Obicetrapib (CETP inhibitor for dyslipidemia)

Continuing here a discussion that started there: Rapamycin and risk of cardiovascular disease - #3067 by AnUser (topic now closed)

Obicetrapib seems extremely promising to reduce cardiovascular events and maybe also prevent diabetes and dementia (see previous discussion).

Yesterday, the company behind it, NewAmsterdam Pharma, released its 2023 financial results: NewAmsterdam Pharma Reports Full Year 2023 Financial Results and Provides Corporate Update | BioSpace

On-track to report topline data from Phase 3 BROOKLYN trial in HeFH in 3Q 2024 and Phase 3 BROADWAY trial in ASCVD in 4Q 2024

If succesful, could it mean approval in early 2025? I’m not the only one to be excited:

https://twitter.com/Drlipid/status/1762840999427018954

In the phase 2 trial, after 8 weeks, obicetrapib 10 mg reduced ApoB by 29.8%, non-HDL by 44.4% and Lp(a) by 56.5% and increased HDL by 165% and apolipoprotein A-I by 47.8% (P for all < .0001). (source)

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CEPT inhibitors might also increase lifespan:

Causal effects of lipid-lowering therapies on aging-related outcomes and risk of cancers: a drug-target Mendelian randomization study 2023

We identified six lipid-lowering variants that were associated with increased lifespan, including PCKS9 (Beta 0.11; 95% CI: 0.06 to 0.15; p-IVW=4.55×10-6, FDR=5.95×10-5), CETP (Beta 0.24; 95% CI: 0.14 to 0.34; p-IVW=3.72×10-06, FDR=5.31×10-5), APOC3 (Beta 0.08; 95% CI: 0.04 to 0.12; p-IVW=4.67×10-5, FDR=4.58×10-4), LDLR (Beta 0.15; 95% CI: 0.11 to 0.19; p-IVW=1.08×10−11, FDR=2.83×10-10), and LPL (Beta 0.12; 95% CI: 0.09 to 0.195; p-IVW=1.62×10-15, FDR=8.48×10-14). There was little statistical evidence of longevity-associated effects among NPC1L1 (Beta 0.06; 95% CI: -0.16 to 0.28; p-IVW=0.58, FDR=0.76) and HMGCR (Beta 0.08; 95% CI: 0.01 to 0.15; p-IVW=0.03, FDR=0.11).

Genetic insights into the association of statin and newer nonstatin drug target genes with human longevity: a Mendelian randomization analysis 2023

The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan.

(same authors, too bad they didn’t look at gender differences though)

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I’ve seen stuff the AD - are the mechanisms thought to be broader form of dementia?

We actually discussed it a few times in 2023 so might want to see if anything valuable from those past discussion for you

Also Peter Attia had a Drive episode with one of the top guys involved with the trials (the fall or so of 2023 so relatively fresh), so might want to check that out.

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Anyone heard how they are thinking about post so pricing of the drug if approved?

There’s actually more data on non-AD dementia if you believe their own preprint MR (to be replicated by an independent team): Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis 2023

image

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 Parkinson’s dementia risk (OR 0.26, 95%CI 0.14; 0.48).

For now the trials are only on top of high statin dose for uncontrolled hyperlipidemia. So unless they do new trials to show that they can replace statins as first line treatment I would assume the price to be similar (per year). Maybe a bit lower as it’s a pill so they can expect more sales (I assume that they want to reach the same revenue and are okay to lower the price if that means more sales). So about €/$/£10k/y?


Also there are interesting papers on diabetes:

The effect of CETP inhibitors on new-onset diabetes: a systematic review and meta-analysis 2022

Although RCTs have shown mixed results regarding the impact of CETPi on cardiovascular disease, they have shown a consistent reduction in the risk of new-onset diabetes with CETPi therapy. Future trials of CETPis and potentially other HDL-raising agents should therefore specify new-onset diabetes and reversal of existing T2DM as secondary endpoints.

CETP and SGLT2 inhibitor combination therapy improves glycemic control 2023

:warning: Preprint by the obicetrapib team :warning:

Our findings suggest that CETP inhibitors, which are currently in clinical trials to treat cardiovascular disease, can be repurposed to treat metabolic disease in a combination therapy approach with SGLT2 inhibitors.

(synergistic effects with SGLT2i :heart_eyes: )

If confirmed, I understand that obicetrapib would be the only lipid-lowering drug that also increases insulin sensitivity (others are either detrimental or neutral) and prevent dementia (others either have detrimental effects on cognition or are neutral). Huge if true… (and I would be the first customer to buy it…)

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Great post.

This is the one piece I’m not sure we can say based on data. Even statins may be net positive and there is more signal that PCSK9i might be.

Re the MS signal in your charts from the MR. Any sense if this means that there may be other immunological downsides from obicetrapib?

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In PD, statins cause faster neurological decline (per RCT + MR + longitudinal studies). In healthy people, the picture is less clear, and there’s conflicting data, but at least I think we can agree that by raising blood glucose they might have a negative effect on cognition. Whether this is a net positive or net negative probably depends on your pre-treatment LDL & ApoB levels. So on that point for sure, a lipid-lowering drug that increases insulin sensitivity would be amazing.

