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The use of Glp1+ drugs for weight loss should dramatically increase the use of surgical skin removal and tightening approaches. My dermatologist friend says the referrals for these types of procedures have grown dramatically over the past few yrs, and the associated surgeons I have been told are quite busy.
Not sure I see an investment angle here, however.
Try this information, and please note that I am only an amateur immunologist:
NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment
Tanakorn Srirat
Taeko Hayakawa
Setsuko Mise-Omata
Shigeyuki Shichino
Minako Ito
Akihiko Yoshimura
Highlights
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The deletion of NR4a1/2 in T cells enhances anti-tumor immunity
•
Loss of NR4a1/2 increases TCF1+ stem-like precursors of exhausted CD8+ T cells
•
Lack of NR4a1/2 in T cells promotes glycolysis and oxidative phosphorylation
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NR4a1/2-deficient T cells enhance persistence in the tumor microenvironment
No, none of my posts are recommendations to buy. I post data as I see that it could be important in one way or another. Everyone has different goals with their hard earned money, and it would be foolish for me to make public recommendations. I find CRVS as an interesting stock, ie T cell exhaustion and potential mechanisms to alleviate this issue. Management has had a solid past history in terms of developing blockbusters and being successful. I am not an immunologist, so I would not listen to myself if I read recommendations from a neuro guy whom specializes in hormone and neurobiological/neurotransmitter mechanisms and their importance in network phenomena. And I did not sleep at a Holiday Inn last evening.
Everyone needs to perform their own due diligence, and they have to watch their entry points and be careful out there. I simply am continuing my work on CRVS, and also realize that they need to raise $$ at some point in time. Most often I use these boards to come up with investment ideas, but then I perform some deep research to see if the potential investment is consistent with my risk/reward level.
Thus, caveat emptor is the mantra one should verbalize when reading any of my posts.
For those interested in CRVS, and Inducible tyrosine kinase inhibition (ITKi) for oncology et al wrt to T cell exhaustion, I will step onto a limb and submit that you are seeing an immunology paper classic in advance of it becoming one.
www.cell.com/cell-reports/fulltext/S2211-1247(24)00226-2
The LEXX website "Corporate Highlight Sheet" states a couple of ongoing studies evaluating their DehydraTECH methodology for semaglutide, and a comparison toRybelsus. AUC comparisons with their technology looks good.
Thx for posting on LEXX.
An oral bioavailability for VK2735 of 5-10% would be a World Series grand slam home run. I give that a much less than 50% chance.
Hi DD (Roy), its been a long time but I still hold my original buy of MDGL from the $15-16 range. Looking fwd to March 14.
Blade-
I only frequent this board somewhat infrequently, so I just came upon your posts on IFRX. I do not like data dredging, but one may get signals from such that need to be followed up, especially if you ask clinicians whom do not have a good grasp of statistics.
I believe that IFRX has some really solid complement pharmacologists on staff, a couple having substantial training/research in Peter Ward's Pathology lab at the University of Michigan. They have published solid works on complement pharmacology. But having the knowledge does not make a drug. HS turned out to be a tough indication, and PBO responses were extremely problematic. Hence the failed 2nd HS trial.
The second antibody that IFRX has appears to be better than the first. Not sure that is a significant issue. I will also say that small molecules should be better than antibodies here, due to cost of goods, compliance and several other convenience factors. But hard to get really potent C5a antagonists with good physico-chemical properties. Avacopan is a good start.
I would say that IFRX is a speculative buy, as they are trading below cash. But trials progress is what counts. At this time I will not post my other complement picks, but should say that ALXN has lots of competition. Complement inhibitors should be quite useful in ocular diseases.
Yes, I hold CARA and I held through the news. Now I am back to the price where I started. BIg PBO effect in the oral trial, and Chalmers did not know why and seemed like a deer in headlights, responding to multiple similar Qs.
Possibly overdone, IV seems solid. And to think I missed selling 70% of my position by a couple of pennies a couple days before the release.
Dew, any view on the RVNC follow on? I am looking to re-load.
I focused on the KOL Lipton discussion only.
A trainee of mine is head of a Peds Headache Clinic at a major medical center. The CGRP related drugs have been a game changer according to Andy. I am just shocked at the numbers of migraine pts that appear to have limited efficacy with several of the marketed drugs.
Rapid dissolve Maxalt (rizatriptan) works great for my wife, but the sublingual generic was a failure due to the chalkiness of the formulation.
Could you please point out any data on plaque reduction data for the 3 agents? My cholesterol is borderline on the higher side, but I currently take no meds, as suggested by my doc.
I potentially worry about 'stable' plaque reduction as problematic, according to my cardiology friend.
AXSM has been a trading stock for me. Many biotech investors do not like drug combos, and I understand that several could combine (potentially) the generic versions of each.
