904 days left


Lots of news out there. Regurgitating it is not useful. Plenty of websites out there for that. Insight? Not much of that around.

AGN whiffing on Naurex assets is not surprising. Long ago real diligence revealed peptide-based NMDA is a really insane way to try this hypothesis. The data were VERY suspect, which is why Naurex went for remarkably little (~$500m if I recall). Speaking of which, Spravato was approved. Must be administered in a physicians office. It appears they underpriced it. If the average price is $750 and I guess patients will use 6 doses per course average, it is very modestly priced for a last-line option in a very severe patient population. Depression patients just don’t go to the office frequently. Getting out of bed is hard enough! In the real world, ketamine is dosed as needed and not on a fixed-schedule. Could break $1 billion if it gains massive adoption, which seems unlikely. J&J is usually very good at launches but flops happen (Invokana, Intelence).

Despite all the advances in CF (like the VX-445 data the other day), CF patients’ lungs are still badly colonized by bacteria. Who will be their white knight in an age where antibiotic development is persona non grata? See Papers I’ve Read section.

For FCSC, KRYS and ABEO, stay cautious. Data quality is really important and companies will put their findings in the best possible light. Be skeptical of single-center data, non-published or non-presented data, etc.

Some big pharma stocks getting tantalizing: GILD, ABBV.

Papers I’ve Read

Once-Daily Plazomicin for Complicated Urinary Tract Infections. Wagenlehner et al. NEJM 2019.
Needed: Antimicrobial Development. Cox, Nambiar, Baden. NEJM 2019.
Plazomicin for Infections Caused by Carbapenem-Resistant Enterobacteriaceae. NEJM 2019.

Plazomicin looks like a new and useful aminoglycoside. An accompanying editorial laments the lack of choices in antibiotics but, alas, the authors are lying. Plazomicin, sold by AKAO, had a whopper of a first quarter, selling around $500,000. I think Britney Spears’ back catalog did better than that. Trashy, my cat, probably earned more in YouTube revenue. If new antibiotics are needed so desperately, why aren’t you doctors who write these editorials actually prescribing them? AKAO is nearly out of business (give it another quarter or two). So, desperately wishing corporate suicide will not get you far. Torching cash is usually not a preferred method of wealth disposal. For drug companies, the only obvious choice to me is to raise the price of antibiotics, especially last-line agents. Serious treatment-resistant infections are lethal–why shouldn’t they have cancer-like pricing if one’s life is on the line?

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. Bardia et al. NEJM 2019.
These data are incredible. Should be the next Ibrance. What am I missing? Doesn’t that make IMMU a 5x?


I introduced some of my fellow inmates to jazz music. Feels like that Talladega movie with Will Farrell. Sounds like someone is strangling a cat!


905-910 days left


Looks like XON is disappearing. Good riddance to hubris. Soon-Shiong next?

It’s amazing how Sun has bucked the trend in generics. Taro is quite the engine I guess?

Apparently “biotechs” that don’t care about making money and are focused on ‘public benefit’ go out of business. How about that!?

ACAD is still a pretty good short. I think LOE is sooner than it looks for this product and all of the product development costs in the world won’t help it too much. The company needs a new drug. Targeting $300m in 2019 revenue implies +40-50%, which isn’t impossible, or even unlikely, it’s just not a lot relative to the market cap. This is a promotion-sensitive drug, too, where new patients are needed (high turnover).

Congrats to LGND for monetizing Promacta. Smart team!

Microaggresions, Nanobigotry and Picoprejudice – A Critical Review of “Racist Like Me — A Call to Self-Reflection and Action for White Physicians”. Deborah Cohan, NEJM 2019

An editorial written by a white physician, exhorting fellow white physicians to urgently battle their collective alleged implicit bias and racism was published in the New England Journal of Medicine. The author’s self-flagellation is, like most acts of atonement, a subtextual peacocking of virtue and superiority. Even at the outset of her apologia, Cohan comforts herself with her score (not peer-reviewed or in a supplemental addendum) on the implicit-association test, a purported diagnostic for subacute racism. This wavering is no contradiction, but a contrapuntal thrust of her achievements as a truly aware… micro-bigot. From this antecedent, she leaps valiantly with syllogistic ease–noting her ‘mission as a white physician is to be humble and respectful toward my patients… …as a revolutionary act against racism, elitism, and hierarchy’. Nevermind for a minute how we got to elitism and hierarchy: what happened to the Hippocratic oath and common sense? The mission of ANY physician is to be “humble and respectful towards their patients”. Sine qua non, no? Elitism and hierarchy? If treating your “patients with respect is a revolutionary act against racism, elitism and hierarchy”, I guess physicians are the new iconoclasts. Viva la revolution!

Cohan’s desire to fight racism, while honorable, is irrationally metastasing to redefine her role as a physician. There may be tremendous inequality in the world, but a plumber is someone who unsticks toilets and an ob/gyn is someone who delivers babies, examines vaginas, and prescribes birth control. You can try to recast yourself as a champion of equality and race, but you’re not a social sciences philosopher and you’re still doing a job that a computer will eventually replace. What made Dr. Cohan regard herself as Themis for the medical world is not apparent. It takes some gumption to immediately conclude there is an urgent implicit bias-driven racism problem in medicine and that all white physicians “suffer” from this malignant malady, and we need to hear the unlettered Dr. Cohan’s perspective to address it. Urgently.

