1/10/2018

Biopharma/Investing
————————-
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
———————-
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
———–
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
——————–
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
———–
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
————————-
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
——————–
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
——————–
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
———–
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.

12/24/2018

Biopharma/Investing
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Stay market neutral! Stocks fall, too. 10 years of stocks rising has to get reversed at some point. “When the tide goes out, we see who has been swimming naked.”

Papers I’ve Read
——————–
Mutations in TOP3a Cause a Bloom Syndrome-like Disorder. Martin et al. Am J Hum Genet 103, 2018.
The BTRR complex repairs double Holliday junctions. Without any of the BTRR members, this phenotype involving growth destriction, microcephaly and cancer predisposition is seen. TopoIIIalpha is a component of BTRR and these researchers identify 12 patients with TOP3A and RMI1 (another component of BTRR) mutations. It appears TOP3A homozygous LOF is incompatible with life (Li et al, PNAS 1998) and the authors speculate that these are severe hypomorphic alleles. I don’t see much of a therapeutic strategy here, perhaps gene therapy could reduce sister chromatid exchanges and other chromosomal abnormalities seen in this family of diseases, potentially reducing new onset neoplasms, but with no benefit towards dysmorphic symptoms.

Signalling Pathways and Cellular Mechanisms Regulating Mossy Fiber Sprouting in the Development of Epilepsy. Godale & Danzer. Front Neurol 2018.
As is my reaction to many neuroscience papers, I’m more confused on the subject matter after reading this one.

Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder. Liu et al. Hum Mol Genet 2018.
I didn’t know much about the T-box transcription factors going into this paper, so it was helpful to get acquainted with these powerful developmental regulators. DiGeorge syndrome is a somewhat well-known rare disease caused by TBX1 deletion, and it appears there are a slew of other T-box disorders, including now, TBX2 variants. TBX2 seems extremely sensitive to gene dosage, with heterozygote hypomorphs and duplication variants both causing disease. The workers here use similar tools to ones I’ve highlighted before including GeneMatcher and the Undiagnosed Diseases Network. Without giving away my own secrets, the bioinformatics tools used in this paper are comprehensive and impressive. The ortholog work is not–drosophila are clearly not the best species to test TBX variants. Anyway, with only 4 patients found (3 in one family), it’s a little hard to get excited about this work or even think about a therapeutic given the extreme gene dosage sensitivity and the developmental nature of the disorder.

Brief Book Review – The Big Con by David M. Maurer
————————————————————–
“A feast of language” boasts the front cover. Indeed, should you desire satiety from a diet of anachronistic cant, TBC will not disappoint. Maurer is a splendid writer outside of the confidence man’s argot, which is disappointingly dated. One cannot envision the last time someone took “a touch” off of the “rag”. Yet, it is still fun to get a glimpse of the early part of last century’s underworld dialect. With fascinating stories/examples of these touches (confidence games run to successful completion), Maurer keeps his work alive despite a fatally boring premise. In some subtextual senses, the book is about human nature and good vs. evil. But the dreary meta-premise is that perhaps the greedy victim, who Maurer posits is so blinded by cupidity that he is invariably willing to join in connivance with the confidence man (of course only to be fleeced at the end), is really the bad guy. Building sympathy for con artists is hard, and Maurer doesn’t intentionally do so, but his wry commentary and somewhat unbelievable access to this cohort of miscreants makes one wonder which side he’s on. The reality is he is just a linguistics enthusiast, so much so, he was willing to dive head-first into this unknown world to simply learn new usages. There is precious little technical discussion of semantics in the style of a, say, Chomsky. Maurer is just the real deal word guy, giving an incidental window of the lives of the con vernacular.