As of this morning, I traded out of the stock after a 2 month gain >50%.
A CMO once said to me, patients do not care either the mechanism of action of the drug, or if it is a combo. They just want to know if it works. I have been in AXSM for the depression drug opportunity. I still view it undervalued, but me a valuation expert? No way. Market cap around $1.2B
Alexion to buy Achillion for $6.30 a share along with up to $8.30 in contingent value rights.
I expected more than a triple though
Thanks for that, hmpa.
This provides for FGF21 fusion proteins, but in the text I could not find anything regarding coincident Glp-1 agonism. I will continue my search. THe concept is solid, as Glp1 agonists are now being investigated in NASH.
This has the potential to have both metabolic effects directly via the Glp1R, and then fibrosis resolution via FGF21 agonism. Pretty difficult to obtain sufficient potency and slectivity for both Rs in a single polypeptide chain.
This appears to be a very interesting dual acting agonist combination. I would like to see the relative potencies and data.
The sympathy vote on CCXI premarket this morning was a strong buy signal, as I just watched it.
IFRX is a disaster, HS not a well understood skin issue, like several other skin issues like the vasculidities.
But no position in either. I do own a couple other complement companies, both in the green since my purchase.
NGM is on my watch list. I am awaiting oral therapies for a potential investment.
THbeta's still seem to be the best way to play the initial therapies for NASH, and there was a diagnostic 'machine' company, but it now evades my memory.
Jin-Long Chen, founder and CSO of NGM Bio, is a top shelf scientist. Now if they can get oral delivery of any NASH candidate that they are in pursuit, that would be huge.
Also CBAY, thanks for posting. And Dew, thx for the registration link.
A Cowan report on MDGL was brought to my attention today, as Cowan met with MDGL mgmt this past Friday. The MDGL yearly report this past week did not go into any detail on Ph3 designs for either NASH or Dyslipidemias. MDGL is awaiting final meeting notes from the Agency on 2 FDA meetings on these 2 registration studies. One study for each indication, with no liver biopsy in the dyslipidemia trial. MDGL should have a PR and CC on this pretty soon, methinks.
Yearly results stating $483M in cash at end of year.
yearly report on Feb 27
My view on MDGL is that they have the best data to date for a Ph2 trial in NAsH. Strong efficacy for the normalizing of blood lipid levels and liver fat, with good safety to date. A safe and oral THbeta agonist for the treatment of NASH, NAFLD and for other mixed dyslipidemias.
I have been adding significantly to my MDGL long term position under $120 mid December. Something is going on there, as they had an EOPh2 meeting and solidified the trial design. Despite M Yee saying they have fallen to the wayside, Paul Friedman and Becky Taub will rise again. (Jefferies is not an investment banker for MDGL, but is for ICPT, obviously.) With horse trader Paul Friedman, expect the unexpected. I will also point out that buy side holdings are at a low for MDGL, so...
Concluding, MDGL is one of my 4 top biotech holdings, along with REGN, FGEN, and SAGE. I hold about 10-12 other biotechs as well. I did get impatient with my recent RVNC purchase, so have been trading it but no position today. As a friend of mine says, he likes stock that have a northeast trajectory on the charts.
The obvious question to me is why Stifel a this point. I thought that they had to be involved in the recent follow on offering. From that RVNC PR:
I believe the RVNC thesis remains intact. I also believe they need a partner for appropriate market penetration with speed. Timing/pricing of this offering was poor, no doubt. My time frames for holding biotech stocks has been reduced in the past couple of years, too much roller coastering. This could likely be the same.
Pre-commercial companies frequently obtain poor offerings prices, but in hindsight may be a reasonable insurance policy. We shall see. But the best time to raise $$ is when it is not needed, or when the market perceives it is not needed.
I would not be surprised to see biotech offerings dry up in 2019 due to pricing constraints.
Reloaded RVNC, after a long watchful waiting.
I tried to get $17.32 pre-market, but failed. Never thought I would get that price during normal hours.
Should be interesting. Will we see a bounce off the offering price? Sheesh.
Is there public access to the JPM HealthCare conf presentations, provided by JPM as in the past?
Thanks in advance for any help.
OK, I will bite on the NGM Bio collaboration antibody, NGM313.
To preface this, I have followed two areas of research relevant to this discussion, for quite a while. These two areas are 1) "insulin sensitizers" an 2) Klotho proteins.
Merck has had various "insulin sensitizer" projects ongoing for a long time, at least 20 years. The sensitizer should help in the huge diabetes and pre-diabetic conditions, problem of insulin insensitivity, ie insulin resistance. There are several potential targets that could be included in this arena. None of MRK's approaches has yet made it through the clinic including FDA approval. My friend and former colleague Joe Militih from MRK thinks this time may be different.