I think physicians tend to forget the unearned pedestal they blindly climb is largely self-directed. Cohan is not a hem-onc or a PhD or in some field where things are actually happening. In case you haven’t inferred, my view is this pretentious trash shouldn’t be in the NEJM. It most certainly shouldn’t come from a field where the major dilemma is which kind of rFSH works best. Oxytoxics haven’t changed in 100 years–get over yourself, glorified electrician. Model yourself after Virchow. Break barriers in your scientific field. Instead of productive research, we get this unstinting and unsolicited micturition.

Cohan notes she is ‘shaped by the subtle trendils of white supremacy’ that are ‘deeply embedded in our culture’. Poetic and even true perhaps, but if we are all shaped by this undetectable racism, why should we be listening to a white physician’s viewpoint? Why not listen to Phil Ivey, Morgan Freeman or Dwayne Michael Carter who claim racism has had zero effect on their success as black professionals? Racism is a real and ugly thing, but the slippery slope some, largely affluent and white, are chasing is dangerous. There is a Mobiusian inevitability of racism according to this self-abnegating crowd. Progress cannot be acknowledged. I read somewhere that the KKK membership is down 99% from peak. That’s a great thing. But when we need to define implicit bias and microaggression to sustain pangs of guilt, what’s next? Nanoracism? Picoaggressions? The need to implacably advance and define ever-dimishing transgressions is fatuous. It conjures a froward and liverish nerd-hipster hybrid only satisfied with delineating your impiety.

This sort of nouveaux mortification of the flesh is not what Christians had in mind but Cohan adapts it perfectly: “I need to explore the parts of me that are most unwholesome, embarassing, unflattering… …My goal is to dismantle the insidious thoughts…” Sound familiar? The Bible suggests we “put to death what is earthly in you: fornication, impurity, passion.” For me, this evokes an arguably psychotic penance for original sin. Yet here, Cohan is a new self-appointed God, the physician’s original sin is white elitism and her decree-cum-solution is apparently to brag about it all. “As I become aware of my biases, they began to loosen their grip”, Cohan notes. A 12-step program for this “treatable condition” (her words) would be welcomed by fellow San Franciscans.

But the woke police have an ulterior motive. My theory is the genesis of this strange movement is the justification (and guilt) of the movement members’ ordinary intellect coupled with their slightly above average achievements in life. If you’re on television and of minor celebrity (or a doctor), the ‘luck’ you’ve received is really ‘privilege’ and your karmic atonement is necessary lest you upset the balance of power. Forget hard work, natural variability of intellect, or pure luck. Genuflecting to the PC gods allows for your continued place in the slightly above-average and mediocre-at-what-I-do firmament. Acknowledge and accept your “privilege” as your raison d’etre and you may be able to sustain your advantage as you work to undermine and dismantle it. I think most extremely successful people don’t even consider race or racism. Like birthdays and religion, we need a narrative bigger than us to explain why we are what we are. The race boogeyman is convenient for he affluent, pathetic white that need a crutch to lean on and look down over, and a reason to not elevate further. Morgan Freeman notes that we inflate racism to a bigger issue than it is. The problem is people like Dr. Cohan.

Cohan, you are not a racist. You’d be racist if you told a patient of color that you don’t accept Medicaid, pre-judging their income based on skin color. You’d be racist if you refused to treat black patients. You’d be racist if you uttered racial slurs. “I noticed myself sitting farther than usual from a black patient in her hospital bed” is a far cry from a “perpetuating a systemic inequity for patients”. I am truly dumbfounded that a sentient person could write this essay. Instead of implicit bias spreading through health care, may I suggest some form of racist dysphoria is spreading across California, resulting in some bizarre acute sensitivity to a largely imagined collectively guilty conscience. “…health care is not safe for people of color as long as the overwhelming majority of U.S. physicians are white…” How was this published?

The echoes of racism are still alive in the present day. Cohan’s article trivializes real racism by wokesplaining semi-elite guilt. Cohan pathetically shames herself to feel better about the benefits she perceives she’s received from the white patriarchy. If you call a $300,000 round-the-clock job with a ton of debt that you train a decade for ‘privilege’, count me out. I’ll stay here educating inmates who confess their woes come from poverty, not having a father figure around and removing themselves from school to chase a quick dollar selling drugs. The media’s romanticizing of guns and drugs has crippled Black youth and culture. The societal bonds of family and the value of education that have allowed Asian-Americans to out-earn even the “priviledged” white don’t exist in Black culture. Why? I’ll tell you it has nothing to do with white physicians and it is not a problem Dr. Cohan is remotely qualified to assist with. It is heartbreaking to meet man after man here who can barely read and write with the same sad story. “Dad left when I was 6.” “My dad is still locked up.” “I didn’t finish high school–left in the 8th grade.” “Never heard of the Beatles.” I’ll do my tiny part and not selfishly seek attention for actual good deeds.

I’m disgusted that the NEJM and Lancet have becoming stomping grounds for the ultra-progressive agenda. The Lancet has functionally become “Social Justice Weekly with a few clinical trial reports.” I’m a “compassionate conservative”, or really an actual liberal, and I’m trying to read about the latest advances in medicine. The NEJM isn’t the place for some untrained doctor to wax on critical theory.

