11/20/2018

Biopharma/Investing
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There have been a bunch of questions on generics. The first thing to understand is the generics world has always been an cottage industry compared to branded pharmaceuticals. The largest 3 generic companies, Sun, Mylan and Teva, have market caps (EV maybe more accurate!) that are very modest compared to pharma or even single/few-product biotech companies like Vertex, Celgene and Regeneron. The fact that one drug from Alexion is worth more than the biggest generics player in the world is telling enough.
Moving on, there is a “new normal” margin compression in generics. For a long time, generics companies enjoyed 50% (sometimes higher!) gross margins. I actually think this comes from assuming normative gross margins from specialty chemicals (where pharmaceuticals originally evolved). Why shouldn’t a fine chemical medicine company have higher or at least the same margins as someone making polymers? The world has changed. Chinese and Indian companies care little for convention and Western margin is their opportunity. 30% or less gross margin for generics has become the norm and it will continue to plummet until ROICs approach WACCs. In essence, we’ve had it too good for too long and the party is over. This happens in cottage industries, all the time. Why here? The scale of making generic medicines is modest. We’re usually dealing in kilogram scale and rarely tonnage of API. This means that no matter what the product, it is easily made with cGMP quality at low cost. Assuming you have your own manufacturing facility, what is essentially happening is you are entering into a cost-plus dynamic. With no IP, buying consortiums and a FDA quick to approve new generics, the best you can hope for is cost recoupment with a margin. Obviously the higher the margin you can get, you’ll eagerly take, but equilibrium will quickly align ROIC to WACC for most projects.
Companies like Mylan and Teva are surviving because the rest of the world isn’t the United States. In most other countries, generics are still not that substitutable and health agencies are slow to approve new ones (30+ months). That will change. Healthcare costs have been growing for decades, as demand outstrips supply. Turns out people like living longer and being healthy. Drugs are a small part of healthcare costs and earn disproportionate blame, but generics are a hero and will see continued support from global governments.
Generics are great for entrepreneurs. I would know. It is such a fragmented industry, one can “hit it big” with any ANDA. It’s the pharmaceutical equivalent of a dollar and a dream–a $2 million ANDA could bring you $100 million in wealth if you pick your spots correctly. The problem, of course, is it is very difficult to scale. Like any gambling game, entrepreneurs tend to play too many hands and end up looking like the larger companies they are trying to beat. Occassionally, you get an Apotex or some other company with a hot hand a smart management team selecting great projects. Biogenerics are really high return projects from what I can tell, for instance. Inhalers and topicals appear to be similar. Oral solid dose is dead and likely dead forever (with the caveat that conditions can change).

Steve Cohen says a bear market is coming. Cohen also mentioned that Buffett is no Cohen. Cohen has a much higher investment return than Buffett but Buffett built a company that gets a multiple. I forget how old Cohen is (60?). They are probably neck-and-neck in terms of wealth for inflation and age adjustments. Cohen’s long-term returns are probably still in the 30% range, which is nothing sort of astonishing. Reminds me of the Stephen King book, “The Last Gunslinger”. Nevertheless, many feel he deserves an asterisk next to his name, like Barry Bonds. Cohen built a company of sharks who swarmed the waters for any advantages. Needless to say, many crossed lines that they should not have. Despite that, Cohen’s work ethic and talent speak for itself. He is an innovator in so many respects: the use of trading psychology, the focus on short/medium-term (more than 1 day, less than 1 month) IRR to achieve very high returns, the investment in technology to increase returns, perfecting the hub-and-spoke model, supreme talent acquisition, etc. SAC still deserves special mention in the firmament of great investment houses: Soros/Druckenmiller, Buffett, Cohen, Simons.

Bloomberg gave away $2 billion. I guess that means he is running for President. Good luck, Mike. Michael is one of my business heroes and I was fortunate to briefly meet him in college. Politically and personally, I think he would be a decent president. He is a little too left for me, normally, but he is a very practical guy that would appeal broadly to Americans. Trump’s best challenger for 2020, by far.

I saw DNLI announced “positive clinical results” and when I opened the story, it was Phase 1 healthy volunteers. Poor PR/IR person there.

Papers I’ve Read
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Thermodynamic characterization of the multivalent interactions underlying rapid and selective translocation through the nuclear pore complex. Hayama et al. JBC 2018.
These Einstein and Rockefeller researchers break the reader’s brains with their biophysics. The final frontier of molecular simulations amuses me. If you want to hurt your head, read this. They apparently solve the nuclear pore paradox. I, for one, didn’t know it existed. All jokes aside, this is interesting work on protein complexes that are “fuzzy”. I’m not sure they get it right because they’re probably not sure they get it right. I have to suspend enough disbelief to measure static in silico entropy changes.

