16 Metabolic Disease Drugs
In February, the FDA approved Esperion Therapeutics’ Nexletol and Nexlizet respectively. On the basis of controlling diet and taking the maximum tolerated dose of statins, both drugs are suitable for adjuvant treatment of adult patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease who need further control of low-density lipoprotein cholesterol (LDL-C) levels. Nexletol and Nexlizet were launched in the United States in March and June, respectively. These two products were also approved in the European Union later in the same year and were marketed under the trade names Nilemdo and Nustendi respectively for the treatment of adult patients with primary hypercholesterolemia or mixed dyslipidemia. Bepadoxic acid is an ATP citrate lyase (ACLY) inhibitor of the first innovative drug. NACLY acts on the upstream of HMG-CoA reductase (the target of statins). Under its catalysis, it catalyzes the cleavage of citric acid into oxaloacetate and acetyl-CoA outside the mitochondria. Inhibiting fatty acid synthase will reduce the total production of acetyl-CoA, thereby limiting the two-carbon units required for fatty acid and cholesterol biosynthesis.
The proprotein convertase subtilisin 9 (PCSK9) is another relatively new target for lowering low-density lipoprotein cholesterol. PCSK9 is a circulating protein that can increase blood cholesterol levels by promoting the degradation of low-density lipoprotein receptor (LDLR). Reducing the substance can reduce the risk of low-density lipoprotein cholesterol and cardiovascular disease.
Up to now, there are two anti-PCSK9 monoclonal antibodies, Alixumab and Evoculumab, for the treatment of hypercholesterolemia; however, due to their high cost, they are limited to patients with very high-risk cardiovascular diseases. At the end of 2020, the European Commission approved small molecule interference ribonucleic acid (siRNA) and PCSK9 expression inhibitor Inclisiran (Leqvio; Novartis) for the treatment of adult patients with hypercholesterolemia or mixed dyslipidemia. The drug was approved based on strong ORION clinical research results. In this study, Inclisiran can effectively and continuously reduce LDL cholesterol levels in patients who have not been able to lower LDL cholesterol after receiving the maximum tolerated dose of statins in the past, with a maximum reduction of up to 52%. The drug only needs to be administered twice a year, and it is expected that Inclisiran can achieve long-term medication compliance in patients. Novartis developed the drug after it was licensed by Alnylam.
In March 2020, the Drug Administration of India (DCGI) approved the NDA application for Saroglitazar magnesium (Lipaglyn) submitted by ZydusCadila for the treatment of non-cirrhotic non-alcoholic steatohepatitis (NASH), making this PPARα/γ dual agonist the world’s first marketed drug for this indication. Zydus reported favorable results from a phase III clinical trial (EVIDENCESII study). The study used a liver biopsy evaluation method to compare Saroglitazar with placebo in NASH patients in India. The study used liver biopsy at the end of 52 weeks to evaluate the improvement of liver histology in patients with NASH, and the results showed that the study reached the primary and secondary endpoints. Saroglitazar can significantly reduce liver fat and liver enzyme levels and reduce disease activity. In a phase II trial (EVIDENCESI study), Saroglitazar treatment improved liver enzymes and blood lipid levels in NAFLD patients. A Phase II clinical trial of Saroglitazar (EVIDENCESIV) in NASH patients in the United States also reached its primary and secondary endpoints. This is a new indication for PPAR agonists. The drug was first marketed in India in 2013. The indications approved at that time were that statin monotherapy could not control the complications of type 2 diabetes (that is diabetic dyslipidemia and hypertriglyceridemia). In January 2020, the drug was approved for the treatment of type 2 diabetes. In December 2020, DCGI approved Saroglitazar’s expanded indications for non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver (simple steatosis) and non-alcoholic steatohepatitis (NASH).
In patients with hyperuricemia and gout, uric acid excretion drugs mainly reduce the level of uric acid by inhibiting the reabsorption of urate anions by the proximal renal tubular epithelial cells and promoting the excretion of uric acid by the kidneys. The human anion exchanger URAT1 (Urate Transporter 1, also known as Solute Carrier Family 22 Member 12) is a member of the organic anion transporter family and has been found to be the central mediator of the uric acid excretion process. Inhibition of URAT1 has been identified as the mechanism of action of most existing uric acid excretion drugs, which can prevent uric acid from being reabsorbed by the kidneys, thereby promoting its excretion. In January 2020, the new URAT1 inhibitor Dotinurad (Urece; Fuji Pharmaceutical) was approved in Japan; and in May, it was listed by its commercialization partner Mochita.
