Obicetrapib (CETP inhibitor for dyslipidemia)

I hope you’re right! That being said you can still mention the cheap cost of manufacturing to signal the potential for high margins.

We should look at the price of ezetimibe (Zetia) at launch. I would expect a similar price for obicetrapib as they’re both cheap 10-mg pills created to be used on top of statins for people at high risk. However depending on the source I find that Zetia was launched at $70/month or $500/month Is there a way to find the “official” launch price?

[EDIT: https://www.sec.gov/Archives/edgar/containers/fix011/64978/000095013003002276/dex13.htm here they mention $25m for 100k prescriptions so $250/month. That was in 2002 so adjusted for inflation probably more today?]

ASCVD risk decrease through reducing apoB:

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.

It basically seems that it will prevent all diseases, wonder drug, but we’ll probably have to wait and see longer for the other indications.

At present, there is robust evidence to support the potential benefits of reducing CETP for ASCVD risk reduction and increasing indications of its ability to promote longevity by reducing risks of several other conditions including T2D, dementia, CKD, AMD, and septicemia. Ongoing clinical trials of obicetrapib are expected to provide further insight into CETP inhibition as a therapeutic target.

Yes, it looks like a wonder drug. I’m discussing with John Kastelein and the NewAmsterdam Pharma team to get some obicetrapib shipped to Ora Biomedical to see if it extends the lifespan in C. Elegans. They’re interested. Wait and see…

Why wouldn’t they request the ITP to study their compound as well (unless they haven’t already)? Perhaps they don’t see the value in them doing it, and someone else have to write up the request.

I guess they don’t even know about the ITP. I’ll ask them.

On the pricing thing, Kastelein clearly states his intent to keep the price down, and NAM has an unusual corporate structure that may let them resist the market pressure to maximize revenue; we’ll just have to see. It would be great if it were modestly-priced right out of the gate.

As Antoine suggests, they may well not know about ITP: Kastelein is a cardiologist who takes care of kids with FH, not a biogerontologist. In his recent article on CETP inhibition (=obicetrapib) for “reducing risk of morbidity and promoting longevity”, previously posted by Antoine, they don’t mention the ITP, rapa, the Hallmarks of Aging,geroscience, biogerontology, or anything else that would make you think they’re aware that you can actually target aging.

Peter Attia hyping up Obicetrapib, Dec 3, 2024.

If I were running things over at [NewAmsterdam Pharma], I would price them so low that I would obliterate, If the drugs turn out as good as we think they are… they are not just going to eradicate apoB, they’re going to dramatically reduce your risk of Alzheimer’s disease, and reduce your risk of diabetes profoundly. That’s three of the four horsemen you just whacked, with one drug.

I’m not complaining about the chemistry, it could be amazing but what the heck is going on with the name? Do any of the letters mean something to anybody or is it just 11 random letters from a scrabble bag that dumped on the floor?

“-cetrapib” is the standard pharma suffix for CETP inhibitors (CETrapIB, get it?):

It will have a more melodious brand name when approved and sold, no doubt.

CETP inhibition Reduces Cardiovascular Events by Lowering of Cumulative LDL Exposure: Reconciling Evidence from Human Genetics and Clinical Trials 2024
Preprint by the NewAmsterdam Pharma team

Heterozygous CETP protein-truncating variant carrier status reduced atherosclerotic disease risk (odds ratio, 0.70; 95% confidence interval, 0.57– 0.85; P=5×10-4). In clinical trials, we observed a significant interaction between the magnitude and duration of LDL lowering on treatment effects (hazard ratio, 0.69 per 10– mmol/L×years; 95% confidence interval, 0.52–0.90; P=0.007), supporting that reducing cumulative LDL exposure is key to lowering cardiovascular risk. When comparing genetics with trial outcomes, accounting for differences in timing, duration, and follow-up, we observed consistent effects on atherosclerosis-related events per LDL years across genetic and pharmacological CETP inhibition, as well as with statins, ezetimibe, PCSK9 inhibitors, and familial hypercholesterolemia-associated variants (hazard ratio, 0.74 and 0.69 per 10–mmol/L×years, respectively). This suggests that CETP inhibition reduces cardiovascular risk primarily through LDL. Notably, several trials failed to achieve sufficient cumulative LDL reduction to impact clinical events, and this was not unique to CETP inhibitors.
Our findings indicate that future CETP inhibitor trials achieving substantial and sustained LDL reduction will demonstrate efficacy in preventing cardiovascular events. These results highlight the importance of long-term LDL lowering and support further investigation of CETP inhibition as a strategy for cardiovascular prevention.

