Obicetrapib (CETP inhibitor for dyslipidemia)

[Neo]

Couldn’t see actual paper, do we know if this lowering average blood glucose or more even better at cutting spikes?

[adssx]

I think they only posted the abstract. We’ll have to wait for the full paper (if accepted).

[adssx]

Studies funded by NewAmsterdam Pharma:

Obicetrapib Treatment Increases Pre-Beta1 HDL and Lipophilic Antioxidants in the Ocean and Rose2 Studies 2024

In both, OCEAN and ROSE2, no significant changes occurred in placebo groups but in the obicetrapib treated groups plasma pre-beta1 HDL increased by 12% (p<0.04) and 24% (p<0.03).
CETP inhibition with obicetrapib increases pre-beta1 HDL, involved in excess cholesterol efflux, as well as important HDL antioxidants: lutein, zeaxanthin and α-tocopherol. Thus, in addition to atherosclerosis, these results support the potential therapeutic use of obicetrapib in diseases with high unmet medical need, that are associated with low HDL and low levels of lipophilic antioxidants in plasma and tissues, such as AMD, neurodegenerative disorders and sickle cell anemia.

Obicetrapib Demonstrates Significant Reductions Of Lp(a) On Top Of High-intensity Statins 2024

Obicetrapib 10 mg on top of high-intensity statin significantly lowered Lp(a) by 57% vs. placebo in a pooled analysis, a substantially greater reduction than with proprotein convertase subtilisin kexin type 9 inhibitors (15-30%), niacin (30%) or other CETP inhibitors (25%).

Obicetrapib Alone and with Ezetimibe Reduces Non-HDL-C by Enhanced LDL-Receptor-Mediated VLDL Clearance and Increased Net Fecal Sterol Excretion 2024

Obicetrapib, ezetimibe and the combination thereof reduced total plasma cholesterol levels (-42%, -23% and -62%), mainly attributed to a decrease in non-HDL-C levels (-61%, -24% and -80%).

Obicetrapib Does Not Accumulate in Adipose Tissue: Results from Studies in Man and Non-human Primates 2024

In dedicated pre-clinical experiments and in clinical trials, obicetrapib shows no evidence of accumulation in adipose tissue or delayed elimination from the systemic circulation supporting once daily, chronic dosing of 10 mg.

[RapamycinCurious]

NewAmsterdam Pharma Announces Positive Topline Data from Pivotal Phase 3 BROOKLYN Clinical Trial Evaluating Obicetrapib in Patients with Heterozygous Familial Hypercholesterolemia

PDF Version

– Achieved primary endpoint of LS mean reduction in LDL-C on top of maximally tolerated lipid modifying therapies at day 84 with statistically significant reduction (p<0.0001), which was sustained at day 365 (p<0.0001) –

– Obicetrapib lowered LDL-C by 36.3% at day 84 and 41.5% at day 365, compared to placebo –

– Observed to be generally well-tolerated with safety results comparable to placebo –

– NewAmsterdam to host conference call at 8:30 a.m. ET, Today –

NewAmsterdam […] today announced positive topline data from the Company’s Phase 3 BROOKLYN clinical trial (NCT05425745). BROOKLYN, the first of four studies in NewAmsterdam’s pivotal clinical development program, was designed to evaluate obicetrapib in adult patients with heterozygous familial hypercholesterolemia (“HeFH”), whose LDL-C is not adequately controlled, despite being on maximally tolerated lipid-lowering therapy.

The BROOKLYN trial met its primary endpoint, achieving an LS mean reduction of 36.3% (p < 0.0001) compared to placebo at day 84, which was sustained at day 365 with an LS mean LDL-C reduction of 41.5% (p < 0.0001). The observed reductions in other biomarkers, including high-density lipoprotein cholesterol (“HDL-C”), non-HDL-C, lipoprotein(a) (“Lp(a)”), and apolipoprotein B (“ApoB”), met statistical significance and were consistent with data reported from the Company’s prior clinical trials.

LDL-C LS mean percentage change:

…said John Kastelein, M.D., Ph.D., FESC, Chief Scientific Officer of NewAmsterdam. … 51% of patients achieving an LDL-C level below 70 mg/dl. …

In the trial, obicetrapib was observed to be well-tolerated, with safety results comparable to placebo and no increase in blood pressure. The treatment discontinuation rate for the obicetrapib arm was 7.6% versus 14.4% for placebo. The incidence of treatment-emergent adverse events (“TEAEs”), study-drug related TEAEs, and treatment-emergent serious adverse events (“TESAEs”) are summarized in the table below.

said Michael Davidson, M.D., Chief Executive Officer of NewAmsterdam."In the safety population, there was also no increase in blood pressure, nor any difference from placebo in liver enzymes, hs-CRP, or renal function. We look forward to building on these results with topline data from BROADWAY expected in the fourth quarter of 2024, and topline data from TANDEM expected in the first quarter of 2025.”
https://ir.newamsterdampharma.com/news-releases/news-release-details/newamsterdam-pharma-announces-positive-topline-data-pivotal

[Neo]

@adssx @AnUser any thoughts?