PCSK9is seem neutral: https://www.jacc.org/doi/abs/10.1016/j.jacc.2020.03.039

Good question. No idea and they didn’t develop that point at all. I don’t know MS well. A quick Google query led me to:

So… It seems extremely complex…

However, I wouldn’t be worried by MS per se, but, as you said, more by the potential other immunological downsides. Per this 2020 paper: A Novel Role for CETP as Immunological Gatekeeper: Raising HDL to Cure Sepsis?:

Based on solid evidence from studies with isolated macrophages, rodents, and humans, we propose that a major function of CETP may be to modulate HDL in order to help resolve bacterial infections. When gram-negative bacteria invade the blood, as occurs in sepsis, Kupffer cells lose their expression of CETP to increase HDL levels. This rise in HDL prevents systemic endotoxemia by binding lipopolysaccharide and induces a systemic proinflammatory response in macrophages to mediate bacterial clearance. This raises the interesting possibility to repurpose CETP inhibitors for the treatment of sepsis.

See also: The evolving role of cholesteryl ester transfer protein inhibition beyond cardiovascular disease 2023 (by NewAmsterdam Pharma of course!)

image

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From Peter Attia’s interview of John Kastelein last May:

"And it’s very cheap to make; it’s not an injectable monoclonal antibody…

…It’s public knowledge that it costs $36 per year to make this drug, and that will allow them to price it reasonably and ethically"

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This is unfortunately nonsensical wishful thinking. The price of a drug is unrelated to its production cost. Ravicti costs nothing and is sold $600k/y. Relyvrio for ALS costs $158k/y even though it’s just the combination of one generic and one cheap Chinese medicine supplement that you can buy on Amazon.

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If it costs a lot to produce it will be priced higher to the customer to have the same profit.

There exists a significant unmet need for a potent, cost-effective and convenient LDL-
lowering therapy as an adjunct to statins, a class of lipid-lowering medications that are the current
standard of care for high-risk CVD patients with high cholesterol.

https://ir.newamsterdampharma.com/static-files/91cc75c7-08db-4696-9bd6-c05bb01762ed

It seems they want to make about $3 to 4 billion a year.
Cost-effective I think just means less expensive than PCSK9 inhibitors.

Cost-effective for payers. PCSK9 are expensive but cost effective VS apheresis for those who have it. So here it’s probably indeed cost effective VS PCSK9i. So less than $5k/y? Bempedoic acid/ezetimibe costs about $2k/y, I would assume obicetrapib will cost more.

3 to 4bn USD revenue per year, that’s more than 10x more than what Regeneron is making: https://investor.regeneron.com/news-releases/news-release-details/regeneron-reports-fourth-quarter-and-full-year-2022-financial

So either they want to sell at a price just below PCSK9i but sell 10x more. Of they want to sell it at a higher price.

But for now they haven’t started trials on obicetrapib VS statins as first line treatment. They only looked at uncontrolled dyslipidemia despite max statin dose. That’s a smaller market so they need a higher price point to reach their 4bn revenue goal.

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Does the prices on this website mean anything?

I have a ridiculous argument, but technically if it only costs $35 a year to produce they could sell it at 3 billion divided by 35 M patients, from same source I linked above:

We estimate that there are approximately 35 million patients in the United States and EU5 who
are not achieving LDL-lowering goals on current standard of care.

Which is 85 + 35 = $120 / year to the patient. That would be the best option as they make their money and allow as many people as possible reach their target. If I remember correctly anyone could manufacture this. I don’t know what pharma companies typically choose to do.

Very interesting - thanks for share.

Interesting that the papers above generally paint the picture that

  • “Higher HDL-C levels are associated with decreased disease activity.”
  • “Higher LDL-C levels are associated with increase disease activity.”
  • “Immunomodulatory treatment has positive effect on lipid profile in multiple sclerosis.”

Below is an MR on LDL and HLD potential effect on MS that in someways is more similar to the CETP MR analysis

(Btw it also suggests that statin’s non lipid lowering effects might be positive for MS).

Exploring the Role of Plasma Lipids and Statin Interventions on Multiple Sclerosis Risk and Severity: A Mendelian Randomization Study

Results: The results of MR using the inverse-variance weighted method show that genetically predicted RAC2, a member of cholesterol-independent pathway (OR 0.86 [95% CI 0.78-0.95], p-value 3.80E-03), is implicated causally in reducing MS risk. We found no evidence for the causal role of LDL-C and the member of cholesterol biosynthesis pathway on MS risk. The MR results also show that lifelong higher HDL-C (OR 1.14 [95% CI 1.04-1.26], p-value 7.94E-03) increases MS risk but TG was not. Furthermore, we found no evidence for the causal role of lipids and genetically mimicked statins on MS severity. There is no evidence of reverse causation between MS risk and lipids.

Discussion: Evidence from this study suggests that RAC2 is a genetic modifier of MS risk. Because RAC2 has been reported to mediate some of the pleiotropic effects of statins, we suggest that statins may reduce MS risk through a cholesterol-independent pathway (that is, RAC2-related mechanism(s)). MR analyses also support a causal effect of HDL-C on MS risk.

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Do you mean it’s a case where there won’t be a lot of patent protection?

No, just like it doesn’t require specialized equipment.

We could do it at home?

It should be legal to make your own obicetrapib at home, unless the precursors, etc aren’t, so that could be an option. I hadn’t thought about that. Wouldn’t the equipment be expensive though?

You can get it synthesized in China. Ask Wuhan Hhd or Jenny Chem for a quote.

WhatsApp: +86 166-210-06118

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