947-951 days to go

JNJ’s results are interesting. Their portfolio has never been this volatile. Remicade is plummeting, run-rating at just under $5 billion now, with Stelara and Tremfya still growing. This doesn’t bode well for AMGN–they have no next-generation autoimmune drugs (not even a stinking JAK inhibitor). Still no Zytiga generic–something will probably launch this quarter.

Read an article about an amyloid-beta vaccine. I actually met the husband-wife team around 10 years ago. Very nice couple, did not think the drug would work then, do not think it works now. There is a lot going on in the AD world right now that I perhaps will write up shortly.

Papers I’ve Read
In Vitro Pharmacological Characterization of Buprenorphine, Samidorphan, and Combinations Being Developed as an Adjunctive Treatment for Major Depressive Disorder. Bidlack et al. JPET 2018.
As we prepare for the FDA rejection of ALKS5461, this article came across my ‘desk’. The article begins by suggesting there is evidence of an effect of buprenorphine in depression. I disagree. As my jail colleagues point out, the three citations supporting this claim are unfounded. First, Bodkin in 1995 trialed only 10 patients with buprenorphine in an acute setting–far too few to draw reliable conclusions, especially without a control. In a review article, Kosten pointed to two studies, principally the horrific Alkermes phase 2 which suggested 2mg/2mg of ALKS5461 “worked” (-2.8 vs placebo on HAM-D) and 8mg/8mg failed (-0.5 vs placebo HAM-D). Of course it is fun to throw away data that doesn’t support your claim and rely on this evanescent and unpredictable (and untenable) dose window where ALKS5461 has a treatment effect but at only 4x the dose, it disappears. The rational thing to do is group the data–doing so would result in failure, of course. The phase 3s were no better. Kosten also calls out the Yovell, et al. trial of ultra-low-dose buprenorphine with a p=0.04 result and unclear (to me, at least) statistical treatment of dropouts. The Ehrich, et al. phase 1/2 tested a 4mg–>8mg dose which provided the ironic impetus to go to phase 2, where that dose had no effect.
Moving forward, we have an addictive opioid and a proprietary antagonist/partial agonist (samidorphan). The theory is samidorphin will somehow limit the abuse liability of buprenorphine while sparing the alleged anti-depressant effect. How or why this is possible is not really discussed nor accessible to the imagination. The actual experimental results here are not interesting–buprenorphine is a partial agonist at the triad of opioid receptors. The workers found a difference between the high-affinity state/low-affinity state binding of our favorite ligand, with unclear implications. There were no obvious conclusions to be drawn from the fairly advanced BRET assay used to interrogate specific G-protein coupling (Galphai/o). One is left wondering if there is a therapeutic effect here at all (and there is not), then why not just use opioids? In fact, one paper suggests before the 1950s, opioids were the mainstay treatment for “melancholia”. And why do we need a new opioid partial agonist/antagonist in samidorphin? Isn’t naloxone or naltrexone enough? Right, patents. Samidorphin is a “new chemical entity” and would protect the “invention” here. But what is the attenuation of samidorphin really worth, even assuming a therapeutic effect? Couldn’t you achieve the same outcome with a lower dose of buprenorphine or an even weaker opioid agonist? This is pharmacology done wrong. Thankfully ALKS5461 is headed to the wastebasket of drug ideas.

Great NFL weekend! Algorithms found the games too close to call, and I guess they were! I hope the Patriots lose.

I really want to learn Spanish. I just have no time… it’s funny how quickly “this bid” is going. I’m going to miss it!

16 thoughts on “1/22/2019”

  1. Wow. these posts are getting unreal. I wanna go to jail so I can study with Martin Shkreli. What a treat for these inmates. All the best. I never thought I would be jealous of being an inmate. Hope everyone stays safe. What do you think of QURE therapy for Hutchinson using gene silencing/editing/degradation technology.

  2. Yeah would kinda be cool to be an inmate with Martin at club fed now. It’s more like an ascetic study monk retreat. And in the times that aren’t so great then it’s simply a training ground for stoicism. Martin really is a living breathing stoic amongst us. Marcus Arelius would be proud.

