Obicetrapib (CETP inhibitor for dyslipidemia)

[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.

[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! )