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!