Amanda J. Hooper

Description: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.

Description:Homozygous familial hypercholesterolemia (HoFH) is a rare, inherited disorder characterized by severe LDL-hypercholesterolemia and accelerated atherosclerotic cardiovascular disease. It typically presents in childhood or adolescence, and if untreated, may be fatal in the first decades of life. The microsomal triglyceride transfer protein (MTP) is essential for the assembly and secretion of apolipoprotein (apo)B-containing lipoproteins. MTP inhibition with lomitapide effectively lowers plasma LDL-cholesterol as an adjunct therapy in adults with HoFH. We discuss the role of MTP as a therapeutic target for HoFH, describe the pharmacodynamics, pharmacokinetics, and metabolism of lomitapide, and report on the findings of the phase III APH-19 trial in pediatric HoFH. Lomitapide is an oral small molecule inhibitor of MTP, which reduces LDL-cholesterol by 53.5% in pediatric patients with HoFH on maximal standard lipid-lowering therapy, including lipoprotein apheresis. Moreover, small case series have shown that pediatric patients on lomitapide were able to cease or reduce the frequency of apheresis. Safety and tolerability studies are consistent with the known mechanism of lomitapide on the gastrointestinal and hepatic systems, being generally mild and manageable in pediatric patients with HoFH. The results of longer-term safety data are awaited.

Description: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 a 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 optimal dosing schedule for cardiovascular outcome studies.

Description: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.

Description:Background: Pathogenic heterozygous melanocortin-4 receptor (MC4R) variants are the most common cause of monogenic obesity, affecting central satiety and appetite regulatory areas of the brain. Methods: We report a pedigree with a pathogenic MC4R variant (c.380C>T, p.Ser127Leu). In the proband with obesity (BMI 35 kg/m2) and severe insulin resistance, use of combination of semaglutide and naltrexone-bupropion was successful in reducing insulin requirements and weight. His adult monozygotic twin daughters both had childhood-onset obesity; however, weight trajectories differed. Twin 1 had a peak BMI of 29.1 kg/m2, which decreased to 19.7 kg/m2 with intensive exercise and diet control without weight-lowering medication. Twin 2 had a sedentary lifestyle and epilepsy and had a peak BMI of 30.1 kg/m2; she responded well to naltrexone-bupropion and BMI decreased to 26 kg/m2. Conclusions: The manifestation of obesity, even in cases of monogenic obesity, can vary significantly due to the influence of environmental and lifestyle factors.