Obicetrapib (CETP inhibitor for dyslipidemia)

[Neo]

@adssx

I don’t understand: who are the controls? and these are the HDL and LDL concentrations at which age? at death?

Mendelian randomization, have looked at this in depth, just skimmed the slides after @AnUser shared them.

First slide I pasted above seems to show which variants they are comparing.

This slides also helps with some form of dose response.

Hopefully they will publish it soon (if not already?) and any details not explained in the transcript will hopefully be more clear

[scta123]

@adssx

I don’t understand: who are the controls?

I found the original paper. Find it below.

barzilai2003.pdf (153.1 KB)

[adssx]

Just published: Obicetrapib as an Adjunct to Stable Statin Therapy in Japanese Subjects: Results from a Randomized Phase 2 Trial

This double-blind, randomized, phase 2 trial examined obicetrapib 2.5, 5, and 10 mg/d, compared with placebo, for 8 weeks as an adjunct to stable statin therapy (atorvastatin 10 or 20 mg/d or rosuvastatin 5 or 10 mg/d) in Japanese men and women who had not achieved 2022 Japan Atherosclerosis Society Guidelines and had LDL-C ＞70 mg/dL or non-high-density lipoprotein cholesterol (non-HDL-C) ＞100 mg/dL and triglycerides (TG) ＜400 mg/dL.
In the 102 randomized subjects (mean age 64.8 y, 71.6% male), obicetrapib significantly lowered median LDL-C, apoB, and non-HDL-C, and raised HDL-C at all doses; responses in the obicetrapib 10 mg group were -45.8%, -29.7%, -37.0%, and +159%, respectively (all p＜0.0001 vs. placebo).

Fewer adverse events than placebo, especially for the lower doses:

Treatment-emergent adverse events (TEAEs) were reported by 47 (46.1%) of the 102 participants: 15 (57.7%) in placebo, 9 (36.0%) in obicetrapib 2.5 mg, 8 (32.0%) in obicetrapib 5 mg, and 15 (57.7%)

On Sunday, NewAmsterdam Pharma will present new results as well: 1433-211 / 211 - SYNERGISTIC EFFECT OF OBICETRAPIB AND EZETIMIBE ON CIRCULATING LDL PARTICLES

Can’t wait!

[Neo]

@adssx

obicetrapib significantly lowered median LDL-C, apoB, and non-HDL-C, and raised HDL-C

Do we know what the impact on Lp(a) was?

[adssx]

@Neo

Do we know what the impact on Lp(a) was?

They didn’t measure it (see full text):

Another potential limitation of this study was that it did not measure the effects of obicetrapib on the concentrations of lipoprotein particles or lipoprotein(a) among Japanese subjects. In the Study to Evaluate the Effect of Obicetrapib in Combination with Ezetimibe as an Adjunct to High Intensity Statin Therapy, 10 mg obicetrapib in combination with 10 mg ezetimibe significantly reduced total and small LDL particles by 72% and 95%, respectively, and altered the HDL profile in a manner suggesting it increased cholesterol flux through the HDL fraction. The results from the Randomized Study of Obicetrapib as an Adjunct to Statin Therapy also indicated that 10 mg obicetrapib on top of highintensity statin reduced lipoprotein(a) by 56.5%. In addition to the ongoing cardiovascular outcome trial of obicetrapib mentioned previously, PREVAIL, three other phase 3 trials of obicetrapib are underway, as well as several phase 1 and 2 trials designed to further investigate the effects of obicetrapib on lipoprotein metabolism, and its safety and PK profile in various populations.

[Neo]

• @AnUser

ROSE2 met its primary and secondary endpoints, with statistically significant and clinically meaningful reductions in LDL-C and apolipoprotein B (“ApoB”) observed. Statistically significant improvements in lipoprotein(a) (“Lp(a)”), non-HDL cholesterol (“non-HDL-C”) and total and small LDL particles were also observed. In addition, the combination of obicetrapib and ezetimibe was observed to be well-tolerated, with a safety profile observed to be comparable to placebo. With these data in hand, the Company has selected a formulation for a fixed-dose combination tablet and intends to advance the compound into a Phase 3 trial in the first quarter of 2024.

https://ir.newamsterdampharma.com/news-releases/news-release-details/newamsterdam-pharma-presents-full-data-phase-2-rose2-trial/

[AnUser]

That’s from 2023, nothing new, we already know it decreases LDL etc.

[adssx]

Yes, they mostly repeated results already given in the 2023 paper published in the Journal of Clinical Lipidology.