Altered Mitochondrial Acetylation Profiles in a Kainic Acid Model of Temporal Lobe Epilepsy. Gano et al. Free Rad Bio Med 2018.
Never heard of this journal before but the workers do a good job demonstrating that SIRT3 is clearly a mitochondrial deacetylase and could be related to epileptogenesis. So let’s jump on it and make lysine acetyltransferase inhibitors? Not so fast. There is a lurking causality problem here, as usual. Despite that I think the results are worth further experimentation if you can find a selective enough inhibitor of acetyltransferases or SIRT3 mimetics.

Neuropsychiatric expression and catatonia in 22q11.2 deletion syndrome: An overview and case series. Butcher et al. Am J Med Genet Part A 2018.
Who isn’t fascinated by catatonia? This paper doesn’t add much to the picture but I certainly will follow-up on 22q11.2DS.

The cellular chloride channels CLIC1 and CLIC4 contribute to virus-mediated cell motility. Stakaityte et al. JBC 2018.
This was very interesting–MCPpV causes Merkel cell carcinoma. I don’t know the difference between a polyomavirus and an arenavirus but virus-causing cancers have always interested me. Their takeover of the CLIC4 and CLIC4 ion channels for motility is convincing and lends a clear pharmaceutical intervention. Very nice work.

Sports
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1-1 on Sunday. Titans stunk but the Bengals kept it close. Returning to mean, nothing to see here.

Poker continues to mystify me. “Game theory optimal”? Here’s one hand. I’m short stacked at a 6 player table. UTG raises 3x BB. One caller and then me. I’m holding KJs. I call, BB calls. Four of us are in. BB checks and the UTG raiser bets half the pot. Caller to the right calls. I raise, only doubling the bet (my stack is almost gone). Everyone calls and the original bettor goes all-in with a huge stack. 3 of us call (my stub stack calls for roughly 3x BB). Raiser turns over AKo, caller to the right flips over KQo and I’m stuck in third place. No consolation prize.

I also went all-in post flop in a button pre-frop-raise where the BB called me after seeing 8 2 2 flop. My hand? 3 3. He calls and turns over K K.

Personal
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It was nice to see the big homie speakeasy Sunday. One of my closest friends!

I like this Queens House of Representatives Democrat. Young woman. Hyphenated last name. You know who she is. She needs to go to college but at the same time she’s really independent and anti-establishment. Viva anarchy!

11/18/2018

Football
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Ran all the numbers (rather laborious) and believe the two mispriced games are TEN and CIN. I think TEN is twice as worthy as CIN. Everything else is fairly priced with one exception which is even less compelling than CIN. I did not include the late Sunday night game or Monday night game, due to fatigue.

11/17/2018

Biopharma/Investing
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Celgene deep-dive is progressing smoothly. I’ve skimmed hundreds of papers (4000 Revlimid entries in Pubmed), docket entries and more in preparation. Thanks for the crazy amount of mail.

Fascinating, if not desperate, deal to save $UTHR with $ARNA.

Papers I’ve Read
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Computational antimicrobial peptide design and evaluation against multidrug-resistant clinical isolates of bacteria. Nagarajan et al. JBC 2017.
I had fun flipping through this “end-to-end” paper that astonishingly starts with computer/math concepts and ends with in vitro testing. It’s too bad antibiotic resistance isn’t the threat some are making it out to be. The piper cites that deaths due to antimicrobial resistance are expected to exceed 10 million by 2050. I am very suspicious of that number and if you consider deaths by all infectious microbes, I’m not sure what the apples-to-apples comparison is.

Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Dasgupta et al. Nature 2018.
This brick-by-brick/no-tricks paper is a good example of core biology informing pathogenesis. This Baylor group starts with SRC-3 and tries to determine its phosphorylation kinase. The group convincingly demonstrates PFKFB4, a glycolysis (read: Warburg) enzyme, is the culprit. A series of experiments demonstrates enzyme/TF hyperactivity in a high-glucose environment. The noting of SRC-3/estrogen receptor coactivation unfortunately is not followed up on beyond some transcriptional data. I would have included ER antagonists to determine the functional relevance of PFKFB4 blockade vis-a-vis ER redundancy. Nevertheless, the group proceeds to microarrays where they demonstrate purine synthesis as the downstream consequence of this axis. One wonders if we’ve returned to square one with chemotherapy that often targets nucleotide synthesis. Anyway, once xenografts are included, we see etremely convincing evidence o this axis driving metastasis and tumor growth. Finally, they even find human evidence that SRC3-PFKFB4 overactive TNBC patients have poorer outcomes. Truly a Nature-worthy paper. Would be drug-hunters may be interested in developing PFKFB4 inhibitors.