@Davin8r did you see anything about impact on Lp(a) yet?

[Davin8r]

@Neo

@Davin8r did you see anything about impact on Lp(a) yet?

ehh…huh? I don’t think I’ve posted in this thread (although I’ve been following it with great interest! )

[Neo]

@Davin8r I can’t keep track of what thread is what, but you seem to often have had the best thoughts re Lp(a) across threads

[Davin8r]

@Neo

often have had the best thoughts re Lp(a) across threads

Thanks! At this point, my strategy is to keep ApoB as low as possible and to optimize all other factors (BP, visceral fat, VO2max, etc) while waiting for meds that decrease Lp(a), since my PCSK9i (Repatha) seemingly hasn’t done anything to lower it.

[Neo]

@Davin8r Yeah, I’m in the same boat. Obicetrapib might end up being our first option - hope the 50-60% lowering of Lp(a) ends up holding up

And the we’ll have a next lp(a) specific drug approval roughly per year if things go well

[adssx]

Thoughts on what? I created this thread so I’m 100% team obicetrapib

[Neo]

@adssx On the

@RapamycinCurious

Topline Data from Pivotal Phase 3 BROOKLYN Clinical Trial

Haven’t seen anyone discuss them

[adssx]

It looks as good as their previous trials. Safety is especially reassuring. But it’s a very special patient population so TBC on patient for usual primary prevention. Trial results expected soon

[Neo]

Thanks

@adssx

as good as their previous trials

Previous were only Phase 2s so far but right? So this was first Phase 3

[adssx]

@Neo

Previous were only Phase 2s so far but right? So this was first Phase 3

I think so. I might be wrong but the phase number does not matter much to me. I’m more interested in the outcomes. So far trials only looked at the LDL, HDL, Lip(a), etc. increase or decrease. The ongoing trials will primarily look at the outcomes (MACE, mortality, new onset of diabetes, etc.). Let’s hope for the best!

[adssx]

That being said the market was disappointed: NewAmsterdam obicetrapib data disappoints some investors | pharmaphorum

Shares in NewAmsterdam Pharma were sliding today after it reported a phase 3 trial of obicetrapib that met its primary objective but didn’t meet the expectations of some analysts and investors.
At 84 days, obicetrapib reduced LDL-cholesterol by 36%, with the difference widening to 42% after a year, but that was less than had been seen in phase 2 and fell short of what analysts had been hoping to see.
Investors were clearly nervous about the results, but NewAmsterdam chief executive Michael Davidson said the outcomes were consistent with earlier studies and “support obicetrapib’s potential to significantly reduce LDL-c in a challenging patient population.” The safety data for the drug was also encouraging, with adverse events occurring at rates roughly in line with the placebo group.
Despite the scepticism shown by some investors, NewAmsterdam has more shots on goal coming up. Next up is the BROADWAY monotherapy trial in patients with atherosclerotic cardiovascular disease (ASCVD) and/or HeFH, with data due in the fourth quarter, followed by the TANDEM combination study of obicetrapib with ezetimibe in ASCVD and/or HeFH in the first quarter of 2025.
Further down the line is an outcomes study, called PREVAIL, designed to confirm that the reductions in LDL-c seen with NewAmsterdam’s drug are accompanied by a reduction in cardiovascular risk, by reducing things like heart attacks and strokes. That is due to read out in 2026.

[adssx]

Sorry for the triple post, but some interesting information here:

[Davin8r]

Seems like 40% reduction in LDL is quite impressive given that these folks are already taking maximal tolerated doses of statins. Since it’s a pill, hopefully it will get FDA approval soon for FH and the generic manufacturers in India will start making it

[adssx]

A Randomized, Parallel, Open-Label, Single-Dose and Multiple-Dose Clinical Trial to Investigate the Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Obicetrapib in Healthy Participants in China

After 7 consecutive days of dosing, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol reached their minimum and maximum changes of 42% reduction and 108% increase, respectively.

[DeStrider]

Hasn’t higher levels of HDL been linked to higher incidence of malignant prostate cancer?

I think there is no truly ‘good’ cholesterol, and I wouldn’t go about raising HDL.

[adssx]

@DeStrider

Hasn’t higher levels of HDL been linked to higher incidence of malignant prostate cancer?

Figure 4 here suggests that CETP inhibitors such as obicetrapib would have no effect on prostate cancer risk: Comparing the effects of CETP in East Asian and European ancestries: a Mendelian randomization study 2024