Clinical Trials I’ve Noticed
——————————-
Study of Potential for Drug Interactions Mediated by CYP3A4 Inhibition With Aramchol in Healthy Volunteers. Galmed Pharmaceuticals.
I had almost forgotten about bile acids since I had built Retrophin’s bile acid business in 2014 (which should be going generic soon, by the way). Galmed has a cholic acid combination product I was a bit worried about. Not sure what they’re up to. $GLMD

Safety and Efficacy of Autologous Umbilical Cord Stem Cells Infusion for Preterm Infants. Guangdong Women and Children Hospital.
I’m confused about what is so wrong with preterm infants that they need ‘stem cells’. Oh, China.

The Effects of Microgravity on Human Sperm. Parabolic Flight. Institut Universitari Dexeus.
God bless these intrepid researchers.

Personal
————
Half of all US adults have had a family member sent to prison. So, obviously, criminal “justice” is a disaster in the US and we have to make major rollbacks. But why not also acknowledge the professional failure of the law enforcement apparatus that includes the FBI, DOJ (DC and USA/AUSAs), etc.? Grand juries, juries and judges are to blame as well. The U.S. didn’t become a police state by accident–everyone is culpable. I’m not frustrated–I think that comes clear in these blog pages. I just feel terrible for all the guys here with truly undeserved long-term sentences. The accusers are often more guilty than the accused!

Government shutdown? Sounds great to me. Some of it should be permanently shut down!

Is Ruth Bader Ginsberg okay? Can someone check please?

Glossary
———–
I’m going to make this section iterative. We’ll start with simple definitions for some terms and “update” them over time.

dentate gyrus (updated): Part of the hippocampus, the DG receives input related to new stimuli from the entorhinal cortex. The DG is thought to be instrumental in forming new memories and spatial processing. The DG has granule cells with unique axonal projections called mossy fibers. Mossy cells constitute a substantial population of DG cells.

ribosome – The translation apparatus of the cell, using tRNA and mRNA to create proteins. Exceptionally complex, future definitions will build details.

syntenic – on the same chromosome, usually used when comparing conservation across organisms/orthologs

12/21/2018

980 days left.

Biopharma/Investing
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Relay raising $400m is a bit silly and should mark a top for the private biotech world. I know a lot about in silico chemistry (helped design a cloud platform with two very talented people)–there is nothing on the cutting edge here that will meaningfully change drug discovery. In silico modeling has been around since the 70s and the QM framework for calculating ligand affinity has not really matured meaningfully since then. Atomic simulations have improved and more and more drug discoverers are using them, which seems to be Relay’s schtick. Crystallography is still a gating factor followed by synthesis and in vitro work. Get a MOE, Schrodinger or open source suite and you have 95% of what you need to be a successful in silico researcher, but you still need to, you know, verify that your drug works by actually making it. The CEO is from Allergan which is probably the last place I’d want my high-tech drug discovery company CEO to come from.

Doing a ‘deep dive’ on Amgen, should be available in a few days. Don’t worry, I’ll look at some smaller companies soon.

Poor DBV huh?

And how about SPPI!? Is “breakthrough” designation a thing anyone cares about? CLDN received breakthrough designation.

RTRX finished enrollment of the drug I (and two wise colleagues) conjured for PKAN. I think this first try is not the best effort, unfortunately. The logP of the drug is quite low. I give this a 50-50 of working. We’ll find out if my first attempt at drug design works in about 6-9 months. My newer drugs are a little more exciting, but I’m rooting for the hundreds of dying PKAN patients.

Papers I’ve Read
——————–
FGF signaling deregulation is associated with early developmental skeletal defects in animal models for mucopolysaccharoidosis type II (MPS II). Belless et al. Hum Mol Genet 2018.
Substrate accumulation and its sequelae is thought to be the primary defect in MPS/LSDs. These authors put forth a bit of a new theory and the data is somewhat interesting.

Clinical Trials I Noticed
——————————
A Novel Therapeutic Target for Alzheimer’s Disease in Men and Women 50-85 Years of Age. University of Rhode Island. Dabigatran vs. placebo n=60.
Good luck!