Closing The Gap — Making Medical School Admissions More Equitable — Talamantes et al. NEJM 2019 – A Brief and Critical Review

Just pages before Cohan’s essay lies this masterpiece lamenting the disparity of minority physicians versus minority makeup of the general population. There is no mention of the Asian minority, interestingly. Nowhere does Talamantes suggest that socioeconomic equality could possibly be a result of cultural differences. No, the answer lies in changing medical school admissions qualifications. Throw away the MCAT, and let’s value “distance traveled” (how far a student has come in light of discrimination or a lack of resources or support).
When it’s you on the operating table, you can take the surgeon with the low MCAT score and higher “distance traveled”. I’ll go with the high scorer and not give race a second thought.

Actual Science Papers I Read

Flight of an aeroplane with solid-state propulsion. Haofeng Xu, Yiou He, Kieran Strobel, Christopher Gilmore, Sean Kelley, Cooper Hennick, Thomas Sebastian, Mark Woolston, David Perreault & Steven Barrett.
Flying with ionic wind. Nature 2018.
These MIT researchers fly a plane that has no moving parts and makes virtually no sound. Ionic winds power this 5kg solid-state system to flight. Incredible!

Clinical Trials I Noticed

Safety, Tolerability and Immunogenicity of NBP607QIV in Healthy Adult Volunteers. SK Chemicals Co., Ltd.
A new flu vaccine player has appeared.

A Study of How Tutin and Hyenanchin, Two Toxins Found in Honey, Are Absorbed and Processed by the Body. Christchurch Clinical Studies Trust Ltd.
Don’t eat too much honey! Apparently glycine receptor modulators are in there!



More thoughts on gene therapy taking over the world of medicine. This will take years and execution is still key–having any old vector won’t do the trick. Nevertheless, SRPT, QURE, PTCT, BOLD, ABEO, SGMO, RCKT, FOLD, FCSC, AXON, etc. are all intriguing investments.

Thanks again to all of my friends & family who navigate my social media tirelessly for me (including the occasional troll!). James, Dan, Taylor, Mark, Dad and those who won’t be named–you make all of this so much easier! It is great to receive emails, posts, tweets, etc. by jail-email. Anyway, continuing a LinkedIn conversation–it is not a unique idea that online news companies are NOT a good business model. Apparently we touched a nerve. Just look at TST! It is pretty much the consensus that these types of companies lose money, forever. Building a brand like WSJ or NYT takes a very long time and a ton of money. I’m not even sure it is possible anymore. Even by diving into the sludge with salacious and often erroneous or fraudulent content doesn’t guarantee a product. High-integrity journalism (nowhere to be seen) definitely reduces margins. And remember, this is all during a peak-margin period. In a recession, it’s over. Perhaps I’ll be a buyer of last resort. But again, it is not news that news doesn’t sell.

Clinical Trials I Noticed

Study of Efficacy and Safety of Investigational Treatments in Patients with Moderate to Severe Hidradenitis Suppurativa. Novartis.
This trial studies Novartis’ CD40 mab CFZ533, which I’ve noted is in a few other indications, and a fairly unknown and mysterious candidate LYS006. HS is one of the lesser-known TNF-constellation autoimmune diseases. Once you’ve done RA, psoriasis, PsA, Crohn’s, UC, pediatric forms of the aforementioned and AS, uveitis, Bechets or HS is next on the list for your pan-autoimmune medicine.

KPL-301 for Subjects with Giant Cell Arteritis. mavrilimumab. Kiniksa Pharmaceuticals.
This is a really interesting company that is probably a good long investment. KNSA is the stock ticker, about $1 billion market cap. KPL-301 is AZ’s mavrilimumab, a GM-CSF antibody. I played with one of these types of drugs at KBIO. That might have been a G-CSF antibody? Pretty similar. Either way, an interesting autoimmune angle. The old RA data for this drug was pretty good. I’m not sure why it wasn’t moved forward, but repurposing for even narrower indication is akin to what I did with sparsentan.

A Drug-drug interaction study between PF-06650833 and PF-06651600 follow multiple doses in healthy participants. Pfizer.
DDI combining Pfizer’s IRAK4 and JAK3 inhibitors. Don’t knock out the whole immune system while you’re at it!

A Study to Evaluate the Efficacy and Safety of 2 Dose Regimens of Intravenous TAK-954 for the Prophylaxis and Treatment of Postoperative Gastrointestinal Dysfunction in Participants Undergoing Large- and Small-Bowel Resection. Takeda.
This was TD-8954, a 5-HT4 antagonist (I think antagonist! could be agonist?). Takeda seems set on conquering the GI autoimmune diseases and all affiliated conditions. Smart.

From Molecules to Cognition: Inhibitory Mechanisms in ASD and NF1. Lovastatin. University of Coimbra.
Sad to try lovastatin, a relatively inert first-generation statin on autism patients. Can’t do any harm other than false hope. The first small study looked good, the large study, of course, failed to replicate. So here’s try 3. A desperate community, to be sure.

Delgocitinib Cream for the Treatment of Moderate to Severe Atopic Dermatitis During 8 Weeks in Adults, Adolescents, and Children. LEO Pharma.
Topical JAK. Finally?

Ibrutinib in Steroid Refractory Autoimmune Hemolytic Anemia. Dr. Nikitin.
Could work!

