1/16/2019

953-956 days to go – 31 months

Biopharma/Investing
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Not surprised APTX doesn’t work. The depression stuff doesn’t work either.

Papers I’ve Read
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Discovery and characterization of AZD6738, a potent inhibitor of ataxia telangiectasia mutated and rad3 related (ATR) kinase with application as an anti-cancer agent. Foote et al. J Med Chem 2018.
AstraZeneca’s ATR project has yielded a clinical candidate. 6738 is a suloximine (S=N), replacing the sulfonamide moiety of the hit AZ20. Apparently, this SNOH- moiety hanging off the cyclopropyl did the trick to improve solubility and eliminate CYP3A4 liability (that and one atom on the heterocycle). Anyway, ATR is part of DNA damage repair. You’ve probably heard of it from Vertex, who sold their VX-970 to Merck KgaA (now M-6620 or berzosertib) for a pretty penny. I don’t trust anything from Vertex Cambridge drug discovery (including and especially Derek Lowe). So far I don’t think anyone is bowled over by the data for ATRs–no monotherapy efficacy. There’s a Bayer compound out there, too. It seems like the AZ predecessor compound was around for a while.

6-Benzhydryl-4-amino-quinolin-2-ones as Potent Cannabinoid Type 1 (CB1) Receptor Inverse Agonists and Chemical Modifications for Peripheral Selectivity. Zhang et al. J Med Chem 2018.
J&J researchers produce a peripherally-restricted CB1 agonist to avoid the AE profile of the storied Accomplia. I didn’t know GC1 was the MOST abundant GPCR in the brain–kind of amazing, huh?

Cytokine-Induced Expression of HIV-1 in a Chronically Infected Promonocyte Cell Line. Folks, Fauci, et al. Science 1987.
Human Immunodeficiency Virus-Infected Individuals Contain Provirus in Small Numbers of Perpiheral Mononuclear Cells and at Low Copy Numbers. Simmonds, et al. J Virol 1990.

Still in the way-back-machine for HIV.

Personal
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Lauren Duca divorced her husband and is gay now. Just 2 and a half years ago she thought it was wise to marry a man. Now all she tweets about is how terrible and useless men are. Play to your audience, I guess. Perhaps she will even become an author, selling her book to a like-minded left-wing gnat (or nut?) at a publishing company that doesn’t realize they’ve been appropriated by ideology. Maybe I should rollup that industry and instill some libertarianism. People should be able to read whatever is appealing, not what some self-anointed anti-business SJW gatekeeper decides.

I wrote more on this and recent revelations that Duca is a body-shamer (the body-shaming posts are awful) and even an ablist/classist as she panned community colleges in a recent Facebook post if you’d like to read it. Evidently even further revelations are forthcoming. Guess her book deal may be off-the-table.

1/12/2018

957 days left

Biopharma/Investing
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Biomarin’s CEO said there is no drug pricing crisis or problem and this issue is “all politics”. He is 100% correct. If you analyze disposable income, funds spent on pharmaceuticals vs. entertainment, poverty rates, insurance coverage rates and other data sets, you cannot possibly reach any other conclusion. As I said in my Ivy League tour, think with facts and reasoning, not with emotion, and you’ll discover the truth–assuming it is the truth you were seeking in the first place.

Papers I’ve Read
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Vpu Mediates Depletion of Interferon Regulatory Factor 3 during HIV Infection by a Lysosome-Dependent Mechanism. Doehle et al. J Vir 2012:86;8367-8374.
6 years ago, Vpu was discovered to label a core host viral defense mechanism, IRF3, “garbage”, prompting the obsequious cell to digest its comrade in the greedy lyosome. The conniving interloper wins.

Hydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa. Tshilolo et al. NEJM 2019:380;2
Why? A single-arm study of a well-known drug. Just why?

Next-Generation Sequencing to Diagnose Suspected Genetic Disorders. Adams, Eng. NEJM 2018;379:14
Simple backgrounder for anyone who has been asleep.

Personal
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Keep the government shut down until our debt is retired. It will balance the budget. Just 10 years? Keep collecting taxes. In 2035, no taxes, no government. Perfect answer, and it worked in the 1800s 🙂

1/11/2019

958 days left

Biopharma/Investing
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Carl Icahn (or any other large swashbuckling investor) should take a stake in BMY, scuttle the CELG deal, which is suboptimal at best and wasteful at worst, and sell the company to PFE instead. Buying 100-200 million shares at $45 and cancelling the deal makes you $1-2 billion alone. Then, if PFE, Novartis or JNJ, who no doubt would want Opdivo, would be interested in a $100 billion or higher offer for BMY, one could net $2 to $4 billion on the trade.

What can be said about Bezos that hasn’t been already said?
Vinik coming back to hedge funds is interesting news.