However, they gave one more result not present in the 2023 paper: “In addition, we observed a median reduction in Lp(a) of 47.2% and 40.2% in the monotherapy and combination arms, respectively.”

They didn’t give total cholesterol, so I calculated it as HDL-C + NON-HDL-C (in mg/dL):

• Baseline:
  • P: 126 + 42.5 = 168.5
  • O: 122 + 47.0 = 169
  • O+E: 116 + 46.0 = 162
• 12 weeks:
  • P: 162 (-4%)
  • O: 190 (+12%)
  • O+E: 160 (-1%)

[Neo]

@adssx

“In addition, we observed a median reduction in Lp(a) of 47.2% and 40.2% in the monotherapy and combination arms, respectively.”

Very nice perhaps the talk at the conference will share additional info too

[adssx]

@Neo

perhaps the talk at the conference will share additional info too

Nothing, unfortunately, it was just marketing: https://twitter.com/ErinMichos/status/1777085891338735870

Kastelein gave additional information on Twitter, though:

(link to tweet)

BROOKLYN and TANDEM don’t seem to measure MACE, so I’m surprised. BROADWAY (2,532 participants) does, though:

So, in any case, we’ll have MACE data for obicetrapib by the end of this year. If extremely positive, approval next year? (“Looking at individual stages of the process, the averages were 2.3 years for Phase I, 3.6 years for Phase II, 3.3 years for Phase III, and 1.3 years between Phase III and regulatory approval.” [source])

[adssx]

From the phase 2 trial, I understand that obicetrapib (alone or with ezetimibe):

• Increased large HDL (8.8–13 nm) by about 150%
• Decreased medium HDL (8.2–8.8 nm) and small HDL (7.3–8.2 nm) by about 50%

Is this good? A quick search led me to several papers finding an association between higher levels of small HDL and better long-term outcomes:

• The small HDL particle hypothesis of Alzheimer’s disease 2022
• Lower levels of small HDL particles associated with increased infectious disease morbidity and mortality: a population-based cohort study of 30 195 individuals 2022
• Differences in HDL-related mortality risk between individuals with and without hypertension: a prospective cohort study in UK Biobank 2023

Or did I misunderstand something?

[adssx]

NewAmsterdam Pharma R&D Day: May 16, 2024 at 9:00 AM EDT

Their own conclusion: “If approved, obicetrapib will be the first high efficacy oral LLT since statins”

[Neo]

Do people have thoughts on how we can lower small LDL-P today?

[Virilius]

Anything that lowers LDL-P will also lower s-LDL-P. Additionally, SGLT2i also lower s-LDL-P although they sadly do increase l-LDL-P.

[Neo]

Thx.

@Virilius

Anything that lowers LDL-P

What’s lowers LDL-P in best ways?

[Virilius]

I would guess PCSK9i > statins > bempedoic acid > ezetimibe.

[Neo]

Interesting, thx.

I’m on PCSK9i and Eze and depending on next blood work was potentially going to add either Bemp or Statin… so this in one more thing to consider.

[adssx]

European Atherosclerosis Society (EAS) Congress 2024: OBICETRAPIB DEMONSTRATES SIGNIFICANT REDUCTIONS OF LP(A) ON TOP OF HIGH-INTENSITY STATINS

Median baseline Lp(a) for 10 mg obicetrapib and placebo was 29.9 and 45.3 nmol/L, respectively, in ROSE1 and 44.0 and 37.8 nmol/L in ROSE2. Median % changes from baseline for obicetrapib 10 mg and placebo were -56.5 and +4.00 in ROSE1 and -47.2 and +2.3 in ROSE2. Pooled (N=127) median di"erence in % change corrected for placebo was 57.1% (p<0.001). In both trials >50% of obicetrapib subjects had a >60% reduction in Lp(a).
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%).

[Neo]

2024 generally been good for the stock

[adssx]

CETP and SGLT2 inhibitor combination therapy increases glycemic control: a 2x2 factorial Mendelian Randomization analysis 2024
Provisionally accepted

We find that genetic inhibition of both CETP and SGLT2 leads to significantly lower glycated hemoglobin levels than control, SGLT2 inhibition alone, and CETP inhibition. Furthermore, joint CETP and SGLT2 inhibition is associated with decreased incidence of diabetes compared to control and SGLT2 inhibition alone. Our results suggest that CETP and SGLT2 inhibitor therapy may improve glycemic control over SGLT2 inhibitors alone. Future clinical trials can explore whether CETP inhibitors can be repurposed to treat metabolic disease and provide an oral therapeutic option to benefit high-risk patients before escalation to injectable drugs such as insulin or glucagon-like peptide 1 (GLP1) receptor agonists.