A Study to Compare Bioavailability of Naloxone Nasal Spray, Naloxone HCl IV and IM in Healthy Volunteers. Insys.
Two studies from Insys on what is their putative Narcan competitor. I guess they can get you addicted on the left hand and rescue you with the right.


912-914 days left


Roche’s acquisition of Spark makes sense. Acquiring scale and know-how in gene therapy is probably more important than specific vectors themselves. It is very difficult to find gene therapy manufacturing experts (feel free to email me! martin@thotpatrol.com) and Roche, Novartis, BioMarin, Sarepta and other companies can’t find enough of them. Who will win the hemophilia race? It probably doesn’t matter. You can just buy all the stocks: ONCE SGMO QURE BMRN as I suggested and do just fine. Pretty much all of these companies are good long ideas–even VYGR has made a comeback. How hot they may get in any given month or year is beyond my pay grade, I just know that gene therapy is changing genetic diseases and that is a 30-year tailwind one cannot deny. Still, price is always the most important thing in making any purchase: securities are no exception. Buying Nokia stock in 2000 would have made you a genius in predicting a trend but a fool in the financial markets.

Interesting article in NYT on China business policies. I see some US parallels, sadly. In every country, wealth and politics are inextricably intertwined. The other interesting article from a while back is the notion that many Chinese billionaires have died or gone missing in the last handful of years. This is an extreme form of jealousy in an autocratic country, but don’t think it doesn’t happen a little here. Bezos didn’t buy the Washington Post by accident and the atonement philanthropy we see from the billionaire class is less than ingenuous.

Clinical Trials I Noticed

A Study of Three Different Doses of VAC52416 (ExPEC10V) in Adults Aged 60 to 85 Years in Stable Health. Janssen.
Is this J&J’s answer to Prevnar? Crucell hasn’t done very much since the acquisition, so this would be very interesting and create a 3-player race over the next decade or so for pneumococcal vaccines. Kind of bearish for Pfizer.

A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease. Novo Nordisk.
This n=3000 outcomes study in CKD/DN is ambitious.

A Study Evaluating the Efficacy and Safety of ABP 959 Compared With Eculizumab in Adult Participants with PAH. Amgen.
The Eculizumab biosimilar phase 3. No one will be taking this drug in the US in a few years, but maybe Brazil will want it.

Study Evaluating the Safety, Efficacy and Pharmacokinetics of CORT118335 in Obese Adult Patients with Schizophrenia Treated with Antipsychotic Medications. Corcept.
I don’t believe there is a cortisol-weight link, but we’ll see, I guess. All those late-night TV infomercials can’t be wrong, can they?!

Steady-State Pharmacokinetics of Rifaximin 550mg Tablets in Healthy and Hepatically Impaired Subjects. Valeant.
Perhaps a LCM play in the waiting?

A Safety Study of LY3372689 Given by Mouth to Healthy Participants.
A True FIH study with no known MOA.

A Study to Assess the Effects of Multiple Study Drug Regimens in Subjects With Newly Diagnosed Locally Advanced Head and Neck Squamous Cell Carcinoma. ABBV-181, ABBV-368, ABBV-927. AbbVie.
A little late to the party, ABBV has a trial with PD-1, OX40 and CD40 mabs. Better late than never?

Phase 1b Study of CAR2Anti-CEA CAR-T Cell Hepatic Infusions for Pancreatic Carcinoma Patients with CEA+ Liver Metastases. Sorrento Therapeutics.
Bad target, bad modality, won’t work in my opinion.

Potato Consumption and Risk of Mortality. Zhejiang University.
Yes. We study Chinese differential equation make good study.

Hydrogen Gas for Cancer Rehabilitation. Fuda Cancer Hospital, Guangzhou.
Chinese to study hydrogen gas cancer remission good family grandparents very proud. I will allow.

Vidagliptin in Older Adults with Diabetes and Mild Cognitive Impairment. University of Catania.
Wherever Catania is, hope springs eternal.

Papers I Read

Myopia is associated with education: Results from NHANES 1999-2008. Nickels et al. PLoS One 2019.
It works metaphorically, too.


Trashy has rehomed in Brooklyn, NY. Her Philly street-cat temerity will serve her well in my birthplace. For now, though, the hirsuite one is mostly cooped up in closets while she determines the relative safety of my parents. Upon feeding, she gazes at my father, wondering if he is friend or foe. Trashy isn’t the smartest cat, but hopefully she will come out of her shell soon, anyway.


915 days left


REGN analysis is going smoothly. Should have the final outcome for you next week.

Can you really have a drug pricing hearing without me? That’s fine. I’ll be out in 2 years and we can do it then. Sanctimonious ignorance won’t be eliminated in politics anytime soon.

In a bombshell paper in The Lancet, researchers found that Novartis Access, which donates key drugs to poor countries such as Kenya for $1 per month, did NOT help access to medicine. Systems are complex, they say. They are in the U.S., too.