Personal
———–
Projected release date: 8/25/2021. Day 464/1443. Loading… 32% complete.

12/18/2018

Biopharma/Investing
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I never thought Elizabeth Warren could be agreeing with me on a “solution” to the drug pricing “problem”. About a year ago on Maria Bartiromo’s television show I proposed a government-run drug company, owned by the USA taxpayer. Such models have proven very successful in China. A SEO is hardly unheard of in the US, where we have had many GSOs with variable success. Anyway, if the citizenry deems certain generic drugs to be so vital that they are utilities, a state-sponsored generic drug company is not a bad idea. It is especially worthwhile if the company has a publicly traded minority equity, so the financial results are transparent. If it is worth anything, it is an asset for the American people and contributes against our deficit. Such a company would have good scale and could sell products outside of the US, as well. There would be no excuse after the creation of such a company for “high drug prices”, at least from the purported “generic cartel” or alleged “bad actors” such as Mylan (not my opinion). Warren may be surprised at the lack of profitability of selling these old medicines, and would be stockholders might cringe at the negative margins in this business, but at least a “problem” would be solved. The subsequent “problems” would come to light: multi-year FDA regulation and review, unclear interpretation of the law, etc.

Clinical Trials I’ve Noticed
——————————–
A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With lamellar Ichthyosis. Mayne Pharma International Pty Ltd.
CD5789 is a new kind of retinoid (I think).

G-Pen Compared to Glucagen Hypokit for Severe Hypoglycemia Rescue in Adults With Type 1 Diabetes. Xeris Pharmaceuticals.
XERS is public–I recall the private company from a few years back.

Efficacy of a Plant-derived Quadrivalent VLP Vaccine in the Elderly. Medicago.
This is a n=12000 flu trial. Medicago was acquired by Mitsubishi Tanabe a little while back.

Intratumoral/Intralesional Administration of MK-4621/JetPEI With or Without Pembrolizumab in Participants With Advanced/Metastatic or Recurrent Solid Tumors. Merck Sharp & Dohme.
This is RGT100 from the Rigontec acquisition. I believe expectations are quite low here.

A Clinical Investigation to Assess the Performance of Natural Rubber Latex Condoms in Couples. Reckitt Benckiser.
Need a few volunteers. For science.

Papers I’ve Read
———————-
Insights into the pathogenesis of dominant retinitis pigmentosa associated with a D477G mutation in RPE65. Choi, et al. Hum Mol Genet 2018.
Ever try too hard? These researchers go quite a few extra miles to determine the structural relevance of D477G in RPE65, the gene responsible for LCA/RP. Talk about work: they generate a mouse model and do ERG, they do comprehensive in vitro work and for good measure some XRC. Well, they learned everything there is to know about ONE mutation in a rare disease, for all of the handful of people that exist with that disease. Kudos?

Personal
————-
Go go go, criminal justice reform! Let’s get that vote done today! When I get out I think I’m going to Genghis Khan the USA. Is the country ready for 5000 Lil’ Shkrelis?

12/14/2018

Biopharma/Investing
————————-
It is interesting to see which hedge funds are struggling. Alpha, which we can define as human-discoverable arbitrage opportunity, is a variable that has specific behavior. I conjecture alpha is correlated to the VIX. When volatility is high and markets are in panic, alpha opportunities exist as investors lose it. So, it is no surprise hedge funds have weak absolute and relative performance. Therefore, Balyasny’s flat return for the year is no surprise as the firm employs very few quants. Somewhat more surprising is Point72, whose quant team has grown (some say half of the firm’s money is managed statistically), which is also flat for the year. Citadel, a quant firm in multi-manager clothing, is up. Millennium, a hard-to-describe multi-manager fund, is up nicely. Deep value investors are getting destroyed as alpha is close to zero, so there are no rewards for ‘right’ calls and plenty of punishment for wrong ones. Alpha will rise again, and I’ll see you there when it does. In the meantime, my little asset class is more competitive with the Roivant, BioBridge, etcs. of the world. Staying nimble is key–most hedge funds can’t go from 100% exposure in one asset class to another very quickly (nor do they want to!).

