7/1/18

BIOPHARMA
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What to make of Sage? I am skeptical. PPD is unlikely to be a major market and I’m suspicious of the preliminary findings with the GABAergic agent. Studying the history of “GABA antidepressants” (misnomer) has been interesting thus far. Lilly, Roche and others have published in this field on mostly anxiety agents and still found it very hard to differentiate from benzo-like properties.

Nektar. No, the cure for cancer is not pegylated Proleukin. Some in the biopharma industry lost its collective mind for a minute or two. You can’t call it a bubble without some inflation. Back to reality… this drug doesn’t work.

BeiGene. I believe this emporer may have no clothes. Or, at least at this price, you’re paying Armani for Old Navy. It remains to be seen if cancer drugs will sell well in China, and if their own Revlimid is any indication…

Wuxi Biologics. I wish I could think of the right meme here. What is going on with this company? Holy moly. I gather if you look at Celltrion, Samsung Biologics and Wuxi Biologics as a basket of biosimilar companies, you will do see expectations are too high. In full disclosure, I pioneered the idea of comparing Celltrion and Hospira 6 years ago when Celltrion was worth $7B. Today it’s $30 or $40B (who the heck even knows? or cares?). So the total value of these three monsters is close to $100B. Biologic drugs themselves subject to biosimilar competition is, say, $60B. 18 + 7 + 7 + 7 + 6 + 4 + 4 + 4 (Humira, Remicade, Enbrel, Rituxan, Avastin, Prolia, EPOs, Neupos). The possible biosimilar share is arguably 50% — innovators can discount and biosimilars are not interchangable. so you are chasing $30B of business. The problem is these three companies don’t keep all the economics for their drugs — they have an array of deals with various players (BIIB, etc). And they’re not the only three games in town: Amgen, Biogen, Bohringer, Teva, Mylan, Pfizer, Biocon, Allergan, Apotex and others are all developing biosimilars. I’m not saying these companies will never make money, but, I think you can safely bet against them at this point.

Papers I’ve Read Today
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When less is more: a case of phenytoin toxicity. Robertson K, et al. BMJ Case Rep 2013.
Random case report as I navigate the world of epilepsy.

Preventing Sudden Unexpected Death in Epilepsy. Devinsky, et al. JAMA Neurology 2018.
No comment.

Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. Hellmann, et al. NEJM 2018 378;22.
It always puts a smile on my face when Yervoy actually does something. A double smile for whenever antibodies beat chemotherapy heads-up. May the next generation never utter the words ‘platinum-taxane doublet therapy’. Where’s Avastin in all of these studies? Out with angiogenesis, in with immunooncology (what does that say about ‘IO’?)

Essential Tremor. Haubenberger & Hallett. NEJM 2018;378:1802-1810.
Scary illness, not many treatments. What to do? Will read more. Interesting that ethanol resolves symptoms. Perhaps an NMDA antagonist should be tried here… perhaps I should keep that to myself.

Battling the biology of opioid addiction. Nature Medicine 2017;23:790.
Haven’t made any progress in a year. The NIH could be a cool thing for Trump to turn upside down.

Correction of a splicing defect in a mouse model of congenital muscular dystrophy type 1A using a homology-directed-repair-independent mechanism. Kemaladewi et al. Nature Medicine 2017.
More tomorrow…

A tripartite complex of suPAR, APOL1 risk variants and alphaVbeta3 integrin on podocytes mediates chronic kidney disease. Hayek et al. Nature Medicine 2017.
The Sever/Reiser team publishes more of their work on suPAR. The science is clear, compelling and straddles all methodologies: in vitro, in vivo and human. I’ve always been impressed by Reiser but this work is still incomplete and missing the bullseye. I can’t put my finger on it but pharma should be paying attention to suPAR/APOL1.

Biopharma self-education
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I’m a big proponent of self-education because there’s no other kind. Here are some concepts or terms you should know if you follow medicine/biopharma. I take these terms/concepts from the papers I’m reading and note which a person with a career in biopharma should be familiar with. Generally, terms are easy to understand, but remembering them is tricky. Concepts are tricky to understand, but remembering them is easy. A lot of these are really simple but I think most people have only vague understandings of important things. But some are truly elementary and designed for beginner education. I’d highly recommend you understand these core concepts. These are all my own definitions and subtleties or even errors may exist. I’ll keep a running list of them and make a separate page for just terms I think you should know.

Core concepts:
Penetrance. Simple concept, the likelihood a genotype will manifest as a phenotype. Be able to explain why an illness may display high penetrance or low penetrance.

Haploinsufficiency (related term). The result of a non-functional allele in a biallelic state, leaving one working copy of a gene/gene product.
Haplotype. Genotype of a haploid gene, really an allele. Some other usages include linkage-related phenomena.

Splice-site mutation. Any mutation that result in an exon/intron shift, resulting in an incorrect gene product.
Homologous recombination. The process by which DNA strand breaks/errors are fixed using a homologous strand of DNA.
HDR pathway. The homology-directed repair pathway that uses homologous recombination to fix genetic errors with a DNA repair template.

Ataxia. Common neurological finding where the patient is unable to coordinate broad motor function due to lack of coordination of muscle movements.
Nystagmus. Common neurological finding where patient is unable to control eye gaze, resulting in aberrant and involuntary eye movement.
Diplopia. Double vision.
Dysarthria. Speech dysfunction secondary to neurological dysfunction.
Past pointing. A neurological test to detect cerebellar dysfunction.
Intention Tremor. Contrasts with Essential Tremor as a low frequency tremor.
Dystonia. Involuntary muscle contractions.
Paresthesia. Abnormal tingling feeling.
Cerebellum. The “small brain” which controls motor function, movement and coordination.
Hypotonia. Lack of muscle tone, or weaker than normal muscle tone.
Schwann cells. Peripheral nervous system cells that form myelin (among other things).
SUDEP. Sudden Unexpected Death in Epilepsy
Generalized Seizures. Seizures with bilhemispheric origin.
Tonic-clonic seizure. Formerly known as a grand-mal seizure, features both tonic and clonic aspects.
Tonic seizure. Seizure featuring rigidity/muscle tightening.
Clonic seizure. Seizure featuring jerking/contracting movement.
Focal seizure. Formerly known as partial seizure. A seizure originating from a definitive brain area.
Ictal. Related to a seizure.

