John R. Burnett

In response to our recent drug evaluation of the APOC3 antisense oligonucleotide olezarsen [Citation1], Leow details concerns about thrombocytopenia and the potential for paradoxical adverse effects of olezarsen on cardiometabolic and cardiovascular outcomes [Citation2]. We take this opportunity to further summarize published data on thrombocytopenia with volanesorsen and olezarsen and in patients with familial chylomicronemia syndrome (FCS). Volanesorsen (Waylivra), the predecessor of olezarsen, reduced triglyceride and the incidence of acute pancreatitis among patients with severe hypertriglyceridemia [Citation3], however, this was accompanied by significant thrombocytopenia. Sixteen of 33 patients (48%) with FCS who received volanesorsen had platelet count nadirs below 100,000/µL, including 2 below 25,000/µL, whereas none of the 33 patients who received placebo had low platelets [Citation4], leading investigators to implement an enhanced platelet monitoring program with a threshold of 75,000/µL for dose reduction. However, a recent study showed that in FCS patients treated with volanesorsen, despite a reduction in platelet counts, no significant changes in general hemostasis or platelet function were observed, although this was limited by small sample size [Citation5]. In the BALANCE trial of olezarsen in patients with FCS, no adverse events relating to thrombocytopenia were encountered (<25,000/µL or < 50,000/µL with major/relevant bleeding event). One of 23 patients (4.3%) in the placebo group experienced a decreased platelet count, compared with 1 of 21 patients (4.8%) in the olezarsen 50 mg cohort and 3 of 22 patients (14%) in the olezarsen 80 mg cohort [Citation6]. As stated in our article [Citation1], it is important to confirm and strengthen the safety data. Interestingly, patients with FCS have been shown to experience significant, but asymptomatic, fluctuations in platelet count over time [Citation7] and postprandially [Citation8]. In a larger study of 84 patients with FCS due to lipoprotein lipase deficiency followed-up for up to 15 years, 19.1% experienced platelet counts < 99,000/µL at least once, 2.4% had platelet counts < 50,000/µL without bleeding or bruising at least once, and 11.9% had thrombocytosis (>450,000/µL) at least once [Citation7]. We agree that long-term studies are required to evaluate for hard cardiovascular endpoints and trust that the trial monitoring board as well as regulatory bodies will gather and critically interrogate appropriate data relating to outcomes, side effects and thrombocytopenia. Ongoing phase III trials have enrolled over 2,500 participants (CORE, CORE2, ESSENCE) and are awaited in this regard.

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Untreated, PKU may result in severe and irreversible intellectual impairment due to marked hyperphenylalaninemia (HPA). Guidelines recommend lifelong reduction in Phe levels, usually achieved via a strict low-protein diet and sometimes medications. We discuss the role of tetrahydrobiopterin (BH4), an essential PAH cofactor in Phe metabolism, describe the pharmacodynamics, pharmacokinetics, and metabolism of sepiapterin, as well as reporting on its efficacy and safety in children and adults with PKU. Sepiapterin, an oral synthetic form of a natural precursor of BH4, can reduce HPA in some patients with PKU. In relatively short-term studies, sepiapterin has been shown to be safe, well tolerated, and like the BH4 analog sapropterin dihydrochloride effective in reducing blood Phe levels in responsive individuals. The reductions in blood Phe observed with sepiapterin in the phase III APHENITY trial has the potential to allow more PKU patients to attain Phe treatment targets or alternatively easing of the onerous dietary Phe restrictions. Results of longer-term studies in patients with PKU, including neurocognitive and functional outcomes, nutritional status, and quality of life are awaited.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, by preventing the degradation of LDL receptors, either through interference in the binding of PCSK9 to LDL receptors or through silencing of PCSK9 at a molecular level, have revolutionized lipid-lowering treatment and offer the opportunity to further improve clinical outcomes for patients with hypercholesterolemia. We discuss the role of PCSK9 as a therapeutic target for hypercholesterolemia, describe the pharmacodynamics, pharmacokinetics, and metabolism of recaticimab, and report the recent clinical trials with this 'humanized' IgG1 monoclonal antibody (mAb) against PCSK9. Recaticimab has high affinity for PCSK9 that confers a prolonged duration of action. Recaticimab durably decreases LDL-cholesterol, non-HDL-cholesterol and apoB, but can also lower Lp(a). Recaticimab may offer advantages over current mAbs in clinical use in terms of its long half-life, dosing interval of up to 12 weeks, and potentially a lower cost, however, long-term concerns regarding immunogenicity remain. Longer-term studies in a variety of more diverse patient cohorts will be needed to further evaluate the efficacy, safety, and durability of recaticimab and to ascertain the best dosing schedule for cardiovascular outcome studies.

Apolipoprotein (apo)C-III, a key regulator of plasma triglyceride (TG) levels, is a prime candidate for the treatment of hypertriglyceridemia (HTG), prevention of acute pancreatitis, and reduction of future atherosclerotic cardiovascular disease (ASCVD) events. We discuss the role of apoC-III as a therapeutic target for HTG, describe the pharmacodynamics, pharmacokinetics, and metabolism of olezarsen, as well as report on the findings of recent clinical trials with this liver-directed APOC3 antisense oligonucleotide (ASO). Olezarsen, a GalNac-conjugated ASO targeting apoC-III, can reduce TG levels by ~ 50% in patients with extreme HTG due to familial chylomicronemia syndrome, as well as in patients with moderate HTG. Attention is now focused on whether olezarsen reduces ASCVD risk in patients with moderate and severe HTG. While olezarsen does cause elevations in liver enzymes, these changes are not clinically meaningful, and are not associated with thrombocytopenia, an issue with its predecessor, volanesorsen. The need for 4-weekly administration puts olezarsen at a disadvantage to competing injectables. Results from the CORE, CORE2, and ESSENCE phase III clinical trials in patients with severe HTG, expected in the second half of 2025, will help determine the requirement for a larger cardiovascular outcomes trial.

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality worldwide. Lowering LDL-cholesterol, by lifestyle modification or therapeutically, reduces the risk of ASCVD. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein which binds to the LDL-receptor and induces degradation, is a clinically validated target to lower LDL-cholesterol. Injectable PCSK9 inhibitor therapies have demonstrated substantial reductions in LDL-cholesterol with associated decreased risk of ASCVD events. MK-0616 is an orally bioavailable, renally excreted, macrocyclic peptide inhibitor of PCSK9. The article provides an understanding of the chemistry and development, pharmacokinetic and pharmacodynamic characteristics of MK-0616 and insight into its clinical efficacy and safety. In clinical trials, MK-0616 produced dose-dependent reductions in LDL-cholesterol, non-HDL-cholesterol, and apolipoprotein (apo) B levels. Furthermore, MK-0616 modestly lowered lipoprotein (a) [Lp(a)]. MK-0616 is a potent, oral macrocyclic peptide inhibitor of PCSK9 that is not only able to reduce LDL-cholesterol, non-HDL-cholesterol, and apoB, but can also lower Lp(a). Safety and tolerability studies reported to date are promising. MK-0616 may offer advantages over injectable anti-PCSK9 therapies in terms of ease of dosing, patient preference and cost. The results from phase III trials of MK-0616 on cardiovascular outcomes are awaited with interest.