How great is Quanta magazine? Finally, real science journalism for intellectuals. These articles give me a frisson I haven’t felt since childhood. Why? Because Nature is so vast, profound and inscrutable–irreducibly complex in its beauty–how could that not be fodder for great stories? (This magazine was brought to you by Renaissance Technologies, taking 0.0005% out of every trade in the stock market, 30 years running. Joking. Kinda.)

Remember, only one 30 month stay per ANDA! Looking at you, CORT.

Gotta love the pricing dynamics for EpiPen. $50 –> $300. Generic one: $300 sounds good. Generic two: Meh, $250. Turning a $50m drug to a $400m drug for a few years, then sharing the $400m market with 2 other players means you stll double your revenues long-term. Doubt many people want to make this product for a lot less than $250. There is a silly logical fallacy that prevails with price increases: BUT IT MUST HAVE BEEN PROFITABLE BEFORE!!!! BRING IT BACK! No. Not the way it works, unfortunately. Emotions cannot replace reasoning–no matter how heartfelt.

Interesting to see LCI and TLGT maneuver in what are tough times.

Merck spending 10x sales to buy a animal health software company. How is this not the worst strategic big pharma there is? SGP merger-of-equals to get MORE Vytorin/Zetia exposure, luckily bailed out by Keytruda… and how many other dud acquisitions?

The JNJ stuff is dumb. Stock not cheap enough to dive in but if Vioxx can’t take down Merck, talc isn’t going to bruise JNJ.

Papers I’ve Read
——————–
Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells. Wada et al. Biochem Biophys Res Commun 2016.
Wada makes up for the prior poor work by demonstrating that cereblon, our 442-amino acid friend, is a nuclear/cytosolic shuttled protein with no obvious NLS but two NES (nuclear localization/export signal). They then show (fairly convincingly), via CRBN domain deletion, that the N-terminus of CRBN binds to Ikaros. They also demonstrate downstream gene effects on enkephalin, an Ikaros target. I always thought enkephalin was a pain target, but perhaps it does more. Recall the CRPS trials for Revlimid (they failed).

A genome-scale CRISPR-Cas9 screening in myeloma cells identifies regulators of immunomodulatory drug sensitivity. Liu, Anderson, et al. Leukemia 2018.
Great expertiments here from Chinese researchers and Harvard’s eminent myeloma expert Ken Anderson which reveal more about CELG’s IMIDs. We see here that the degrader of the cereblon E3 ligase that the IMIDs bind to (creating/modifying a protein-protein interaction) is SCF(Fbxo7). Interestingly, and for the first time, we see that CSN9 deactivates SCF (via deNeddylation. So the homeostasis of this complex apparatus is putatively revealed. There’s a good cartoon of it in the paper.

Marcogliese et al., IRF2BPL Is Associated with Neurological Phenotypes, The American Journal of Human Genetics (2018), https://doi.org/10.1016/j.ajhg.2018.07.006
Another newly discovered rare disease. I was suspicious of the drosophila ortholog work until it actually recapitulated the bizarre human phenotype of neurological regression. Definitely impressive work, but not much to do from a pharmaceutical perspective. Learning that this protein is implicated in neurological processes is a victory itself. What it actually does (E3 ligase domain!?) will be even more interesting. Nothing to do from a therapeutic standpoint yet.

Chess – Martin is Black
—————————
1. d4 Nf6 2. e3 d5
I am a horrific d4 defender, where I try to play the Budapest to throw White off. I am even worse at playing against thematic ‘systems’ where sometimes no obvious response exists. I am much better at memorization than abstract concepts in chess for some reason. So this is the Colle or Stonewall? I don’t know but I do know 2…d5 isn’t the best response. Perhaps 2…g6 is better?