Clinical Trials I’ve Noticed
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Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Anti-tumor Activity of FN-1501 Monotherapy in Patients With Advanced Solid Tumors. Shanghai Fosun Pharmaceutical Development Co., Ltd.
SF is one of the bigger Chinese pharma companies. This is a FLT3/CDK2/4/6 inhibitor.

A Study Examining The Effect of eFT508 in Patients with Advanced Castrate-Resistant Prostate Cancer (CRPC). Effector Therapeutics.
This is a private company focused on MNK1/2 and eiF4A inhibitors. They raised $38 million in a Series C. Definitely one to watch.

Efficacy and Safety Evaluation of Glepaglutide in Treatment of SBS. Zealand Pharma.
Zealand is still alive and actually might be a decent investment.

REGN2810 in Pediatric Patients With Relapsed, Refractory Solid, or Central Nervous System Tumors and Safety and Efficacy of REGN2810 in Combination With Radiotherapy in Pediatric Patients with Newly Diagnosed or Recurrent Glioma.
If you’re Libtayo, this is the part of the cancer world not carved up by Opdivo and Keytruda. Cancer’s Australia, if you will.

VNRX-5133 With VNRX-5022 in Subjects With Varying Degrees of Renal Impairment. VenatoRx Pharmaceuticals.
VenatoRx is apparently an antibiotic private biotechnology company. Also known as a company that is unlikely to survive. See above comments.

Cell Therapy for High Risk T-Cell Malignancies Using CD7-Specific CAR Expressed on Autologous T Cells. Baylor College of Medicine.
Interesting…

Feasibility and Efficacy of the Ketogenic Diet in Alzheimer’s Disease. University of Kansas Medical Center.
Don’t hold your breath!

Study of Anti-CD19 CAR NK Cells in Relapsed and Refractory B Cell Lymphoma. Allife Medical Science and Technology Co., Ltd.
Another mysterious Chinese CART player.

Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease. Gold Coast Hospital and Health Service. CannaTrust Inc.
Smonk weed?! What can this miracle plant NOT do?

Adherence to Walking on an Alter-G Anti-Gravity Treadmill. Texas Tech University.
Sign me up!?

NY-ESO-1 TCR Engineered T Cell and HSC After Melphalan Conditioning Regimen in Treating Participants With Recurrent or Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. Roswell Park Cancer Institute.
Why not contact Roswell Park for a partnership here, if you believe in NY-ESO-1?

Study of SHR-1210 in Combination With Chemotherapy in Advanced Esophageal Cancer. Jiangsu HengRui Medicine Company.
This is a Phase 3 trial of camrelizumab in China, licensed to Incyte fo $25m. A PD-1 mab, and the… 5th? Chinese PD-1 mab (Innovent, Cstone, Beigene, Jiangsu and one other I’ve forgotten… not to mention PD-1s already approved in China: Keytruda, Opdivo and more coming…) Good luck to all.

A Prospective Study Evaluating the Effect of Ocrelizumab on Brain Innate Immune Microglial Cells Activation in Multiple Sclerosis Using PET-MRI With 18F-DPA14. Roche Pharma AG.
Ah. A Clue!

VX15/2503 in Combination With Ipilimumab or Nivolumab in Patients with Head and Neck Cancer. Vaccinex Inc.
Apparently, these guys are public: VCNX. This is an antibody to not such an exciting target (at first blush).

Investigating the Cardiovascular Toxicity Exposure of Electronic Hookah Smoking. NIH.

Brief Book Review – Chernobyl: The History of a Nuclear Catastrophe. Serhii Plokhy
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Plokhy takes you inside the control room as Unit 4 of the Chernobyl Power Plant explodes and threatens the viability of the Eurasian continent. The author can’t help but be riveting thanks to the subject matter. No film or novel could match the truth of April 26, 1986 and Plokhy does the moments before, during and after justice. Those expecting Patterson will be disappointed, however. Plokhy is still a plodding Harvard history professor and he admirably contextualizes Chernobyl in the appropriate Cold War milieu. Given a 10% meltdown of just one of four adjacent reactors more than thirty years ago threatened millions of people, one cannot help but be petrified of nuclear energy (or nuclear anything) today. I’m sure reactor design has improved substantially to the point where uncontrolled reactions are unlikely (if not impossible), but the risk of “unknown unknowns” (Fukushima comes to mind) would preclude my support for nuclear power. Anything where the option of wiping out the planet is on the table is a risk to great to bear. That’s just me.

Sports/Poker/Chess
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How about those Knicks?

I am so, so bad at poker. Can’t wait to play Ivey for $5 million when I get out.

What does everyone think of the Carlsen match so far? I bet he comes back strong in the back-to-back white games.

