CHMP backs first CETP inhibitor after two decades of failure

Why it matters: A new class of cholesterol drug is finally close to reaching the European market. Obicetrapib will be the first CETP inhibitor to ever gain a regulatory nod and to do so on this side of the Atlantic first.

The big picture: Statins remain the first-line therapy for treating high LDL-C levels, yet many high-risk patients never reach their target goals.

• “Barriers to optimal lipid management include suboptimal adherence to statins due to concerns about adverse effects, limited incremental LDL‐C lowering efficacy of some orally administered nonstatin therapies, and access barriers or patient preferences against injectable medications, particularly for PCSK9 inhibitors,” a recent article published in the Journal of the American Heart Association explains.
• “This persistent treatment gap highlights the urgent need for novel, effective, orally administered, and well‐tolerated lipid‐lowering therapies that can substantially reduce atherogenic lipoproteins.”

Zoom in: The CHMP decision concerns two products using obicetrapib: Ubeslo, a once-daily oral tablet composed of obicetrapib 10 mg, and Evlarco, a combination of obicetrapib 10 mg with ezetimibe 10 mg in a single daily tablet.

• Both were filed by Italian pharma group Menarini, which holds European rights from the Dutch developer NewAmsterdam Pharma.

Backstory: CETP is the target that buried a generation of programs. Pfizer halted torcetrapib in 2006 due to excess deaths and cardiac events. Roche shelved dalcetrapib due to insufficient efficacy in 2012, while Eli Lilly’s evacetrapib faced the same verdictin 2015.

• MSD came closest to a success in 2017: its candidate anacetrapib demonstrated a reduction in the incidence of major coronary events in a group of over 30,000 adults, yet the company declined to pursue regulatory approval due to an unfavorable clinical profile.

• Obicetrapib was caught in that retreat. Amgen bought the molecule in 2015 along with its Dutch developer Dezima Pharma, then dropped it in 2017 for strategic reasons before it reached Phase 3. Forbion, the Dutch fund that had sold Dezima to Amgen, bought the asset back in 2020 and built NewAmsterdam Pharma around it.

How it works: Obicetrapib blocks cholesteryl ester transfer protein, which shuttles cholesterol between lipoprotein particles. Ezetimibe blocks cholesterol absorption in the gut.

• In the Phase 3 TANDEM trial the obicetrapib-ezetimibe tablet cut LDL-C by 48.6% against placebo over 12 weeks. Obicetrapib alone managed 31.9%.

Enter Menarini Group: Menarini took European rights in June 2022 for €115 million upfront plus €27.5 million in committed research funding, amounting to a guaranteed total of €142.5 million.

• Milestones run to a further €863 million, taking the potential value of the deal past €1 billion, and NewAmsterdam takes tiered royalties on net European sales of up to about a quarter. The countries covered by the agreement are France, Germany, Italy, Spain and the UK, plus 27 other European countries.

Also notable: The same meeting produced two other lipid decisions. CHMP backed Lyrokaul (lerodalcibep) from US-based LIB Therapeutics, a monthly self-injected PCSK9 blocker that has been on sale in the US since May. Amgen’s Repatha also had its indication widened, from established atherosclerotic cardiovascular disease to adults merely at high risk of it.

Bottom line: A target four drugmakers abandoned has been revived from the discard pile of a fifth, and Europe will be the first market to put a CETP inhibitor on prescription.

• If and when the Commission follows, European patients will obtain access to two new tablets and a monthly injection for patients who cannot reach their goal and, in Repatha’s case, a wider license for an option already shown to cut heart attacks and strokes.