adssx
#81
The wonder drug:
OBICETRAPIB TARGETS ALL ATHEROGENIC LIPOPROTEINS BEYOND LDL-C 2024
In addition to significantly lowering LDL-C by up to 50.8%, Apo B by up to 29.8%, and non-HDL-C by up to 44.4%, in ROSE2 obicetrapib 10 mg monotherapy compared to placebo significantly decreased total LDL-P, small LDL-P, and sdLDL-C by 54.8%, 92.7%, and 30.9%, respectively. A pooled analysis of Lp(a) demonstrated a placebo-corrected reduction of 57.1%. Obicetrapib plus ezetimibe also significantly reduced total LDL-P (-72.1%), small LDL-P (-95.4%), and sdLDL-C (-44.4%), beyond its significant effects on LDL-C (-63.4%), non-HDL-C (-55.6%), and Apo B (-34.4%). Obicetrapib had an adverse event profile similar to placebo, and it was nearly completely eliminated from circulation within 4 weeks after dosing.
Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity 2024
Although the mechanisms are incompletely understood, evidence is mounting for a benefit of CETP inhibition on reducing the risks of type 2 diabetes mellitus and dementia, and most recent data point to an improvement of high-density lipoprotein structure and functionality.
Recent evidence suggests favorable associations between CETP inhibition and reduced risks of several other conditions including age-related macular degeneration, chronic kidney disease, and septicemia.
The increased prevalence of CETP loss-of-function gene variants in centenarians, as well as the potential benefits of CETP inhibition in ASCVD and other conditions associated with aging, suggest lifelong low levels of CETP activity may promote longevity.
When will it be approved?!
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amuser
#82
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adssx
#83
Thanks!
However this suggests it might be approved earlier based on āLDL-C data 2024Eā:
So 2025 at the earliest, otherwise 2026/2027 (or never it trials fail).
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Cross your fingers for an earlier approval date.
Honestly, if you are controlling your lipids through other meds, you can probably wait the 1-3 years for it to get approved.
Waiting for it to be generically available in India might take the longest. Do we know how long it takes from FDA approval until India makes a generic of a drug? 6 months? A year? Years???
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adssx
#85
Other meds donāt lower Lp(a) (PCSK9 only a bit) and they donāt eliminate small LDL-P by 95%: Obicetrapib (CETP inhibitor for dyslipidemia) - #52 by adssx
If confirmed, the reduced risk of T2D and dementia would be amazing.
Still worth waiting for the MACE data in 2026.
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adssx
#86
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I donāt think itās so straightforward. Bempedoic Acid is an outlier. I think the BA patent already expired in India, or there is some other reason why it wasnāt granted. In general, India also follows patent terms before generics can be authorized. So, itās not as though ever drug will launch as a generic in India right away. The difference is that India doesnāt bend over completely for pharma companies and wonāt entertain frivolous patent extensions and is perhaps more reserved in granting patents to begin with. Semaglutideās patent expires in India and China in 2026. Itāll be interesting to see how the market shapes up for that.
You may be right ā but the consumer may get lucky. GlobalData, which describes itself as āa leading data and analytics company,ā noted in 2022 that āIn February 2020, the FDA approved Esperionās bempedoic acid under the brand name Nexletol and EMA approved it in April 2020 under the brand name Nilemdo.ā āZydus Lifesciences launched a first-in-class oral, non-statin lipid-lowering drug, bempedoic acid, under the brand name Bemdac, for the first time in India in May 2022ā and āWithin eight days of the launch by Zydus Lifesciences, three companies Sun Pharma, Akum Drugs & Pharmaceuticals Ltd and Cadila Pharma have already announced plans to launch bempedoic acid in India.ā " Notably, there are no generics available for bempedoic acid in the US or Europe." āIndian players can launch bempedoic acid in India as there is no valid product patent in India." āFurthermore, none of the Indian players have any partnership with Esperion for bempedoic acid.ā āBempedoic acid has a huge potential in India, based on the overall dyslipidemia patient population and the patients with uncontrolled LDL-c levels.ā
This Indian government IP site lists two patents for obi: āOBICETRAPIB FOR TREATMENT OF DEMENTIASā and āCOMBINATION THERAPY OF OBICETRAPIB AND EZETIMIBE FOR USE IN STATIN INTOLERANT PATIENTSā.
https://iprsearch.ipindia.gov.in/PublicSearch/PublicationSearch/Search
If thatās exhaustive, it might mean that Indian pharmas could sell generic obi monotherapy for lipid-lowering whenever they chose to.
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adssx
#89
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Neo
#90
Nice
Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinsonās dementia risk (OR 0.26, 95%CI 0.14; 0.48).
That PD OR is incredible
Do you know who that other team is? (Or were you just saying āhopefully will be replicatedā?)
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adssx
#91
Itās PD dementia not PD itself (but still an OK OR for PD, and better than other lipid-lowering therapies).
Ah yes I wasnāt clear and meant āhopefully will be replicatedā.