Personal
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Less than 33 months to go! There seems to be some incredulity here. 84 month sentence – 14 months in = 70 months – 13 months good time = 57 months – 12 months program referenced in sentencing = 45 months – indeterminate but no less than 9 month home confinement and no more than 12 month half-way house = 33 to 36 months. Read the statutes. Pending reform remove a month or two. Don’t forget my appeal and possible media exposure calling for my immediate release.

11/13/2018

Biopharma/Investing
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Moderna is a good short. With winter’s inexorable arrival, concept biotech looks like a good short while there are pockets of good value in high probability development projects and specialty pharma (non-generics).

New generic ROIC has dropped from unbelievable to meh. Only those who can invest heavily in capex or find extreme niches will find success. The overlevered landscape is not auspicious and may help deflate competition at the margin, but an ugly ‘new normal’ is here for generics. I would not be long TEVA, for instance. Buffett may be right (by accident) if the bet is on biosimilars (which Teva is fairly weak in), or perhaps ROW generic performance. But as far as the US is concerned, these armageddon conditions will prevail.

GSK has done a marvelous job replacing Advair/Seretide. A generic Advair would mean next to nothing to GSK now. They’ve also reshaped the portfolio quite well. Still my favorite big pharma.

SOBI’s new antibody will be really interesting.

We will be doing Celgene as the first “deep dive”. Thanks for your comments.

Papers I’ve Read
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Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member. Dahl-Halvarsson, et al. PNAS 2018.
I am not too familiar with most of the rare disease purely-cardiac myopathies. This was a good catch-up without being a review. The workers overexpressed “Abba/Thin” to rescue Mhc-mutant phenotyes.

Local structure can identify and quantify influential global spreaders in large scale social networks. Hu et al. PNAS 2018.
I’ve been reading more applied math articles. A lot of work has been done on information “spreading” models.

Brief Review – “Things That Mattter” by Charles Krauthammer
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Krauthammer is a transcendent essayist who I’d almost enter into a conspiracy to write like (criminal justice joke). This collection of essays is humbling for any writer, professional or begrudging practitioner (guess which one I am). Further, I just like this guy–a chess and math fan, a conservative and a PHYSICIAN! A lifelong spinal cord injury victim who recently passed away (I think), Krauthammer is a fairly inspirational (and perhaps missed) figure in politics.
This collection of his works shines when it discusses personal affairs, such as the death of a family member, a baseball game and other mundane “things that matter”. His political writing, especially on domestic affairs is also and convincing. He writes accessibly, endearingly and logically–usually without beating the reader over the head. The essays on his interventionalist leanings are less exciting, probably because of my own personal isolationist perspective, but still provide a narrative to consider. I recommend the book to any conservatives confused by the current hyperpartisan/no-compassion meta-neocon-nihilist environment.

Poker
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In a run of bad cards or bad beats, one feels like such an idiot. In the opposite run, an unstoppable player ready for WSOP. Taming those emotions is tough and probably more than 50% of the game. The actual theories are fairly trivial and probabilistic. I think sometimes we read too much into some variables in the game: the ultra-meta is probably not where “the money is”. I’m still feeling my way around this game but I get the sense that interpreting primary game conditions (player tendency variables such as loose/tight, aggressive/passive, pre-flop playbook, general aptitude, always cbet/not always cbet; aggregate table tendencies such as volume, speed, etc.), emotional control and good theoretical underpinnings are the likely key to the game. Most top players will not edge each other out over the long run. I could be very wrong on that but I doubt the money is made being Tom Brady vs. Brett Favre, but just in being a NFL starting QB vs. not being an NFL starting QB.

My last big bad beat was a Qs flush from the flop, outdrew by the Kxo when the fourth spade flopped. Drawer is gonna draw.

Sorry for the typo in the last hand I posted! Will try not to make it happen again.

Football/Basketball
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My Bills came through, in the “battle of the bums” against the sorry Jets. I pushed on the sorry Jags and lost with the Dolphins. So 9-2-1, last 12 games. I’ve toned down the NBA as my bankroll suffered but will be returning soon.

Why did it suffer? I took the Golden State moneyline, which was a “too good to be true” 40c on the dollar. Of course, for their 2nd loss of the season, the Warriors went down.

Personal
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To all the US Senators who were not re-elected and used me as a campaign prop. You barked up the wrong tree. That tree fell on you. I make no apologies–you made your own bed. To all future would-be political opponents: I have a very long memory and an enormous amount of money growing at a rapid pace. Play games with your career at your own risk.

 

11/7/2018

Biopharma/Investing
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Earnings season is in full swing! Oh ALNY… probably a good long here…

Would readers prefer a “deep-dive” on CELG or AMGN?