Papers I’ve Read
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A Conserved Role for Serotonergic Neurotransmission in Mediating Social Behavior in Octopus. Eric Edsinger, Gul Dolen. Curr Biol 2018.
Nature advertised Octopi on Ecstasy, so I had to look this paper up. It’s about as weird as expected, with some fairly high p-values. Octopi (and virtually all other species) express SERT and the MDMA-binding site on SERT is fairly homologous to human SERT, although homology on a small part of a huge transmembrane protein shouldn’t get one too excited. Anyway, they use a “three chamber” study design often used with rodents and find MDMA has a very weak effect size, driving male octopi to females as opposed to their unaffected state where they prefer examining a unique object. What does this tell us about behavior? Who knows, I’m just a drug guy.

Theoretical Prediction of the Creation and Observation of a Ghost Trilobite Chemical Bond. Eiles, Tong & Greene. Phys Rev Lett 2018.
Rydberg atoms can form bizarre “trilobite” bonds. The electron probability functions look like actual trilobites from eons ago. These Purdue physicists demonstrate a “ghost bond”, where such a Rydberg electron exists in a strange (>100nm bond length!) state WITHOUT the other atom present. Ghost bonds. Truth stranger than fiction…

In vivo fate of HIV-1-infected T cells: Quantitative analysis of the transition to stable latency. Chun, et al. Nature Medicine 1995.
A seminal paper, 23 years old, on identifying the latent ‘reservoir’ of CD4+ proviral T cells.

Personal
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In a few days (the 13th) my monthly jailiversary will be here. Celebrating 16 months in and 31 to go.

1/10/2018

Biopharma/Investing
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I don’t think LLY gets their money’s worth with LOXO.
BLUE comments on gene therapy very interesting: 5-year payment plan sounds reasonable. $2.1 million cap on pricing also interesting to note.

Papers I’ve Read
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Polyamine modulation of anticonvulsant drug response: A potential mechanism contributing to pharmacoresistance in chronic epilepsy. Beckonert et al. J Neurosci 2018. DOI: 10.1523/JNEUROSCI.0640-18.2018
U Bonn (Germany) researchers suggest spermidine (just a polyamine, don’t get too excited) concentrations are linked to CBZ resistance in epilepsy. The data don’t convince me too much but it is interesting–the uM/mM concentrations should scare readers. Nonetheless, there is a catabolism inhibitor opportunity here if one was so inclined.

New Promise for Vaccines against Tuberculosis. Barry Bloom. NEJM.
I wouldn’t call the GSK vaccine promising. p=0.04 shouldn’t be in NEJM.

Antisense Gene Therapy for Neurodegenerative Disease? Haque & Isacson. Exp Neur 1997.
Early huntingtin antisense experimental failure. A fun attempt at oligos from circa 20 years ago by Harvard workers probably sheds zero light on the Isis/Roche product candidate, but is a fun time warp.

Personal
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I have such weird dreams in here. One feature that has carried over from from my apartment to this group home is my dreams are long-running narratives with active and developing plots. There are some obvious themes: the progression from adolescence to adulthood still clearly haunts/taunts me if I give any credence to these semi-lucid moments at all. Does anyone keep a “dream diary”? Isn’t it all the subconscious regurgitation of nonsense? Neurons misfiring their engrams into the dark gaps of synapses–an uncoordinated melody of discharged waves: read into it at your own risk.

I purchased a SAT test-prep book for the guys in my room. We’re having fun preparing for a world without drug dealing and guns–whenever we get out.

If any medicinal chemists are out there and interested in being a penpal, I have a lot of topics to discuss–martin@thotpatrol.com is my email that is rapidly copied sent to my email here at Fort Dix. I’m working on prodrugs of quinone molecules among other interesting ideas.

1/7/2019

962-964 days to go

Biopharma/Investing
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The BMY-CELG deal is not too unexpected. I had modeled a AMGN-CELG merger and felt it was too long-term dilutive to AMGN and it is probably also long-term dilutive to BMY, unless luspatercept does more than $3bn and the CARTs do more than $4bn combined, which is possible. Ozanimod also adds to the puzzle. My estimates were reasonable and the deal was too dilutive. BMY is betting that their commercial execution will outpace their R&D execution, which is basically a fair bet across all of pharma. With LAG, IDO and TIGIT looking disappointing, might as well launch new products that actually work. With very low debt costs, it is a reasonable transaction from a practical perspective. One can pontificate about theoretical alternative investment rates, but how many opportunities to deploy $75 billion are really out there? Nevertheless, BMY has waded into the REMSphere, where they will encounter a staunch opponent in the current FDA. Any attempts to delay generic entrance of Revlimid will be encountered by fierce resistance. Given the near-term generics for CELG’s top 3 drugs, BMY will regain their weird lumpy revenue/earnings profile (no kidding the deal is ‘accretive’ in the next few years!), resulting in a return to the Avapro/Abilify cliff story of the past.

During the year and especially at the end of the year I like to sort my universe’s stocks by YTD performance. I’ll try to present the winners and losers of 2018 in an upcoming blog post. Invariably some moron hedge fund manager says “this was a tough year”. No, stupid. This was a year where you failed to do your job–buy the stocks which appear at the top of the list and short the stocks at the bottom. I’m looking at Greenlight, -30% for the year. The list proves *someone* made money in this zero-sum game, and if you can’t spot the sucker at the table… I like pharmaceuticals because of the heterogeneity of the space, which allows for a no-excuses approach for the player, despite changes in alpha and its accessibility.