In late November, Rhythm Pharmaceuticals’ melanocortin receptor 4 agonist Setmelanotide (Imcivree) was approved by the FDA. It was used for obese adults and children ≥6 years old who need long-term weight management with pro-amelanocortin (POMC), proprotein converting enzyme subtilisin 1 (PCSK-1) or leptin receptor (LEPR) deficient confirmed by genetic testing. This approval makes Setmelanotide the first FDA-approved therapy for the treatment of this rare genetic obesity. These three extremely rare types of obesity are diseases caused by mutations in the POMC, PCSK1 or LEPR genes. The melanocortin receptor 4 regulatory pathway in the patient’s hypothalamus is destroyed, and this pathway is responsible for regulating the human body’s hunger, energy expenditure, and weight. Patients with POMC, PCSK1, or LEPR-deficient obesity suffer from extreme hunger and hyperappetite during childhood, leading to early-onset severe obesity. As an MC4 receptor agonist, Setmelanotide aims to restore the damaged MC4 receptor pathway activity caused by genetic defects upstream of the melanocortin receptor 4. After the drug was approved, the FDA granted Rhythm a certificate of priority review for rare pediatric diseases. The FDA has previously granted breakthrough therapy designation for Setmelanotide for the treatment of obesity with melanocortin receptor 4 pathway upstream gene defects, and granted orphan drug designation for POMC (including PCSK1) and LEPR-deficient obesity indications. Rhythm expects the drug to be launched in the United States in the first quarter of 2021.
In June, the FDA approved Ultragenyx’s triheptanoic acid glyceride (Dojolvi) as a source of calories and fatty acids for the treatment of children and adults with long-chain fatty acid oxidation disorders (LC-FAOD) confirmed by molecular diagnostics. Triheptanoin is a highly purified, artificially synthesized 7-carbon fatty acid triglyceride, specifically designed to provide LC-FAOD patients with medium-chain and odd-carbon fatty acids as an energy source and a substitute for metabolites. This is the first therapy approved by the FDA to treat LC-FAOD. Due to the risk of serious outcomes including premature death, the disease has been included in newborn screening programs in the United States and certain European countries. The drug is recognized as an orphan drug for the treatment of this rare pediatric disease. Ultragenyx obtained the exclusive global license of Triheptanoin from the Baylor Institute of America in 2013. The product was launched in the United States (the first market) in July.
Primary hyperoxaluria type 1 (PH1) is an extremely rare disease. The disease is caused by excessive oxalate production in the body, which causes calcium oxalate crystals to be deposited in the kidneys and urinary tract, and causes painful and recurrent nephrolithiasis and nephrocalcinosis. Kidney injury is a disease caused by oxalate-induced renal tubular toxicity, calcium oxalate deposition in the kidney, and urinary tract obstruction caused by calcium oxalate stones. Impaired renal function will aggravate the condition. This is because excessive oxalate cannot be discharged normally, and then gradually accumulates and crystallizes in the bones, eyes, skin and heart, eventually leading to serious illness and death. Treatment options for this disease are very limited, including frequent kidney dialysis or combined liver and kidney transplantation. Although a small number of patients respond to vitamin B6 treatment, no therapeutic drugs have been approved for PH1 so far. In November, both the EC and FDA approved Alnylam’s Lumasiran (Oxlumo) marketing authorization, which is used to treat PH1 patients of all ages. Lumasiran is a siRNA targeting hydroxy acid oxidase 1 (HAO1) messenger ribonucleic acid (mRNA), which encodes glycolate oxidase (GO). By degrading HAO1 mRNA and reducing GO synthesis, Lumasiran can block the production of oxalate, which directly leads to the clinically toxic metabolites of PH1. Lumasiran was granted PRIME qualification and orphan drug qualification in the EU, and obtained accelerated review qualification. The drug was granted Orphan Drug Designation, Breakthrough Therapy and Pediatric Rare Disease Designation by the US FDA earlier in the same year. The British Medicines and Health Products Agency (MHRA) have given a positive review of Lumasiran through the “Early Access to Medicines Program”; according to the program, eligible patients in the UK can even get the drug before EC approval. Lumasiran was listed in the United States and the European Union shortly before the end of the year.
Libmeldy is a new type of gene therapy for the treatment of rare disease metachromatic leukodystrophy (MLD), which was officially approved by EC in late December. MLD is a life-threatening genetic disease of the metabolic system, with a prevalence of approximately 1 in 100,000 live births. MLD is caused by mutations in the arylsulfatase A (ARSA) gene, which causes sulfatides to accumulate in brain tissue and other parts of the body, including the liver, gallbladder, kidney, and/or spleen. Over time, the nervous system is damaged, leading to neurological diseases such as behavior and movement, cognitive deterioration, severe spasms, and seizures. Patients with MLD gradually lose the ability to move, speak, swallow, eat, and see. In late-onset infantile MLD, the patient’s mortality rate is estimated to be 50% at 5 years after onset and 44% at 10 years. Early-onset MLD includes two disease mutations: late-onset infantile type (LI) and early-onset juvenile type (EJ). The approved indications for this therapy are LI type and EJ type without clinical manifestations of the disease, or EJ type with early clinical manifestations of the disease. Such patients still have the ability to walk independently, and cognitive function has not yet been reduced. Libmeldy is a one-time treatment designed to correct potential genetic defects that cause MLD. During treatment, it is necessary to collect autohematopoietic stem cells (HSC) from the patient, and then use a self-inactivating lentiviral vector to insert a functional copy of the ARSA gene into the HSC genome; finally, the genetically engineered cells are returned to the patient. This therapy by Orchard Therapeutics was approved. The company acquired the product from GlaxoSmithKline in 2018. The gene therapy was jointly developed by Ospedale San Raaele, Fondazione Telethon and GlaxoSmithKline.