Papers I’ve Read
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Will Courts Allow States to Regulate Drug Prices? Christopher Robertson, JD, PhD. NEJM 2018.
This isn’t a paper, just drivel the NEJM allowed published for some self-destructive reason. States can’t “regulate” drug prices. Countries that have ONE payor, that country’s government health body, cannot “regulate” drug prices, either. What happened when Greece couldn’t pay for Roche’s cancer drugs? Do you think Roche let Greece give them IOUs? No. They cut of supplies of life-saving medicines to a country that chose not to pay due to financial difficulty. The writer of the article seems to propose states should have the option to do the same. What this poor fellow confuses is regulation and access. Firms have a choice as to what they’ll supply at what price. If Maryland’s ill-fated attempt (reversed by Circuit Court) for drug price regulation were to somehow be found legal again, companies like mine would just stop selling to Maryland.

Maybe they can ask Greece for advice?

Clinical Trials I Noticed
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CLN-0046: Treatment of AMD Subjects with OTX-TKI. Ocular Therapeutix, Inc.
I had no idea this was a public company. Pipeline is kind of neat. OCUL is the ticker.

Vaginal Elasticity Assessment Before and After Vaginal CO2 Laser Treatment.
You got me after vaginal elasticity assessment. How do I enroll?

Briefly Reviewed: Perfect English Grammar by Grant Barrett
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Initially, I bought this small (3/4th size, 200pgs) guide for my language-impaired roommates. Of course, not being a remotely adept writer myself, I had to go through it first before recommending it to others. Barrett writes for an audience somewhere between their needs and mine. “PEG” probably should not be read by someone who hasn’t finished high school, but I found it too incomplete and scattered for a scientific or financial professional looking to improve his knowledge of English.
Despite that, unless you’re familiar with copulas, gerunds, determiners and the myriad mind-numbing derivatives of various parts of speech that come with writing for a living, this is a nice refresher for the “too busy to care”. You should care, though.

Sports
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9/10 for my last ten football selections (some were ML). I don’t have a read on the Panthers/Steelers game, but if I make a decision before gametime, I’ll try and make a quick post. Basketball will be interesting tonight. I’m going with DEN -3 and ML, DAL+9.5 and ML, CHI+10.5 and ML, SAC+8 and ML and ATL+1 in order of conviction. I’m enjoying the NBA and predictions increase the edifying feeling.

Poker
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Bummed over some bad luck. In a 1/2 unit 6-player game, I’m 3rd to act after the binds. UTG check, call of 2 to my right and with AdJh I raise to 6. All fold except our caller villian. Flop shows Jc 2d 3s. Pot has 15 in it. Villian checks, I bet 7. Villian calls. Turn card is a 7c. Pot has 29 in it. Vil checks I bet 15, Vil calls. River is a Kc. Villain checks, I bet only 10, Vil calls and turns over 8Jc. Did I play it right?

Also lost a frustrating AI hand with JJ vs AKo. My luck!

Personal
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Spoke with my attorneys today. Brafman is really a great fellow. Lawyers are generally despised, typically for good reason. Ben is not one of those. Several of my other attorneys are fantastic friends and great advisors. They all know who they are, but I have about 10 fantastic attorneys that have become friends. Hopefully it’s not just for the bills 🙂

11/5/2018

Biopharma/Investing
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So, I guess we’ll find out if the Pfizer/Glycomimetics drug for sickle cell works next year.

I still like SRPT and GBT.

Interesting to see VRTX’s early stage programs include FSGS (hey, that’s my disease!) and PKD. What’s up with that!

I think I will do a “deep-dive” for a stock, including a full DCF (done in my notebooks!). I’ll try and shoot for one stock a week. That’ll cover 52 stocks out of a universe of… 500? Not much coverage but I beg the reader’s forgiveness. Maybe I can do two some weeks.

Clinical Trials I’ve Noticed
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Compassionate Use Individual Request Program for GSK525762 in NUT Midline Carcinoma. Drug: molibresib. GlaxoSmithKline
This BET inhibitor must be working for GSK to take this action.

Lenalidomide in Anti-MAG Neuropathy. Phase Ib Study.
I’ve never heard of Anti-MAG Neuropathy. Seems like myasthenia gravis. Might be a good indication for would-be drug company builders.

A RETROspective Study of Patients with TK2d. Drug: dC/dT. Modis Therapeutics Inc.
This Orbimed-funded orphan drug company just announced a $30m Series A. I don’t know a lot about this disease or putative drug, but interested in learning more. Someone shoot me a paper or two on this, please.

Assess the Gluten Degradation Activity of PvP001 and PvP002 in Healthy Adult Volunteers. PvP Biologics, Inc.
This Celiac Disease-focused company is fairly quiet about what they do. I wonder what these drugs are… oral enzymes perhaps? Could be a big product but I thought Takeda had rights.