Surface plasmon resonance (SPR). A laboratory technique sometimes used to measure ligand affinity. Works best with two proteins if I am not mistaken. Not very commonly used as there are simpler methods.

Hazard Ratio. Common statistical measurement to determine the risk reduction of one intervention as opposed to another. HR=0.50 is a 50% reduction in the risk of an event over the course of time. This is opposed to odds ratios, which do not account for area under the curve in a Kaplan-Meier plot and are “landmark”-type analyses. Be able to explain why 1-year overall survival and hazard ratio could be very different statistics for the same RCT.

Copy Number Variation. A phenomenon where a stretch of DNA (as little as a trinucleotide or as large as an entire gene) is repeated. May result in no phenotypic change, or some change due to gene product instability, translation changes or gene dosage.

De Novo Mutation. A genetic mutation arising for the first time in a patient, not passed through a classical inheritance from the parents.

Music
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Music is hard to come by here. We have prison-issued MP3 players. Many of the newer albums (and older) aren’t available on our system. You can generally forget about anything mainstream. One song I had on yesterday that I really enjoyed was Pianos Become The Teeth’s “Repine”. I listened to it a lot prior to prison. I’m told they finally have put on a new album but I haven’t heard it. A friend of mine even sent me the lyrics! Imagination’s all I’ve got.

Politics
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Liberals must be losing it. Are Trump’s approval ratings increasing? I have no idea. The economy is doing well, North Korea is finally behaving (imagine he wins a Nobel Peace Prize? perhaps with a bit more progress, he should!), and a new conservative Justice is coming to the Supreme Court. Bad era for the other team, which is why it’s important to remember, we’re all team America. Grow up, liberal pussies. As a conservative, and something of an intellectual, I am dismayed at the sanctimonious left. You’re not better than anyone else, and you’re damn sure not better than me.

Oh, I hope some people are not upset that I’m trolling Lauren Duca. How can you troll your own wife?

Sports
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I’m going to be paying a lot of attention to sports going forward. I’ve always been a sports fan, as a natural competitor. I’ve ignored the major sports, save for following championship games. You can guess why I’m interested in this, all of a sudden. Lebron is going to the Lakers. Not sure what that means quite yet but will make for interesting games later this year.

Disclaimer – You should assume I have a conflict of interest on everything I talk about (even in sports, music and politics!) given my web of complex holdings. I don’t give stock advice, and you should not ever listen to anything I say because I’m an idiot. Never come back here again.

17 thoughts on “7/1/18”

  1. can you also include your daily life in the prison , your new “friends” , events etc that would be cool šŸ™‚

  2. Like I have been saying since I found out about you and started my own research on you ! YOU ARE SMARTER THEN MOST KID šŸ’Žā™„ļø Keep your head high ! Iā€™m waiting to see the day your out and the things you can accomplish! šŸ¤˜šŸ§šŸ¤©šŸ¤”ā™„ļøā™„ļøā™„ļøšŸ’ŽšŸ’ŽšŸ’Ž

  3. Skrelli, glad to hear you are enjoying the clink, it’s a great place to look inside yourself and it is a pleasure to know that you haven’t lost your drive and conviction to dominate with snarky intellect. Thanks for the nod on stock tips, made me chuckle. I am married to an ARNP…and still I must study up on your library of dictionary terms as related to pharna….nope! I’ll stick to what I know best…simple living. Cheers,. Do you miss a swanky bottle of Cab? Or do they sneak some in your grape juice? Anyway….don’t drink the Kool aide! Peace.

  4. Shkrels:
    Pussies can take a beating, so I take this as a compliment. Don’t make me get a job at the jail just to kick your Republican ass, assfucker. I love you.

    Your real wife.

  5. One of a kind! Taking prison like a man and making the best of your situation.
    Thanks for the blog posts. Always a pleasure reading your writings.
    Miss the Sunday night youtube videos.
    Best to you and hope you truly are fairing well.

  6. You have to catch up with Trump if you think he’s doing a good job because he’s about to ruin us with these tariffs. Plus, he sticks children in cages as hostage for a wall no one wants. It’s going to get worse with the Supret Court pick, since they’re conservative, they likely have plans to abolish civil rights. Trump has picked people with ties to European Nazi parties. It’s not a win for the US turning America into Nazi Germany and being Putin’s bitch to ruin Western Democracy. Putin is winning his long term game plan at taking down the West and Republicans are falling for the bait. The West is more divided than ever, and it’s exactly what Putin wanted. He wants to see to see the US crash and burn. Protect country over party, but I don’t think Republicans can do that. You and many of them are just following Trump like sheep to trigger liberals, while our whole country is being destroyed by him working for Putin’s behalf.

    America’s fall be on the blame of the Republican Party because they have all three branches, and every single one of them is now a bitch to Putin and Neonazis. Republicans treating politics as a fucking sport instead of stepping all over the Dems is ruining our country. I know not all of you guys read about how the history of this shit plays out, but it’s imprortant to know that Republicans have been hell bent on destroying the Democrats since 50’s, and it’s destroying our country as a whole. Republicans will toe the party line and sell this country, even while claiming Trump is stupid in public and making fun of him, vote for all his policies to be passed.

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