Papers I’ve Read

MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome. Ciernia et al. Hum Mol Genet 2019.
Rett Syndrome is very promising to drug developers. It’s a somewhat large monogenic illness. Knowing exactly what is ‘going wrong’ in a disease is the first step to designing a treatment. Unfortunately all that is really known about Rett is there is a MeCP2 dosage issue. Nobody knows what MeCP2 does, and the fact that most patients are female creates an interesting gene dosage/X-inactivation question (MeCP2 is on the X chromosome). At four exons, two isoforms of MeCP2 are spliced. MeCP2-exon2 proteins don’t seem to cause disease while MeCP2-exon1 proteins do. This group created the former and spent a lot of time on metabolic profiling, which is interesting but they don’t quite recapitulate the phenotype of the human illness in their mice. Progress will probably be slow in this illness but keep in mind AveXis (now a part of Novartis) has started a phase 1 for their gene therapy.

Clinical Trials I’ve Noticed

Study With Lu AF20513 in Patients with Mild Alzheimer’s Disease (AD) or Mild Cognitive Impairment (MCI) Due to AD. Lundbeck A/S.
Lundbeck has had this weird Abeta vaccine in Phase 1 for 5 years or so. I don’t think it will work, but one never knows. It’s certainly an interesting approach–not one that hasn’t been tried though. I believe Elan had some other active immunization program that blew up (this might be why the trial has taken so long).


918 days left


Lots of interesting things happening!
ICPT might be more commercially viable than the DOA pronouncement given. We’ll see! Will not be simple, for sure. But I wouldn’t figure in zero revenue, either.

When I spoke on the RDEB complex of KRYS ABEO and FCSC, I wanted to make a few things clear. 1) I have NEVER recommended any of these stocks and do not know them well at all. After two hours of research my (very) preliminary conclusion is buying the entire complex will probably achieve a positive return. FCSC is a strange company with a very bad capital structure and a partner I don’t trust (XON). If they dump XON it would be a more valuable company. KRYS only has reported two patients. ABEO is also a company in flux with tons of projects. It is very hard to tell which company will do well, FCSC may not even survive, after all. I don’t have any positions but I’m watching eagerly as this is really rough disease and the global opportunity is in the billions (value, if not revenue).

ACET filed and shocked with a sale of the chemical business for quite the price.

Papers I’ve Read

Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. von Minckwitz et al. NEJM 2019.
Roche hits it out of the park with Kadcyla in this trial. It’s still a bit unclear if you’d rather take Perjeta, Kadcyla or neratinib at this point, but it almost all benefits Roche’s attempt to transition away from Herceptin in any event. HR=0.50 for invasive disease or death is a bit shocking in such (relatively) well-controlled patients.

Residual Disease after Neoadjuvant Therapy – Developing Drugs for High-Risk Early Breast Cancer. Prowell, Beaver & Pazdur. NEJM 2019.
This whiny editorial bemoans the lack of a pathway to shortcut large phase 3s in relatively indolent early-stage cancers. One cannot have it both ways. A robust surrogate requires robust validation, in which case, you’ve so substantially improved the disease from hard outcomes, one cannot possibly be upset about requiring such large trials. At that point, you’re treating a different illness, akin to primary prevention vs. secondary prevention in CVD. If you don’t have a robust surrogate endpoint, then why risk the accelerated approval for a disease that is admittedly indolent and within striking distance for a surrogate?
In HRPC, PSA might become a viable endpoint due to the same circumstances. I just view this narrative as solutionless and fruitless. Pazdur’s suggestion of enriching for sick patients also misses the point that trials should reflect intended population and you’d be making serious errors in generalizing to broad populations if you did as suggested.


When I don’t post for some time, it is because I am very busy. What have I been doing? Mostly reading back issues of PLoS One, Nature Communications, Hum Mol Genet and other favorites. If you don’t hear from me, you should actually be HAPPY, as I am occupied and entertained. Daily posts would be a bad sign!

Good luck to Bernie Sanders, my old buddy! YOU CAN STILL WIN!


921-922 days left – 30 months remaining


The next deep dive will be on REGN.

Here are 10 biotech surprises for the next few years. They are in no particular order.