BHV-4157 in Adult Subjects with Spinocerebellar Ataxia. Troriluzole. Biohaven Pharmaceuticals Inc.
I know very little about BHVN but I do know a lot about riluzole. I suspect this riluzole derivative will do nothing, but who knows.

Daunorubicin and Cytarabine With or Without Uproleselan in Treating Older Adult Patients With Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy. NCI.
This is Glycomimetic’s E-selectin drug.

Pinometostat and 5-Azacitidine in Treating Patients With Relapsed, Refractory, or Newly Diagnosed Acute Myeloid Leukemia With 11q23 Rearrangement. NCI.
This is Epizyme’s DOT1L drug.

Brief Review – My Inventions – The Autobiography of Nikola Tesla
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I found this tiny volume confirmatory of the recent biography: Tesla is simultaneously delusional and brilliant. He’s a man of science but also of the supernatural. Truly one of the most bizarre individuals I’ve ever read about.

I’ll try to make a book “section” of the site. If anyone is a WordPress pro perhaps my people can reach out to you to coordinate this. A simple list of books I’ve read while I’ve been in my New Jersey office might be interesting to the reader.

Sports
———-
The Patriots, Steelers and Chiefs came through and my small token on the Bills did not (so much for their fearsome defense). I’m 8/9 in my last few football selections. My algorithm is a fairly simple relative-strength stochastic. I think the big question is how much “decay” one builds into memory. Does a team’s performance from last year matter? Two years ago? Is there a variable one could create to model individual player performance longitudinally and another variable to assess team roster identity? Lots of ways to improve an algorithm. Lots of ways to mess it up, too 🙂

So much for the Knicks as well. I forgot to include the “never bet on the Knicks” function that all NYers have come to appreciate. The Wizards have a pretty good roster but a bad start to the season. Hard to predict those things. I also flunked on the T’Wolves game but did pick up the Raptors/Lakers. Poor Lebron. My basketball look-back period is very short, unlike football, and a few other differences exist between formulae.

Personal
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I have to refill prescriptions here, just like in the real world. Go figure. No copay.

75% of the people here shouldn’t be here. I doubt our founding fathers wanted a prison state where most individuals are incarcerated for long periods of time for owning guns and peddling “illegal drugs”. Very sad. So often, jail is an expected outcome of a troubled, urban youth. The cost of incarceration is incredible and few lessons are learned. If anything, the inmate is set back further from potential redemption.

I fear the plethora of cats that cohabitate this compound will be very cold this winter. The tough guy persona the reader has come to love is betrayed by my love for these furry interlopers. The cats are well-fed, thanks to inmate willingness to share lunch. I sometimes wonder if while lounging about they ask each other what they’re in for. “Ate the dog’s treats.” “Catnip, possession and intent to sell.” “Dogslaughter. (gasp!)”.

11/4/2018

Biopharma/Investing
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Poor PBYI. Hard to tell if its a ‘value stock’ now.

Innovent is public. $3b USD MC. Another PD1 player (and Beigene competitor).

Clinical Trials I Noticed
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Neoadjuvant and Concurrent PD-1 Blockade Combined with Definitive Chemoradiation in Nasopharyngeal Carcinoma. Innovent.
Sintilimab is Innovent (and Lilly’s) PD1 mab. See above for brief comment on innovent.

Safety, Tolerability, Pharmacokinetics, and Antitumor Study of ADCT-601 to Treat Advanced Solid Tumors. ADC Therapeutics.
An AXL armed antibody. This is in addition to their CD19, CD25, CD22, PSMA and DLK1 ADCs. This company is probably worth a few billion.

A Study of Lobaplatin/Etoposide With or Without Anlotinib Maintenance Therapy in Patients with ES-SCLC.
Well, China is here. Between anlotinib and apatanib, you have two home-grown TKIs from China. Lobaplatin is a Chinese platinum as well. China is sort of like the new Japan for pharma.

Clinical Trial Using the Proteolytic Fraction P1G10 From V. Cundinamarcensis to Heal Diabetic Foot Ulcer. Federal University of Minas Gerais.
Not for me but possibly a good opportunity for would-be in-licensors out there.

Comparison of the Efficacy & Safety of Resusix with FP24 in Patients with Acquired Coagulopathy. Entegrion, Inc.
Pretty interesting alternative to FFP.

Sports
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Nothing too exciting this weekend. I think the Patriots -5 are fairly safe against the lowly Packers. It’s painfully clear Rodgers can’t carry them this season. Also trying the Knicks+ 7 tonight. We’ll see!

10/31/2018

Biopharma/Investing
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Celgene is going to have a rough next decade. With 12 of 15 billion in revenue disappearing in the form of generic Revlimid, Otezla and Abraxane, I’m not sure CART, JAK and S1P1 will do the trick. The company spent a lot of money on buybacks and finds itself in a potent net debt position. Novartis reported $20m in revenue in the second full quarter of their CART product Kymriah. You know what to do!