3. Nf3 c6
Again, I’m a bit lost. 3…c5 stronger as well as 3…g6.

4. Bd2 Bf5 5. Nc3 e6 6. a3 Bd6 7. Ne5 Nbd7 8. f4 O-O 9. Be2 Ne4 10. Nxe4 Bxe4 11. Bf3 Qh4+ 12. g3 Qd8 13. Bxe4 dxe4 14. O-O f6 15. Ng4 e5 16. c3 exf4 17. exf4 f5 18. Nc5 Nxe6 19. fxc5 Bc7 20. Bf4 g5 21. Be3 Kh8 22. Qh5 f4 23. gxf4 gxf4 24. Rxf4 Rxf4 25. Bxf4 Qg8+ 26. Kh1 Qd5 27. Be3 Rg8 28. Rg1 Rxg1+ 29. Kxg1 Qg8+ 30. Qg5 Qa2 31. Qf6+ Kg8 32. Qe6+?? Qxe6 33. Kf2 and the rest of the moves are omitted. I chased the King down and mated.

Personal
———–
32 months or better with CJ reform and 36 months worst-case as of yesterday.

12/10/2018

Biopharma/Investing
————————–
GILD couldn’t have hired a better CEO than O’Day. Severin Schwan was never going to give up his job, so makes sense, even after 31 years with Roche. The only question is what to do with Gilead? Can you gain scale in cancer from zero? Does the O’Day hire imply a continued focus on oncology? Seems challenging… acquire/merge with Celgene or Jazz (not much scale) could be an option. If I were CELG, I’d hit the sell button on a $90b part cash/stock bid. Accretive to GILD, for a little while. Another option is to try and buy Genmab as Gilead has very little large molecule infrastructure. Morphosys is a favorite of mine and another obvious candidate, but one-drug-at-a-time doesn’t bring you scale. Another option is to actually just sell GILD to JNJ or PFE which I doubt could be accomplished (too big and probably not enough interest–JNJ does have an HIV vaccine in phase 2, though). I guess if I were O’Day, I’d start talking up a HIV clearance (cure) by 2030 as the next big commercial opportunity. The drug to end all drugs–a $50-100bn revenue per annum medicine that rids the world of HIV. Who better than GILD?

Poor Axovant with another failure.

Hikma drops its clobazam generic. This was a super-expensive medicine that many have/are raced/racing for an ANDA.

Papers I’ve Read
——————–
Transcription factor IZKF1 is degraded during the apoptosis of multiple myeloma cells induced by kinase inhibition. Liu et al. FEBS Letters 2015.
These Chinese researchers try, but fail to elucidate very much about the cereblon-IZKF1 interaction that is heavily implicated in Celgene’s IMID drugs. By using non-specific kinase inhibitors they tried the hypothesis that phosphorylation impacts degradation of IZKF1–they found the opposite of their hypothesis but did poor scientific work with cell line choices and the ugly choice of kinase inhibitors. We will see some better papers in the next blog post.

Personal
———–
Toothache completely disappeared and some modest pain is now back. Going to the dentist for the third time in two weeks tomorrow.

Happy 15th month in jail is coming up in a few days!!! Going to miss this place!

Football was quite “stochastic”. I dodged the Patriots-Dolphins, Redskins-Giants massacres, but did fall victim to the Rams-Bears and Broncos-49ers upsets. Thankfully, the Bengals kept it close enough to cover. This was the weekend that probably blew up quite a few bankrolls.

12/9/2018

Biopharma/Investing
—————————
Chugai’s SKY59 C5-antibody may be a real threat to Alexion… Phase 1/2 data at ASH looked good.

China’s stock market is -30% this year. In US terms that’d be one of our worst years in history. US is flat YTD.

Alnylam is developing a RNAi for hypertension and also an amyloid-beta RNAi. You can’t make this up… talk about awful targets.

The Altria investment in Cronos is stunning. This isn’t related to healthcare but this is a sight to behold. Bubble or birth of a new industry?

