Biopharma & Investing
I like Global Blood Therapies’ (GBT) drug. I’m still not through with my work but I suspect this is a real disease-modifying drug that treats the underlying cause of sickle cell anemia. A real breakthrough. This company may become as large as an Alexion or Onyx (pre-takeover) in due time.
CAR-T looks like a commercial dud. Sorry, Celgene and Gilead. Those billions are unlikely to come back. Who knows, though. Antibodies had slow uptake at first. What I’ve heard from various sources is institutions don’t want to do CAR-T. The side effects are tough and the reimbursement is difficult. This is good for companies like Morphosys and Seattle Genetics who are using traditional antibodies for CAR-T targets and some are seeing good results. Bad news for the 200 private CAR-Ts, ADAP, CLLS and everyone else who wants to be JUNO and KITE.
The flu market is heating up with new drugs from Roche, Shionogi and Vertex and some promise of a universal vaccine.
Idorsia is chugging along with their rHTN (resistant hypertension) ERA (endothelin receptor antagonist). Guess who also bought an ERA way back when 😉
Starting to watch the vaccine space very closely. One of the few areas of pharmaceuticals that is truly cost-effective, hard to replicate/genericize, etc. Every new vaccine company seems to get acquired (IDBE, CRXL for you old timers).
Papers I’ve Read
I’ve been reading some proprietary materials, so excuse the lack of commentary.
GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Oksenberg et al. Br J Haematology 2016.
Tremendous work from the GBT team here. This panel of preclinical data is comprehensive. Almost every question I would have asked is asked and answered here. The murine transgenic model was a bit of a flop, which was interesting. Nevertheless, GBT440 certainly works as advertised, increasing Hb-O2 affinity, thereby raising the question of whether these HbS-GBT440 complexes are TOO oxygen-hungry and will never release this oxygen to tissues. It would still (or should still) stop polymerization of the aggregation-prone HbS species. One question I would have answered is trying to determine binding kinetics here, especially Koff. Km wouldn’t hurt, we see some EC50s in the micro molar range. The engineering of a compound devoid of plasma binding is somewhat surprising. If I had to decide on buying this whole company, I’d probably run that assay independently to be really sure as it is not often compounds have close to zero albumin affinity.
Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. McDermott et al. Nature Medicine 2018.
The IMmotion150 Phase 2 results. Nothing exciting here. Gene expression-guided treatment is a pretty neat concept and shows were Sutent actually does rather well.
New Developments in Anti-Sickling Agents: Can Drugs Directly Prevent the Polymerization of Sickle Haemoglobin in Vivo? Oder, et al. Br J Haematol 2016.
Decent review. Somewhat stunning that there are 20T (trillion!) red blood cells, which are most of your cells (!!!). Each RBC has 250 million (!) hemoglobin proteins. so that is … 2*10^13 X 2.5*10^8 = 5.0*10^21. You need 20% of that hemoglobin ‘fixed’ according to various in vitro studies, so 1.0*10^21. The MW of GBT440 is 337, so the weight of the drug you need is 3.37*10^23. Avogadro’s # is 6.022*10^23. So you need 500mg of GBT440, but the bioavailability of the drug is something like 50%, so you need 1g/day. That’s roughly what they dosed in Phase 3. Incredible!
I received a rather ineluctable haircut after “looking like Harry Potter” (at least to various other convicts) for far too long. One barber agreed to “give me the Brad Pitt” after discussing various style options. Consequently, I have very little hair left. No longer hirsute, life goes on! Just like the memes, barbers here also insist on reciting “say no more, fam” prior to destroying your appearance.
Why does Bill Gates review EVERY trash book and think they’re good? Poor guy. Bridge & reading psychosocial commentary is one helluva retirement. At least his healthcare stuff seems well done. I’ll probably learn how to play bridge soon.
hemolysis (medicine, basic concept) – destruction of a red blood cell (RBC) that lyses the cell membrane and releases its contents
hemolytic anemia (medicine, basic concept) – anemia due to hemolysis
hematocrit (medicine, basic concept) – RBCs as a % of blood
aromatic (chemistry, basic concept) – adj – a compound with the presence of cyclic sigma bonds and non-localized pi bond
pi bond (chemistry, elementary concept) – delocalized bond present in a double bond (in addition to a sigma bond)
sigma bond (chemistry, elementary concept) – overlapping bond present in a single bond
aldehyde (chemistry, basic concept) – a functional group featuring a C=O bond with a R-C and H-C bond.
thiol (chemistry, basic concept) – a functional group consisting of R-S-H