Obicetrapib decreases LDL, increases HDL in phase 2 trial
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In a phase 2 trial, obicetrapib, an investigational cholesteryl ester transfer protein inhibitor, decreased LDL, non-HDL, lipoprotein(a) and apolipoprotein B and increased HDL at 8 weeks, researchers reported in Nature Medicine.
“Obicetrapib is a next-generation cholesteryl ester transfer protein (CETP) inhibitor that has the potential to be a simple, once-daily, low-dose treatment option for those who are currently struggling to achieve their lipid-lowering goals on traditional therapies,” Cardiology Today Editorial Board Member Michael H. Davidson, MD, FACC, FACP, FNLA, CEO of NewAmsterdam Pharma, which is developing obicetrapib, clinical professor of medicine and director of the Lipid Clinic at University of Chicago Medicine and an author of the study, told Healio. “Many patients are not achieving LDL-lowering goals on current standard of care. While there are several nonstatin treatment options available, including ezetimibe, bempedoic acid (Nexletol/Nexlizet, Esperion Therapeutics) and injectable PCSK9 inhibitors, they are generally limited by relatively low efficacy, side effects or market access hurdles. We believe that a potent, cost-effective, convenient, safe and well-tolerated low-dose oral medication to reduce LDL-C could set it apart from current therapies.”
The ROSE trial
The researchers conducted the phase 2 ROSE trial to determine the effect of obicetrapib compared with placebo on lipids in 120 patients with dyslipidemia on background statin therapy (median LDL at baseline, 88 mg/dL; mean age, 62 years; 56% men). About three-quarters of patients were taking atorvastatin 40 mg or 80 mg once daily, and the rest were taking rosuvastatin 20 mg or 40 mg once daily.
Patients were randomly assigned obicetrapib 5 mg daily, obicetrapib 10 mg daily or placebo (n = 40 in all three groups).
Using the Friedewald method to calculate LDL, at 8 weeks, obicetrapib 5 mg reduced LDL by 42.9%, obicetrapib 10 mg reduced LDL by 45.7% and placebo did not change LDL (P < .0001). Using beta-quantification to calculate LDL, at 8 weeks, obicetrapib 5 mg reduced LDL by 41.5%, obicetrapib 10 mg reduced LDL by 50.8% and placebo reduced LDL by 6.5% (P < .0001). Calculating LDL by the Martin-Hopkins equation yielded similar results, the researchers wrote.
Obicetrapib 5 mg reduced ApoB by 24.4%, non-HDL by 38.9% and Lp(a) by 33.8%, whereas obicetrapib 10 mg reduced ApoB by 29.8%, non-HDL by 44.4% and Lp(a) by 56.5% (P for all < .0001), Davidson and colleagues found.
In addition, at 8 weeks obicetrapib was associated with increases in HDL (5 mg, 135%; 10 mg, 165%; P for all < .0001) and in apolipoprotein A-I (5 mg, 44.6%; 10 mg, 47.8%; P for all < .0001), according to the researchers.
Potential filling of unmet needs
“Obicetrapib was observed to be well tolerated in the phase 2 ROSE trial,” Davidson told Healio. “If approved, obicetrapib has the potential to fulfill an unmet need for a new convenient and cost-effective oral medicine for dyslipidemia.”
He said obicetrapib 10 mg is now being studied in one phase 2b trial and three phase 3 trials, and research is ongoing into whether the agent could play a role in treatment of other metabolic diseases.
“The data provide additional evidence that obicetrapib is a next-generation molecule that is clearly differentiated from prior CETP inhibitors, with the potential to overcome the safety and efficacy challenges that have historically limited the potential of the drug class,” John Kastelein, MD, PhD, FESC, chief scientific officer of NewAmsterdam Pharma, emeritus professor of medicine at the Academic Medical Center of the University of Amsterdam and an author of the study, told Healio. “These data reinforce our confidence that we are advancing a potentially transformative cardiometabolic therapy, which if approved could change the treatment paradigm for millions of patients who are inadequately managed on [high-intensity statin] therapy alone.”
For more information:
Michael H. Davidson, MD, FACC, FACP, FNLA, and John Kastelein, MD, PhD, FESC, can be reached at info@newamsterdampharma.com.
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