Papers I’ve Read
———————
De Novo Truncating Mutations in WASF1 Cause Intellectual Disability With Seizures. Ito et al. Am J Hum Genet 2008;103,144-153.
These researchers used the Matchmaker Exchange to link together and find de novo mutations of WASF1. WASF1 is a fairly unique protein and I don’t see how one could therapeutically target it. It assists actin polymerization by creating a complex… complex. Maybe someone smarter than me can figure it out but I see brick walls. One of the problems is actin is so important in neuronal development and these patients had very profound intellectual disability from birth. Very sad.

Extramedullary Myeloma whole genome sequencing reveals novel mutations in Cereblon, proteasome subunit G2 and the glucocorticoid receptor in multi drug resistant disease. Egan, et al. Br J Haematol 2013.
Again, CELG background research. Interesting case report.

Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction. Sawamura, et al. Biochem Biophys Res Comm 2015.
One of many weak papers which grope for clarity on the IMID target cereblon. CELG background reading.

Personal
———–
I saw the very qualified and excellent dentist here today, again. He shaved the tooth down and it appeared the filling he did last week was a bit high and occluding a proper bite. I am suspicious and believe I am harboring an infection. He is of course, right, and there is almost certainly no infection, despite the pain I feel in my jaw. X-rays showed no abscess. Despite all this I will happily down a prescription of clindamycin, gleefully overusing antibiotics, destroying gut flora, all cost-free to me and $50,000 of annual taxes to you.

What is the DOJ doing arresting a Chinese MNC CFO? The rogue EDNY has again lost its mind. There are evidently not enough American criminals to prosecute. The ever-growing leviathan needs to be slayed. A 50% budget cut to DOJ and FBI would restore piority to these afflicted institutions.

12/6/2018

Biopharma/Investing
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Samsung Biologics has been halted for 3 weeks? These accounting issues have been persistent and the stock did fine. I wonder what is going on in Korea.

Papers I’ve Read
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Isosteric analogs of lenalidomide and pomalidomide: Synthesis and biologic activity. Ruchelman, Muller, et al. Bioorg & Med Chem Lett 2013.
Not the world’s most impressive SAR paper, but exploring the decorations of the indole (phthalimide) and glutarimide moieties led to little improvements. Of course, the only measured changes were TNF response to LPS, IL-2 increase and cell line anti-proliferative effect. At the time, cereblon was already identified as the therapeutic target for the “IMIDs” so it is a bit surprising to see these assays. Also, the “isosteres” aren’t very creative. 4-CH3 improves Revlimid but ethyl does not and other, longer variants were not attempted.

tp53-dependent and independent signaling underlies the pathogenesis and possible prevention of Acrofacial Dysostosis – Cincinnati type. Watt et al. Hum Mol Genet 2018.
This ultra-rare disorder has only been described in a few humans. A ribosomopathy, I’m not sure if its embryonic lethal in all homozygotes or some hypomorphic alleles are compatible with life, or what. This one is caused by a mutation in a RNA Pol I subunit, creating the fundamental and ubiquitous ribosome. Despite that, the pathogenesis is very tissue-specific. It was exciting to read tp53 -/- somewhat ameliorates the POLR1A -/- phenotype but it doesn’t rescue it completely. This CCH group also discovered and named the first patients with the illness. I find it incredible how quickly progress can be made in these ultra-rare/newly discovered illnesses.

Exploring the speed limit of toehold exchange with a cartwheeling DNA acrobat. Li et al. Nature Nanotechnology 2018.
I don’t know anything about engineering but how this DNA literally cartwheels (while one strand is bound to the “floor”, the other strand moves end-over-end to move its free-end to bound again) is fairly incredible. Still, don’t expect DNA nanomachines fixing up your cells anytime soon.

Personal
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7 days in and my tooth is still killing me. All that anyone can talk about here is Meek Mill’s new album.