NewAmsterdam Pharma Announces Positive Topline Data from Pivotal Phase 3 BROADWAY Clinical Trial Evaluating Obicetrapib in Patients with Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia

21% observed reduction in major adverse cardiovascular events favoring obicetrapib at one year
Observed to be well-tolerated with safety results comparable to placebo
Although exploratory at this point, the difference in major adverse cardiovascular events (“MACE”) at one year in BROADWAY supports our belief that obicetrapib could provide greater than expected CV risk reductions through mechanisms beyond LDL-C lowering. In 2025, we look forward to presenting additional BROADWAY and TANDEM data at upcoming scientific sessions and meeting with regulatory authorities to discuss filings for this important therapy to address the global unmet need for effective LDL-C lowering therapies.

All-cause mortality on the good side (but not statistically significant)

Can’t wait for the apoE + AD biomarkers results in March/April 2025!

Astounding that, while the median ldl reduction is 40%, some unlucky few see increases, some over 100%!

Every drug trial should come with a waterfall plot.

I didn’t know what to expect, but they seem happy and the market (~+34%) on this news.

Pleiotropic effects? They are getting the statin treatment as well it seems, lol.

Really incredible. Individual variability is totally displayed in a snapshot.

Obicetrapib might not reduce our risk of Alzheimer’s disease: Response to Schmidt et al.: Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis

In an answer to this paper, Emma L Anderson from University College London says:

A recent paper concluded that cholesteryl ester transfer protein (CETP) inhibition may be a viable target to treat dementia, based on human genetic evidence of a protective effect of target inhibition on risk of Lewy body and Parkinson’s dementia. Alzheimer’s disease, which is by far the most prevalent cause of dementia (around 80% of all dementia cases) was not included as an outcome. Evidence shows CETP inhibition is unlikely to affect Alzheimer’s risk and may even potentially modestly increase risk. There is also little evidence to support an effect of CETP inhibition on all-cause or vascular dementia. Thus, CETP inhibition is unlikely to be a viable target to treat the most prevalent causes of dementia.

It might still be good for Parkinson’s dementia (PDD) and Lewy body dementia. (And obicetrapib might be different or better. And the Mendelian randomization might not replicate the drug effect correctly. We’ll see the results of the trial in March 2025…)

We should be skeptical. AD is complicated, not much has succeeded (yet).
Do you know if they are even going to fund trials for AD prevention? Seems expensive.

They did an Alzheimer’s biomarker trial in APOE4 carriers (positive based on their hypothesis of the mechanism); it’s not clear to me whether they ever plan to do true prevention trials. No additional AD trials are listed on their obi page.

Yes, results in March or April 2025:

Reducing CETP activity prevents memory decline in an Alzheimer’s disease mouse model 2024

Epidemiological studies have shown that lower activity of the cholesteryl ester transfer protein (CETP) correlates with reduced Alzheimer’s disease (AD) risk. While small molecule CETP inhibitors like evacetrapib have previously been assessed for cardiovascular diseases, their involvement in AD has not been investigated. Here, we establish CETP as a novel pharmacological target for AD treatment. Using CETP transgenic mice crossed to a mouse model of amyloidosis and administering evacetrapib, we provide evidence that CETP inhibition maintained memory independent of classic AD markers, increased hippocampal cholesterol, altered plasma lipoproteins, and changed transcription of genes linked to brain barriers. Using proteomic data of cerebrospinal fluid from cognitively unimpaired individuals at risk for AD (the PREVENT-AD cohort), we confirm that our mouse model reflects physiological changes in pre-symptomatic human subjects. We propose the repurposing of CETP inhibitors as an effective therapeutic strategy to delay or prevent cognitive impairment in AD.