The Klotho name comes from the Greek word for "fate", as it is the name used for a FGF receptor complex protein that is essential for FGF 19, 21 and 23 signalling. Beta Klotho is interesting as it is a single pass transmembrane protein that when expression is reduced has a kidney failure phenotype and displayes accelerated aging, and when overexpressed at least in mice, can extend lifespan by some 20-30%. So, beta Klotho is a FGF receptor complex protein that can be viewed as a target to help modify pharmacology, in this case using an activator antibody.
From Biospace.com
To place in the FWIW* column, this series of charts are for a two month time frame, on several of the biotechs I hold or watch closely.
I have been buying several of these over the past week or so for the New Year Rally. Will this rally end with the start of the JPM Healthcare Conference? Now that Ms. Warren has the pulpit...
* = trash bin
After the big swoon in biotech stocks, I checked out how big pharma has performed over the past year. I follow the pipelines of many of these, but do not hold any of the stocks, just not high enough beta, lol.
There are some very solid yearly returns in several of these, as compared to several baskets of biotechs held by many..
You must have missed the data presentation?
Interim Data and Strategic Update
December 17, 2018
http://ir.achillion.com/static-files/bd675aa8-b98b-4770-8455-9d687b41606a
Justin Trudeau.
My thoughts on MDGL vs the VKTX data reported this morning, though I cannot in a brief post, review all the stuff here that I know. Having worked in the business, I pay attention to liver metabolism and tox issues, more so than most analysts and investors. Sometime it is not good to know too much, as risk comes in many forms. I have held both MDGL and VKTX stocks in the past. I continue to hold MDGL, but not VKTX.
Here is a note I sent to some colleagues early this morning, some 90 min before market opening.
"VKTX data looks very good as far as it is reported.
Outstanding comments/questions for VKTX CC
1. How does long term animal tox data fare for VKTX compound? Only short term animal tox data reported by VKTX? How much tox data in 2 species is at hand for a 36 week study in NASH patients?
2. VKTX data not achieved in NASH patients, but in less severe NAFLD patients. Due to a more compromised liver, risk (esp ALT/AST) could be much greater. Safety not derisked.
3. Due to reactive metabolite species for VKTX, can company comment on the metabolite being a CYP P450 3A4 covalent inhibitor? Data for similar reactive species in literature shows this could be a major problem for concomitant drugs to be source for drug-drug interaction. (Note that 3A4 is the source for the reactive metabolite.)
4. Why do you think the Baker Bros bought MDGL huge this past Q? Do you think they had extensive consultation on the chemical nature of the 2 liver specific THbeta agonists from the 2 companies?
Then, Came the conference call this morning. I will stop at the above comments for now, but will link/copy Miljenko's comments from SI. Miljenko is a mechanism and VKTX bull, but in full disclosure we had discussions of metabolism and tox over the past many months. He is a process chemist with a critical eye to science, as all PhD trainees are supposed to have. Having been in the business and knowing what Q's to ask is part of that 'knowing too much". I may comment more, if Q's arise. Pretty busy these days.
Miljenko's CC comments
RE: VKTX
Just finished CC (I like to sleep longer this days, )
While I am gratified that VK2809 did have positive primary and secondary, and most importantly NO safety (so far NO) issue at 10 mg/day dose (I care less for QOD regime, maybe they can introduce 5 mg/day dose???),....there is several points that make me MAD! IS THERE ANY BIO-COMPANY THAT CAN REPORT STRAIT FORWARD RESULTS???
First, when company switch the importance of the end-points (those are pHeHF subjects , not NASH) and exclude arm as trial progress without reporting,...I PISS ON THEM!
Second, when company report numbers for secondary and no numbers for primary (15-40%LDLc reduction relative to placebo is only range, and not mean/median),...I PISS ON THEM!
Third, when company is talking too-much about option to scale down dose,...THAN I ASK: "WHAT IS FUCKING WRONG WITH CURRENT DOSE/REGIMEN???"
Looking forward to full data presentation.
I was slow this morning, so full position on VKTX is still in place.
Re: OMER
That first link did not work, here is the revised link:
Am J Nephrology review here
As to TA and chart action of OMER, I really did not know. The TA guy from which I linked that chart said to prepare for a rebound, but expect the worst. I ended up doubling my position (undersized) at $17.80. I actually think the market and biotechs in particular are a bit shaky in here.
Lots of biotechs off their highs.
As to OMER and their IgA-N trial, I think their proteinuria measures are quite good with OMS-721, but I need to see more data and try to see any eGFR improvements. Patients in the trial need to be on the best current standard of care, reasonable/stable blood pressure and on optimal renin-angiotensin system blockade.
Here are two very good articles on the current state of IgA-N treatment, and some mechanisms in the clinic. Both full articles are free at the PubMed links provided.