Hansa Bio (HMED in Sweden) is one of my favorite stocks. Maybe I’ll do a writeup!
Amgen is fairly valued. Detailed writeup soon!

Papers I’ve Read
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I’ve spent the last few weeks reviewing most (!!!) of the scientific literature of 2018, at least from the preeminent journals. There were a lot of great advances in 2018, especially in biomedical science. Here are some:

1) The evolution from CRISPR to Base Editors.
2) The clearer evidence that microglia is responsible for the pathogenesis of many CNS maladies.
3) CRISPR babies are out there.
4) Further CART successes, including BCMA.
5) Progress towards HIV clearance.
6) Further gene therapy successes, including SMA and hemophilia.
7) VRTX CF advances.
8) A stop codon read-through experiment actually works.
9) AlphaGo and other AI successes.
10) Microbiome successes and failures, further fleshing out of the reality of this niche.
11) Spooky action confirmed, again.
12) Success in quantum satellites/cryptography.
13) Quiet year for math as Goldbach theorem fizzles out and the ABC scandal remind us of the frailty of human logic.
14) Continued success in spinal cord injury restoration/rehabilitation.

Missed anything?

Hemoglobinopathies in the Fetal Position. Pasricha & Drakesmith. NEJM 2018 379;17.
Another “clinical implications of basic research”, a dumbed-down abstract form of another journal’s paper. In this case, Science published a dynamic paper on HRI kinase controlling fetal hemoglobin expression through adulthood. This will undoubtedly herald a race to synthesize a selective HRI inhibitor (send me crystal structure in the mail please). But, again, do us putatively dumb readers of the NEJM need this helping translational hand to read Science?

Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Meisel et al.
Finally, a microbiome paper that isn’t… full of shit. UChicago researchers working with Tet-/- mice found pre-leukemic disorders where expansion of some myeloid cells are highly correlated with driving tumor progression. What is driving that expansion? Amazingly, they find some Lactobacillus snuck into the vivarium, colonizing mice gut microbiomes. This then resulted in IL-6 expression which drove the leukemia. Amazing! It is worth attempting Actemra, Roche’s IL-6 antibody, in some of these human conditions and seeing if the experiment replicates. There are some methodological issues with the experiment, but in general, it is very convincing and exciting.

TAS05567, A Novel Potent and Selective Spleen Tyrosine Kinaase Inhibitor, Abrogates Immunoglobulin-Mediated Autoimmune and Allergic Reactions in Rodent Models. Hayashi et al.
Taiho, not to be confused with Taisho, researchers outline their Syk inhibitor. The thinking here is the Syk inhibitors advanced heretofore have been too sloppy and this more selective kinase inhibitor will avoid the promiscuity seen in the past. I think this class of molecules will remain dead as the therapeutic impact just is not there.

Personal
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Saturday NFL match-ups look too close to call. Sunday I chose the Eagles, who came through 🙂 I really like this team. They’re unlikely to proceed further, but they are far stronger than most think.
I sort of like the new Meek Mill album, an artist I mostly panned in the past.

12/31/2018

969 days left.

Biopharma/Investing
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Have been finding lots of cool things. Things I can’t tell you about.
Anyone following the Egalet/Iroko deal? Interesting times in specialty pharmaceuticals as usual.
Or how about the Concordia recap?
I may also attempt a list of 2018 private companies by valuation. Never seen before data! Largely my guesses! Perhaps it can be an open Google doc (maintained by one of my trusty followers) that is a resource for the biopharma community.

Papers I’ve Read
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I’ll be releasing my favorite journals of 2018 soon. I’m not sure if I should do top 10, top 20 or top 50-200. I read a lot.

Books I’ve Read
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Nightfall and Other Stories – Asimov
I was never a science fiction fan. When I read some Asimov a few years ago, I didn’t like it. No patience, I guess. This collection of “Nightfall” and twenty other stories, all briefly introduced by the author, is spectacular. One forgets the delineation of science fiction as Asmiov plunges the reader into deep reservoirs of human existence. Highly recommended.

Code – Petzold
I read this in 2014 and again at the MDC about 9 months ago. A sort of introduction to the world of computers, Petzold sews hardware with software in several mediums, demonstrating the duality (or unity, if you prefer) of computer engineering. One can’t help but get bogged down in increasingly complex schematics, but if you stick with it, Code takes you one of the most enjoyable reading journeys I’ve ever been on. Thank God for overzealous prosecutors!?

Personal
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Can’t thank Trump and his team enough for CJ reform. All 4,000 of us at FCI Fort Dix and the tens of thousands of friends and families are so appreciative. I have rarely met a prisoner with a “fair” sentence–I’d say 75% of inmates’ sentences are too long, being as objective as possible. The majority of incarceration is related to illegal drugs and guns, punitive ideas whose time may come and should be going. Happy New Year to my fellow “criminals”. We’ll be home soon.