Papers I’ve Read
———————
Mutant APP and Amyloid Beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer’s Disease. Reddy et al. Hum Mol Genet 2018.
Papers like this should not be published. The authors find impaired mitochondria in AD neurons. No shit. Things go wrong, horribly wrong in Alzheimer’s brains. Biological processes are upended and synaptic integrity collapses. Why? Well, we know that mAPP (mutated amyloid precursor protein) patients suffer early-onset AD, which certainly implicates A-beta. Despite this, all attempts to neutralize A-beta have not changed outcomes in AD. This is probably due to a temporal-treatment mismatch. But this paper tries to suggest impaired mitophagy and mitochondrial function as a direct consequence of AB. It certainly is an epiphenomenon, but that is about all that can be claimed. Eating fruit in my home and then throwing it in the garbage results in garbage. Not throwing that garbage into the incinerator or leaving it on the sidewalk results in garbage buildup. Garbage buildup will attract rats. Rats crowding my kitchen garbage can will scare wifey. Wifey punching me in the face will cause a black eye. Eating fruit does not cause black eyes.

Brief Review – Ship of Fools – Tucker Carlson
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Liberals and the bi-curious should read this. Carlson provides the best current thinking from the right. He does not genuflect to Trump (and even seems dismayed), which perhaps is a conscious effort to win credibility from the reader, so don’t think you’re picking up a propaganda pamphlet. With his television charisma transported to the page, Carlson runs through a dozen or so disparate subjects through his perceptive and historically-informed lens. How left-core issues have become right-core issues (labor) fascinated me. I’m not a keen politics observer but I really enjoyed this as Carlson lauds certain old-line liberal principles (which appeal to me) and have been lost in today’s demagoguery.

Football
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The Bills play remarkably well for their record. Their defense made the Patriots look silly and I “sweated” this game substantially. I took the Patriots ML, -13.5 and a tiny bit -21.5. So, I was 3-0 this weekend (Patriots, Panthers, Redskins)! Now if I can only get my poker game moving… I’ll try to post football picks BEFORE the games start. With the return of the old PCs, I am attracted to writing again. I’m still very busy, however! Despite this I am also going to try and pay attention to basketball.

Poker
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Someone tried to play a constant all-in/rebuy game against me. That didn’t work. Taking blinds here and there and then getting slammed on AI calls was a quick lesson for villain.

Personal
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Thanks to my new friend who sent me works on Real Analysis, Topology and other fields. Math sits at the throne of the mind.

10/29/2018

Biopharma/Investing
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ABBV looking attractive at these prices.

Papers I’ve Read
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A mutation-led search for novel functional domains in MeCP2. Guy et al. Hum Mol Genet 2018.
Nothing too exciting, seems to confirm C-terminus deletions in MeCP2 don’t result in functional deficiency but more quality-control/protein-stability problems. Authors speculate on a drug helping but I think when you’re missing most of the translation product due to transcription truncation there isn’t much hope for small molecule approaches.

Impaired Mitochondrial Dynamics Underlie Axonal Defects in Hereditary Spastic Paraplegias. Denton et al. Hum Mol Genet 2018.
I don’t know much about this family of diseases, so this was a helpful paper to catch up with.

Football / Poker
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Took the Redskins -1 and the Panthers ML. 2/2 this weekend. Staying away from Patriots -14 although that rises to the level of actionable. It’ll be a game-time decision.

I am truly awful at poker. One recent hand was J10 (mine) vs QQ (his). J 10 Q flop. I bet, he calls. Q hits. I check he bets heavy, I call. J hits. I’m already mostly all-in. Villain was very tight player but often doesn’t understand preflop hand-strength (noticed he’d raise preflop with K10o J8o etc).

Personal
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End of the year is approaching! 33.5 months until home. Everything is mostly good here. My bestie is leaving for prison camp.

Glossary
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I will be trying to improve this section with sequentially more complete definitions of terms/concepts, hosted on a separate page on my domain. Some of these concepts are very simple but get very complex quickly with more digging.

autophagy – The process of recycling (death) of cellular components.
mitochondria – Cellular organelles that are the main source of ATP. The shape and size of mitochondria are regulated by enzymatic fusion and fission processes. The mitochondria is membrane-enclosed and membrane potential is a measurement of mitochondrial health.
mitophagy – Mitochondrial degradation/autophagy.
negative/purifying selection – The removal of a gene or allele from a species’ gene pool due to disadvantageous properties via natural selection.
Southern Blot – laboratory technique used to detect nucleic acids via hybridization
transcription – The process of transcribing mRNA from a DNA template (gene).
translation – The process of building a protein from a mRNA template.