  1. Microbiome comes up empty.
    There’s not enough here to create true clinical applications. Some of the findings are real but so often the solutions will be cheap antibiotics, leaving VCs (generally bad investors) holding the bag.
  2. Biosimilars never get scale and stink as a business.
    Despite Sandoz having $1 billion in biologics revenue, few companies purveying biosimilars have hit even 1/10th of this milestone. The key problem is without mandatory switching/substitutability, only new patients will get biosimilars. With brand discounting and cautious physicians not wanting to mess with what works (physician rule #1), taking some share of just new patients when almost all of these drugs are life-long chronic therapy is not exciting. Furthermore, by the time a drug becomes biosimilar eligible, there are generally creeping alternatives (exception: Neulasta).
  3. Immunooncology has no second act.
    With PD-1 being the first act (we’ll talk about CARTs in a moment), I don’t think any new “IO” drugs will be meaningfully efficacious. The situation will be akin to 2006-2008’s hunt for angiogenesis inhibitors after Avastin’s success. Turns out you can only deplete blood vessel growth so much. I think it will turn out that you can only prime the immune system so much before bad things happen. I think oncology will be a great area to invest with respect to mutational drivers, tumor microenvironment, metastases drivers, ADCs, and other modalities. IO is finished. RIP GITR, IL-2, TIGIT, OX40, IDO, etc.
  4. CART not useful, off-the-shelf therapies dominate.
    I only wanted to include shocking predictions in this list. With the 4th quarter of Kymriah sales coming in at $28 million, is this really shocking? There just isn’t enough juice in CART that makes it worth the squeeze.
  5. Don’t call major primary care categories being good business opportunities a comeback.
    The trend towards rare/expensive drugs has left major illnesses like osteoarthritis, obesity, pain, cardiovascular in general, etc. without much drug development love. I think the success of CGRP and potentially some new obesity and pain agents will remind folks that selling cheap drugs to millions of people is 1) a decent business plan and 2) avoids the high-price socialism we’re seeing on the fringes of the radical left.
  6. There will not be a new Alzheimer’s drug approved by the FDA for at least 10 more years.
    There is some emerging hope, however. Unfortunately I won’t say anything more on the subject.
  7. CAG/polyQ repeat disorders will not be treatable by the antisense modality.
    The one prediction I might be most wrong on, I believe we don’t have huntingtin, frataxin and other proteins just for them to cause lethal expansions. No, they are functional proteins after development and getting rid of the amyloid aggregates will not solve the problem.
  8. Despite the above nucleic acid therapeutics of all kinds will propser far more than anticipated.
    I think in the excitement of CRISPR and gene therapy, NA-based therapies may be overlooked as only a few companies have the know-how to deploy the chemistry required to be useful medicinally. As that technology passes into the public domain, more companies should employ these techniques.
  9. Orphan pricing will continue to grow unabated – $5 and $10 million per-patient-per-year therapies will be introduced.
    In a Moore’s law-type dynamic, PPPY has increased not because of some malefactors (and their epigones), but because society craves health more than any other good. Health spending since the 60s is on a power law that cannot be stopped by any legislation or NGO. It is not a bad thing.
  10. Artificial intelligence/molecular dynamics software will not improve drug discovery.
    These technologies have existed for decades and the advent of supercomputer clusters passing the baton to cloud computing does not significantly alter the status quo to generate any kind of revolution.

Papers I’ve Read

Universal Medicine Access through Lump-Sum Renumeration — Australia’s Approach to Hepatitis C. Moon & Erickson. NEJM 2019.
There’s a lot wrong with this paper. The authors predictably begin by crying: “high prices can restrict access to medicines in rich and poor countries alike”. Nevermind the determine of what is “high”–virtually any price is high, isn’t it? Australia’s “Netflix” model is put forth as a potential sword against drug pricing. Laughable. What doesn’t dawn on the authors, two (too-) inexperienced academics, is that Australia is 2-4% (being generous) of drug spend. Companies like Gilead don’t focus on Australia and couldn’t care less about maximizing revenue in this territory. The paper humorously ignores the net pricing of DAA in the US, instead assuming list price. We should all be so lucky to live in the world these authors do. It’s always sad to read editorials like this in well-meaning and ordinarily great journals like NEJM. Feelings. Reason. Who should win?


931-932 days left

Looked at the RDEB companies: FCSC, KRYS, ABEO. Looks like an investing opportunity, both long and short. Not 100% sure which stock is which 🙂

Lots of interesting Phase III data sets (including MGNX) to dive into.

Looks like one of SGMO’s assets didn’t work. I never really understood why they are targeting MPS: treatment options exist and there are plenty of other indications with zero medicines. I still like the hemophilia assets. Will try to do a deep dive here.

Briefly Reviewed – Empire State of Mind by Zach Greenburg
Sean Carter (JAY-Z) has had quite the life. Arguably the most famous musician on the planet, he has become a very wealthy man despite what most would agree was a tumultuous start to his life. This first book about the famous rapper does very little justice to explaining a remarkably complex person. While the author can be commended for digging around and chatting with figures such as DJ Clark Kent, massive gaps limit the scope of this work to a pseudo-hagiography. The writer is clearly a Jay-Z fan, limiting his interest in sternly critiquing his subject. It’s hard to land too many gloves on Jay, but various opportunities known to many (and few alike), are missed.
Similarly, very little serious work is done on the artist’s art. Jay-Z’s music has undergone a stunning transformation–from a rapid-fire non-sensical and equally braggadocious and insecure to a triple entendres befitting a literary scholar. I don’t buy that we’re listening to Jay-Z, Sean Carter anymore. The other explanation is possible: Carter has become a hardened writing student. This mystery and many others (what is he marking Tidal at?) are left untouched and replaced with the gloss of easier questions and victory laps.

Papers I’ve Read
Treatment Decisions for Babies with Trisomy 13 and 18. HEC Forum 2017. Isabella Pallotto and John Lantos.
My favorite part of pharmaceuticals is working on illnesses like these. This papers suggests that doctors give up on these patients too quickly, leading to a self-fulfilling prophecy of neonatal death. The ethical issues with giving these very sick patients expensive treatment is discussed. One overwhelming point is the disability paradox: these patients often have a QOL indistinguishable to healthy patients from THEIR perspective. Assigning your QOL to someone else is the wrong perspective, in my opinion.

Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Tae Kim et al. Nature Medicine.
No new insights here.

My cat seems to be doing well as my father is now doting upon her, full-time.

Football season is over. Wasn’t too profitable. NBA is starting to look up. Our poor Knicks better get the 1st round draft pick!
Poker has been dull as well. Big “edges” are hard to get in any competitive area.