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adssx
#92
ApoA1 might be protective against AD (association, causality TBC): Parkinson's disease - #338 by adssx
Good news: obicetrapib increases ApoA1 by +48%: Obicetrapib on top of maximally tolerated lipidāmodifying therapies in participants with or at high risk for atherosclerotic cardiovascular disease: rationale and designs of BROADWAY and BROOKLYN 2024
The BROADWAY phase 3 RCT with 2,600 patients will look at apoE phenotype and AD biomarkers: topline results in the next few weeks, full results next year: x.com 
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Is this indeed good news for everyone? Quite a few of us have already high or very high HDL/ ApoA1. When I get my lipid panel done, they have a range of 104 - 202 mg/dL. Iām already right at the upper limit. I donāt need it raised by 48%, or any percent. Thatās not āgood newsā in my book. If you have low(ish) values, great, but if not, you need it as much as you need more salt water while drowning in the ocean. I recently switched to pitavastatin, and I like everything about it (on paper), except for one thing: it raises HDL, which the marketing pushes as one of the big plusses. Not in my book - I already have very high HDL. My very high HDL makes me uneasy, and the literature on that is not very comforting. In fact, I am going to have a comprehensive lipid panel (and liver, kidney panels) in a few months to evaluate how pitavastatin is working for me. If I see some insane HDL/ApoA1 numbers, Iām dropping it like a hot potato.
Obicetrapib may be the beeās knees, but it may not be for everyone, and I for one donāt see this 48% raise in ApoA1 as good news, instead it triggers great concern for me. As always, YMMV.
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adssx
#94
My understand so far (I might be wrong of course):
- Thereās nothing good or bad per se with high HDL and ApoA1 when it comes to arteriosclerosis. Itās perfectly neutral. This is proven by the previous CETPi trials: large HDL increase => no effect on MACE.
- But for other conditions such as Alzheimerās, higher is better.
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adssx
#95
More on this @CronosTempi:
Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity 2024
Results from observational studies, Mendelian randomization analyses, and randomized clinical trials support the potential of CETP inhibition to reduce atherosclerotic cardiovascular disease (ASCVD) risk through a reduction of apolipoprotein B-containing lipoproteins. In contrast, raising high-density lipoprotein (HDL) particles, as previously hypothesized, did not contribute to ASCVD risk reduction. There is also an expanding body of evidence supporting the benefits of CETP inhibition for safeguarding against other conditions associated with aging, particularly new-onset type 2 diabetes mellitus and dementia, as well as age-related macular degeneration, septicemia, and possibly chronic kidney disease. The latter are likely mediated through improved functionality of the HDL particle, including its role on cholesterol efflux and antioxidative, anti-inflammatory, and antimicrobial activities.
So:
- ApoB and LDL: the lower the better for ASCVD risk reduction
- ApoA1 and HDL: the higher the better for diabetes, dementia, macular degeneration, septicemia, and CKD
?
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The high/extremely high HDL is a can of worms, as even a brief trip through pubmed demonstrates. I get one of those āevaluationā lipid panels, where they break down all the elements and comment on the health implications based upon the statistics they have from the population that uses their labs (which is different from ranges that are simply based on 95% of the population). Based on that, they established the 202mg/dL ApoA1 as the upper limit beyond which they saw negative effects in their test population - what those are, I donāt know, but itās not exactly comforting. We do know, that other efforts to raise HDL were not good, and while I understand that the mechanism of raising was the issue, the high HDL was nonetheless not protective. I suppose I should dig into pubmed wrt. high HDL, but itās overwhelming at the moment, maybe later with more time, but even so I donāt think the issue is anywhere close to being definitively settled.
adssx
#97
I think the issue is settled: the large CETPi trials had a massive HDL increase but no effect on MACE. Mendelian randomization studies are also neutral. Soā¦ Nothing to see.
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adssx
#98
Do they provide a source for the upper ApoA1 range? If not: BS => trash 
Serum apolipoproteins and mortality risk: evidence from observational and Mendelian randomization analyses 2024
Furthermore, both observational and MR analyses found an inverse association between APOA1 and lung cancerārelated mortality (HR comparing extreme deciles: 0.46; 95% CI: 0.26, 0.80; and HR: 0.78; 95% CI: 0.63, 0.97, respectively).
Our findings indicate that circulating APOA1 has potential beneficial effects on all-cause, CVD-related, and lung cancerārelated death risk, whereas APOB may confer detrimental effects on all-cause and CVD-related death risk.
Lucky you!
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ng0rge
#99
I would watch the segment here of 10-15 minutes starting at the 1 hour mark. Thomas Dayspring covers this issue pretty well. There are some potential problems with high HDL, but ApoA1 and HDL donāt always correlate 1 to 1 because there can be many ApoA1s on one HDL particle. ApoA1 can be beneficial for dementia whereas high HDL, not always. Also they talk of obicetrapid.
Revolutionizing Brain Health: Genetics, Lipid Science, and Cutting-Edge Dementia Prevention
https://www.youtube.com/watch?v=8vagLQumiM4
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Neo
#100
Just have to mention that this was an amazing conversation about CETP and how Obicetrapib might become a truly massive hit should the Phase 3 trials replicate the effects seen in Phase 2 trials.
One of the best conversations Peter has ever had on the Drive Podcast in my view
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