10/25/2018

Biopharma/Investing
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Poor SELB. Can’t win them all.

Still like GBT.

BGNE has come in a lot, appropriately. Hard to beat Imbruvica and I think you might need an ionic (standard) binder to change things here. Covalent is covalent, amirite?

Big Revlimid, Soliris, Keytruda and Opdivo numbers. Cancer/Rare disease is eating pharmaceuticals. All the basic necessities of statins, metformin, ARBs, antibiotics have been handled. The pharma industry basically exists to manage the 1%-10% of maladies that create 25-50% of healthcare costs. This is a good place to be. No one wants to die of these nasty illnesses and “greed” can’t come into play when you’ve created the first ever treatment for some rare tumor as opposed to improved dry eye symptoms by 30%.

Maybe VKTX is a long in comparison to MDGL. I remember when VKTX couldn’t find a dollar underneath a couch cushion, but that’s life!

Book Review – She Has Her Mother’s Laugh – Carl Zimmer
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What do we make of “She Has Her Mother’s Laugh”, Carl Zimmer’s latest, and at 600 pages, plumpest work? While ordinarily, I’d say you can skip the theatrics and read Korf’s genetics textbook and keep up with Am J Hum Genet, I still recommend “SHHML” to the layperson and scientist alike.
Zimmer takes disperate fields and has mostly positive results in annealing a reasonable and cohesive narrative that leaves you satisfied. From the history of heredity, which is mostly an exercise in anthropology, and perhaps zoology, Zimmer then tackles the Darwin-Mendel-Lamarck-Galton pre-genetics era with the air of a historian. The problem is that half of this volume is retelling what Gould, Dawkisn and others have already done, and better. There’s far too much “gemmule” and far too little exon.
So why pay attention? First, Zimmer is a tremendous writer. While it took time to finish and synthesize SHHML, there are few moments when the story drugs or is unreadable. Second, Gould is dated: epigenetics, let alone CRISPR, didn’t exist when he was alive. Zimmer impressively weaves bleeding edge advances without temporal distinction. In general, the book moves from the past to the future, but Zimmer prevents SHHML from becoming an encyclopedia by dragging the future backwards and vice versa when appropriate, and by bringing his personal genetics journey into the story to illuminate the science. Unfortunately, this works only to break monotony of what would be a reasonable textbook on the history of genetics–Zimmer feels impersonal and detached. She may have her mother’s laugh, but we never hear the joke.
Another shortcoming is the substantial body of recent advances and basic facets of the subject which are completely left out. We can forgive Zimmer for excising topics like synthetic biology, alternative splicing, vaccines, CART and more, as he’s approaching the limit for a reasonable printing of a somewhat technical subject. This is not Principia Genetica.
Despite this amnesty, Zimmer comes up short when we ventures into a few places, including alternative modes of inheritance. Nodding to the meme, Zimmer nonetheless biopasses prions or any discussion at all of computer science and bioinformatics. Recent papers on algorithms imitating nature and vice versa would have been a nice addition to admittedly already myriad vignettes.
So, occassionally long-winded Zimmer does a great job of explaining sometimes abstract, sometimes concrete and always dense science. We’re left with an awfully preachy and bizarrely placed ending rant on the environment and politics. It would not be a modern mass-market published work without some social justice plea, I suppose. As someone who has made his living off of the subject matter in question, I can’t help but love SHHML. If you’re looking for a modern, up-to-date and reasonably comprehensive history of heredity and genetrics, Zimmer delivers.

Brief Book Review — Molly’s Game – Molly whoever
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This vapid scrawl outlining a classic tail of Hollywood failure never leaves the reader feeling sorry for its protagonist. Molly is a preeminent putative overacheiver who doesn’t realize she’s achieved nothing and is a product of parents who haven’t pushed her hard enough despite believing the opposite. Naive Molly doesn’t understand that going from her demeaning cocktail waitress job to “running the poker game” is not a graduation. The wealth of the men leering at you like a delicious pastry does not change the fact you are objectified. Still, she’s the proud poker princess pushing herself to the pinnacle of … party planning? Inevitably poor Molly involves herself (or vice versa) with organized crime and it all comes crashing down. Fuck Molly and the three hours it took to read this sorry chick flick.

Personal
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Is it okay to have a crush on Chelsea Clinton?

One life goal is to get served with a lawsuit every day. I probably average around one a month. Gotta step it up.

Wealth is massively increasing again. What to do? Sports teams have gotten stupid expensive for assets that do not produce income (unless I’m not in the know). Paintings seem like better investments–sports is eternal in some ways but shifts quite a bit within 50-100 years.

I am reading a lot on and playing a lot of poker.

I’m going to learn Java.