935 days left

Amgen deep dive – Price target: $250 per share – 6% discount rate – 1% reinvestment/ROIC rate, -1% at maturity in 2030-2035 – no buy/sell recommendation
Well, I’ve been following Amgen since I was a teenager. Their evolution into one of the largest biopharmaceutical companies is an instructive one. One general theme emerges: business and manufacturing excellence slightly outweighed a poor R&D and M&A record to record reasonable investor returns. The strategy going forward will be outlined here, and while intruiging, I only believe the stock is slightly undervalued (within the margin of error). With my sometimes too conservative estimates, however, one might be tempted to buy.

Enbrel — $5.0b in 2018, $4.5-4.1-3.7-3.3-1.5 billion estimates for ’19-’20-’21-’22-’30
Acquired via Immunex in 2003 (if my memory serves), Enbrel has come a long way from the $750 million supply constraint challenges and partial American Home Products (AHP became Wyeth, which Pfizer acquired) ownership. Peaking recently, Enbrel had defied gravity along with Humira, but the TNFalpha era is ending. With drugs like Cosentyx, Stelara and many more superior autoimmune drugs, very few new starts will be seen for TNFs, especially Enbrel and Remicade (inferior dosing schedules). Writing a NRx of Enbrel for, say, psoriasis, is basically malpractice. Of course, the rule I’ve observed for a decade will apply: current patients who are happy will not switch. So, we will see a slow melt. Recall Amgen books US revenue, so there is no EU biosimilar impact. There is no US biosimilar, despite the Sandoz filing, and Amgen even considers Enbrel to be IP-protected. I disagree and expect within 5 years or so a true biosimilar will emerge. Still, the atrophy will be slow. Amgen wisely wholly owns devices such as SureClick which are advanced administration devices that might hold share (see OnPro). What is a bit more surprising is Amgen’s inability to develop any other autoimmune medicines to replace Enbrel. It appears they forgot about this field: while AbbVie and J&J were busy replacing their older franchises, Amgen stayed quiet and let JAK, IL-6 IL-12, IL-4 (they were early here, too!), IL-23, and more pass them by. All we have left that’s even close is tezepelumab with AZ. Poor R&D and BD&L/strategy management strikes again.

Neulasta — $4.5b in 2018, $4.0-2.8-2.0-1.8-0.9 billion are my estimates for ’19-20-21-22-30
Not much to say on this very old product. Several biosimilars are in market with several more coming. “OnPro’, a particularly neat device, represents 60% of Neulasta right now. Again, a fairly bright S&M managerial move to extend this franchise. Payors may allow use of OnPro over a biosimilar and it gives Amgen managed markets a chance to pitch their story, which is one of the few ones that is believable. Even Mylan notes their market share relative to the long-acting market EXCLUDING this drug-device, which suggests this market is already bifurcated in some ways. Amgen has a long history of matching price against J&J in the EPO category, so expect them to battle “account for account” as they’ve said. Despite all this, I expect a big shrink in sales as OnPro only slows a complete implosion. I do think biosimilars get bigger and bigger share in the coming years.

Prolia — $2.3b in 2018, $2.5-2.7-2.9-3.1-3.2-1.6 are my estimates for ’19-20-21-22-23-30
Denosumab is probably the most important asset to Amgen right now. After all, Enbrel and Neulasta are yesterday’s news. Prolia/Xgeva is not exactly a new drug, but I think there is more growth here. Amgen recently said they’ve penetrated 25% of the osteoporosis market. I think that’s a lot and actually is bearish relative to my prior expectations. This is a low-priced, mass-market product, which we will discuss as a theme momentarily. Most of these kinds of products don’t get to see 50-75% penetration that we see in other fields. There is a lot of inertia in medicine–even cancer patients resist treatment. So despite the impressive continued growth of Prolia, we will probably see a ceiling in a few years.

Far more important is IP. Now, Amgen is the IP king of biotech. Despite that, notice the 7718776 patent which expires in 2023 (at best 2028). OPG (now known as RANKL) is an old idea. Amgen played with these molecules for a very long time before denosumab came to light. I would not be surprised if biosimilar companies like Celltrion, Samsung and others start talking up denosumab as a pipeline opportunity in the next few years. Keep in mind there is no “Orange Book” for biologics. There is a “Purple Book” but it does not list patents.

Xgeva — $1.8b in 2018, $1.9-1.9-2.0-2.0-1.0 are my estimates for ’19-20-21-22-30
The same IP situation applies to Xgeva as Prolia. Beware that this product will not last forever.
The Xgeva oncology indications should saturate more quickly than Prolia, and I believe they have, even though decent growth numbers continue. Better and better underlying drugs may prevent metastasis and you may even see the drug start to shrink in a few years.

Aranesp — $1.9b in 2018, $1.7-1.5-1.2-1.0-0.6 are my estimates for ’19-20-21-22-30
Not much to say here as this product has become less important. Interestingly, given the lower sales, this is less of a target for large numbers of biosimilars. The same dynamic may apply to Epogen and Neulasta, which are very tiny, and inferior products, but will still be stickier than products with biosimilar risk. Vifor is the branded competition here.

