate, but things have apparently not gone very well since then. The drug was recently approved as Zurampic, but AZ has now sold off the US rights to the drug to Ironwood for “up to 265 million” in payments, plus single-digit royalties. That does not sound like a very good return on the roughly one billion dollars they spent to acquire it and the money they’ve spent since then to get it to market.”

    All part of the Pascal Soriot “Strategery” . He made all of those promises in the midst of the Pfizer attempt that AstraZeneca would deliver $45 billion of revenue in 2023. How’s that working out so far? $24.7 B last year; their top revenue producer Crestor goes off patent next month. Stock is down from $40 at the time of the Pfizer attempt to $29 and change. Pfizer and even Lilly have still managed modest gains over the same time period.

  4. Mark Thorson says:

    Update #4: Sarepta lost.

    http://fortune.com/2016/04/26/sarepta-duchenne-patients-fda/

    “FDA, please don’t let me die early!” said one young patient in one particularly blunt moment.

  5. Anon says:

    Update #5: Final report on Bial 10-2474 investigation. Link to English version at bottom of page.

    http://ansm.sante.fr/S-informer/Actualite/Essai-clinique-de-Rennes-Rapport-final-du-CSST-inhibiteurs-de-la-FAAH

    1. Design Monkey says:

      Mmyeah. The bottom line (spoilers ahead) – Bial compound was inherently sloppy crap. Low activity (micromolar), thus elephant doses, and no selectivity, hitting all serine hydrolases in a row. All additional subtle or not so subtle screwups in biology and trial setup were just icing on the cake.

    2. tangent says:

      Section 8 on the dosage calculation is shocking to me. Extrapolation from animals suggested 100 mg would be safe and 10-40 mg would be effective at FAAH inhibition. Human data showed near-complete FAAH inhibition at 5 mg. Don’t you add a safety margin to reflect when you know the human pharmacology differs by 2x-8x from any other species tested? And how in hell do you go ahead and dose humans at 20x the max level you have any mechanism-based justification for?

      Does this stuff sound less shocking to someone with knowledge of the field, or more?

  6. tangent says:

    “The dose‐effect curves (here inhibition of FAAH activity) of BIA 10‐2474 show this in particular when we enter an unusually
    narrow concentration range, going from absence of to almost complete inhibition.”

    What’s a likely cause of this rapid dose-response transition? Like at lower doses the drug gets non-specifically sopped up elsewhere, until it saturates all that enough to hit FAAH?

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