Am J Nephrology review here
Am J Nephrol. 2018;47 Suppl 1:43-52. doi: 10.1159/000481636. Epub 2018 May 31.
Immunoglobulin A Nephropathy: Advances in Understanding of Pathogenesis and Treatment.
Lafayette RA1, Kelepouris E2.
Author information
Abstract
BACKGROUND:
Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis and has clinical associations with a wide range of inflammatory and infectious diseases. There is a substantial variation in clinical course and outcomes, with many patients not diagnosed until they present with sequelae, which may include gross hematuria, hypertension, renal insufficiency, and/or significant proteinuria. Treatment options are currently limited and directed mainly toward control of these sequelae and have limited ability to reduce the incidence of end-stage renal disease or treat the primary IgA defect.
SUMMARY:
Growing knowledge about the pathogenesis of IgA nephropathy and research into its genetic basis are helping to elucidate the course of this widely variable disease. IgA accumulation in the kidneys is thought to be the result of a number of different pathways in a "multi-hit" process that includes an initial traumatic trigger (often infection related) and subsequent memory responses that are amplified in those with a genetic predisposition to the disease and lead to an inflammatory response in susceptible individuals. Genome-wide association studies are providing new insights into the genetic variance of this autoimmune disease and are yielding information that may address both its causes and consequences. Key Messages: New treatment approaches are urgently required for the management of patients with IgA nephropathy. Novel interventions based around its inflammatory nature and "multi-hit" pathogenesis are being investigated to potentially limit disease progression.
© 2018 S. Karger AG, Basel.
International J Nephrology and Renovascular Disease review here
Int J Nephrol Renovasc Dis. 2018 Apr 12;11:137-148. doi: 10.2147/IJNRD.S129227. eCollection 2018.
Primary IgA nephropathy: current challenges and future prospects.
Penfold RS1, Prendecki M1, McAdoo S1, Tam FW1.
Author information
Abstract
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, exhibiting a variable clinical and pathological course and significantly contributing to the global burden of chronic kidney disease and end-stage renal disease. Current standards of care focus on optimization of antihypertensive and antiproteinuric therapies (typically renin- angiotensin system blockade) to reduce disease progression. Much recent attention has focused on whether additional immunosuppression confers better outcomes than supportive management alone, and indeed, several trials have demonstrated renoprotective effects following the use of oral corticosteroids. However, results have been inconsistent, and perceived benefits must be balanced against risks and adverse effects associated with generalized immunosuppression, as highlighted by the high-profile STOP-IgAN and TESTING clinical trials. Recent translational research in vitro and animal models of IgAN have generated greater insight into potential therapeutic targets for this complex autoimmune disease. Deeper understanding of the roles of the mucosal immune barrier, complement activation and deposition, T-cell dependent and independent mechanisms of B cell activation, and of the deposition and downstream inflammatory signaling pathways of nephritogenic polymeric IgA1 complexes (e.g., signaling of immune receptors via spleen tyrosine kinase) has formed the rationale for the development of novel agents and clinical trials of more targeted therapies. However, translating findings into clinical practice is challenging, with many immunopathological features of IgAN specific to humans. Recent comprehensive reviews outline current understanding of mechanisms of IgAN as well as ongoing and future clinical trials; it is not our aim to replicate this here. Instead, we take a mechanistic approach to current treatment strategies, outlining advantages and limitations of each before exploring ongoing research with potential translation into future targeted therapies for this complex disease.
Re OMER
I had several comments on another forum regarding my displeasure with the OMER conference call. Most of the programs, the early ones, have 0 NPV in my estimations.
But what I was mostly looking for was OMS721 Ph3 programs enrollment success and a discussion from the recently hired CMO on this front. Things like sites opened, early enrollment, and strategies to aid in enrollments. It turns out that there are several ongoing trials that are competing for such patients.
The issue of a money raise has always been there. Still is.
I remember the Elan (ELN) company and stock, and there were many kool aide drinking Elanians. Seems to be the case for OMER as well, as they have "so many valuable" programs. After I read the CC transcript last evening, I was worried that the stock would go down in price, as too much talk on early programs and plans for newer programs and progress. Those programs are a huge $$ burn. The hiring of the new CMO, in my view, is a recent very positive sign, I should point out.
I ended up selling my modest CARA position at $21, held just under a year, on the surgical pain positive news several days back. I had a GTC order in, and at the time, I was in Alaska on the Kenai Peninsula fishing for the "spawn til you die" sockeye (or red) salmon. I was away from internet service much of that rugged 2 week trip. Also went halibut fishing, and came home with 90 lbs of salmon and halibut fillets.
I started buying back CARA yesterday on the offering news, and picked up some more this morning, renewing my position.