  3. “I wanna go to jail so I can study with Martin Shkreli.”
    ^ Early contender for Quote of the Year.

    Spanish? Why? You already know Mandarin? How about OCaml?

    1. Mandarin to speak only in a 3 countries, 2 of them having people speaking English. The remaining one is dialectally divided between people speaking Mandarin (70% with various terribles accents that makes them sometime not even able to understand each others), Cantonese and many other languages. No, it is not a good investment at all to learn Mandarin. People with whom it would be interesting to talk already speak English anyway.
      Spanish opens you the doors of basically all Central and South America (except Brazil, Suriname, both Guyanas) and a good part of Caribbean islands. It also opens you the doors of other latin languages like French ( France and basically more than half or Africa speaks it), Italian and Portuguese (Portugal, Angola, Brazil and in a lesser extent Macau). You can add the immensely rich Spanish literature to those points, and I could keep going if I didn’t have better to do with my time.

      1. I studied Mandarin for 4 years, have used it in work for the past 3.5, consider myself pretty much fluent.
        To say that the people worth speaking to already speak English is one of the most ignorant blanket-statements anyone could make on the topic of language learning.

        If you’re too busy to learn a language Martin, I would have a go at learning to read (just read, not understand) the Korean alphabet. You can get a solid grasp in 15-30 minutes and is more satisfying than Sudoku and cheaper than Poker.

        1. You should really pay attention to the context before to give such lectures. What is the only reason that could push someone to say “why Spanish ? Do you already know Mandarin ?” if it was not an economical, technological and academical reason ? It is in that context that i said “interesting”, comprendes ? I work with people from China too, and the ones who are taking the decisions do speak English (at least at my level, which is pretty high). Who would be idiotic enough to say the only people who are worth to talk to are the ones who speak English ? Next time, read me more carefully before labeling my statements as “blatantly ignorants”.

  4. Martin you suck
    I’ll be sending you a post card from Compton CA

    Yes, people in Compton invest, mostly index funds…

    From Martin <—Spanish

  5. Your New Media bear case is playing out nicely so far. “BuzzFeed to lay off 200 staff in latest round of cuts” (24 Jan 2019).

    Your previous comment (Nov 2018):

    I will not be surprised when more web properties shut down as Google/Facebook continue to gain Internet ad spend share, spend which will decline in a recession, leaving leaders like Vice, Business Insider, Buzzfeed, etc. scrambling for capital and cost-cutting, and totally bankrupting most of the “New Media” no one reads and fewer (readers or advertisers) pay for.

  6. The rationale to add an opioid antagonist to Buprenorphine is to block it from activiating mu-opioid-receptors, while retaining the kappa-opioid-antagonism of Buprenorphine. The latter is supposed to be the important mechanism of action, while mu-opioid-agonism is useless and only causes addiction. This kappa-opioid-antagonism is unique to Buprenorhpine. You don’t find it on any other opioid-agonist, thus you cannot just use another opioid-agonist and expect to achieve the same effect. Using naloxone is not possible, because it has to be injected in order to work. Naltrexone COULD theoretically be used, but it often is intolerable. Samidorphan might have the advantage of having less side-effects.

    While on the phase-II trial you mentioned above ALKS-5461 had only a barely significant effect on the HAM-D, you failed to mention that it had a highly significant effect on the MADRS. Effect size was about d = 0.5, which is higher than other antidepressants, which are often in the 0.2 to 0.3 range. I also think HAM-D is not really a good measure for depression, because it focuses on tension and sleep problems, but does not ask for the core symptoms anhedonia and emotional numbness. The latter ones might be responsive to kappa-opioid-antagonism, but the HAM-D cannot detect this. On the other hand purely sedative drugs like Mirtazapine are declared by the HAM-D to be antidepressants.

    Unfortunately Alkermes also failed to see what their drug might really help for and did not employ measures for anhedonia and emotional numbness in their phase III trials. Only their currently ongoing clinical trial asks for these symptoms, which might be too late. Many people with anhedonia, emotional numbness, including myself, hoped for ALKS-5461, but it looks like FDA is not going to approve it and hell will continue.

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