Aimovig — $117m in 2018, $510m-850-1100-1265-1328-1869m are my estimates for ’19-20-21-22-23-30
My numbers are conservative. The drug is off to a fast start. This is another low price-large number of patients market which strategically diversifies Amgen from the rest of the industry. Amgen is acting more like pharma and pharma is acting more like biotech. I think Amgen may be smart here, targeting markets they basically have to themselves: osteoporosis, migraine, obesity, cardiovascular. These are forsaken lands compared to cancer and they may just do well employing this strategy.
Aimovig clinical data sucks, the whole class is meekly efficacious. Amgen has at least two other migraine compounds, however. My numbers may be a tad conservative, still. If you are a big CGRP believer, this could be the next massive class with several $5 billion products. I don’t see it–maybe I can see it getting to $2 or $3 billion. Keep in mind Novartis gets something.

Repatha — $550m in 2018, $696m-974-1267-1520-1824-1915-2100 are my estimates for ’19-20-21-22-23-24-30
Another low-price, large-market drug in a not-so-crowded area. I see Repata doing well, but new entrants are coming from ESPR and AMRN also makes things tricky. There are millions of addressable patients and my numbers might be VERY conservative, which is a little hard to believe for a $550 million drug forecast to become a $2.1 billion drug. I wouldn’t be shocked if Repatha could hit $5 billion or more in peak sales.

omecamtiv — Poor sales for Entresto keep me on the sidelines here. The RP deal was a bit insane.

Evenity — launching soon
I only see $1 billion peak sales here. If you look at the data for Prolia, it is very rare to have a fracture on Prolia + bisposphonates. If you really need Evenity you are a rare treatment-resistant osteoporosis patient. It will be interesting to see how they price this drug as well. With a potential black box on cardiovascular, and Amgen not particularly enthused body language, I think $1 billion is fair for now. UCB gets a chunk here, too.

Krypolis — Only thing to note here is the relatively near-term LOE. The composition of matter goes in 2025. This is NOT a biologic. The Onyx deal is a wash–a lot of people don’t know they get a decent royalty on Pfizer’s mega-blockbuster palbociclib.

Biosimilars — $1b in 2025 and $1.8b in 2030
My forecasts are conservative. Amgen has the best execution in biologics manufacturing and may just sell $5 or $10 billion in biosimilars with time. This is a brilliant strategic decision by them despite early softness in biosimilars. It’s also a very smart hedge for their business.

tezepelumab – 2030 estimate of $1.0b — AZ partnership
Probably the most exciting drug in a meek pipeline. Risks are to the upside of my estimates.

Various R&D comments
Amgen is still a poor research company. Look at the oncology targets: CD19, BCMA, DLL3, MCL1, PSMA, KRAS. Zero originality here. Decent execution with AMG510, which may be huge, shows some better performance on delivering drugs but creativity is what you need in R&D. Completely absence from PDL1 or CTLA4 is telling. I don’t trust BITEs and think the CD3 affinity doesn’t get you anything special. Look at how poorly Blincyto compares to Kymriah. I don’t see BCMA holding up over the long haul either.

With obesity targets like AMG598 and cardiovascular targets like AMG890, Amgen is being creative with the return-to-large markets hypothesis that other companies are abandoning. “Zig when they zag?” I like it.

I assume zero R&D cost after 2019 and no new drugs other than a small handful. I discount cash flows at 6% (similar method for CELG with a 6.5% discount there) and assume they reinvest accumulated cash for a return of 1%. I assume maturity in 2030 or 2035 and cash flow declines at 1% per annum then. SGA is 25% of revenue and COGS are around 12% of revenue. Cash flow and net income are the same here. All this yields the slight upside of $250 per share. Holding this framework constant across the industry (while changing discount rate, reinvestment risk and maturity to reflect portfolio risk, management intellect and industry conditions) has served me well.

I was told Munger and Buffett refer to other “value” investors as “groupies” and joke about their poor performance. Buffett clones and Graham/Dodders are often poorly mimicking 50s-70s stock-picker Buffett without the same comforts: cash flow, no LPs, etc. That may have worked for a few years, or in an up-only market, but this strategy was never meant for public hedge funds.

Papers I’ve Read
Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. Manson et al. NEJM 2018.
Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. Manson et al. NEJM 2018.
Well, cancel all your vitamins, they don’t do anything. p=0.24 and p=0.47 should clear your medicine cabinet of at least two worthless drugs. The only question is do these “supplements” (code word for “non-useful medicine”) help a certain cohort of patients as opposed to all-comers. Subsets are hypothesis-generating, at best, and I don’t see a clear trend other than omega-3s helping patients at serious pre-existing CV risk (already well-known).

Book Review – The Cartel by “Ashley” and “Jaquavis”
This “hood book” is touted as the epitome of the genre. “Urban” fiction is usually written in a mix of street slang and proper (mostly) English, and typically draws on life in the milieu of poverty, drugs and crime. The Cartel is a bit different, taking us inside the fictitious Diamond family, who dominates the Miami drug trade. While not quite as suspenseful as Patterson, The Cartel features fairly intimate character portrayals that clearly connect with the reader. The fanciful plot is a bit far-fetched at times, but this is fairly typical in the genre. Still, I enjoy my ‘hood books’ when they’re as gritty and reflect the downtrodden grime that comes with the reality of the streets. The Cartel glamorizes drug trafficking, to an extent, suggesting that there is a path to wealth and legal success. While truth can be stranger than fiction (look for my next review), the inane focus on branding and the appearance of wealth drowns an otherwise reasonable plot. If you’re looking for your first ‘hood book’, try Good2Go Publishing. For the curious, it is all some of us practically read in here. If you’re still confused, think the book version of the film “Belly”.