05 Cardiovascular system drugs
The sodium-glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin (Andaton; AstraZeneca) has been on the market as a hypoglycemic agent for nearly 10 years. Another indication of the drug was approved by the FDA in May last year and subsequently approved by the European Commission. This new indication is to reduce the risk of hospitalization and cardiovascular death due to heart failure (HF) in adult patients with heart failure (NYHAII-IV) with reduced ejection fraction. The approval of this indication is based on the positive results obtained in the landmark DAPA-HF Phase III study. The study showed that compared with placebo, Dapagliflozin reduced the incidence of CV death or hospitalization due to HF, and the results have significant statistical and clinical significance. The drug received priority review and fast-track qualifications, and was subsequently approved. Dapagliflozin is the first SGLT-2 inhibitor approved by the FDA for the treatment of heart failure.
The FDA also approved a new indication for the glucagon-like peptide-1 (GLP-1) agonist semaglutide (Ozempic; Novo Nordisk) last year (the drug was launched as a hypoglycemic agent in 2018): Reduce the risk of major adverse cardiovascular events (MACE) in adult patients with type 2 diabetes and adult patients with known heart disease, such as myocardial infarction, stroke or death. The approval of the drug is based on the results of the SUSTAIN6 cardiovascular outcome trial (NCT01720446). The study evaluated the cardiovascular safety of adding semaglutide or placebo to standard treatment in adult patients with type 2 diabetes and confirmed cardiovascular disease. In this two-year study, GLP-1 agonists significantly reduced the risk of the three main MACE endpoints (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke). The estimated relative risk of MACE in the semaglutide treatment group was 26% lower than that in the placebo group, and the proportions of the primary composite endpoint events in the two groups were 6.6% and 8.9%, respectively.
Similarly, the FDA approved another GLP-1 agonist Dulaglycotide (Trulicity; Eli Lilly) for the reduction of the incidence of MACE in adult patients with type 2 diabetes who have been diagnosed with cardiovascular disease or have multiple cardiovascular risk factors. This approval makes Dulaglutide the first and only type 2 diabetes treatment approved for MACE primary prevention and secondary prevention in patients with or without cardiovascular disease. This is a new indication for Dulaglutide, which was previously marketed in 2014 for the treatment of type 2 diabetes.
The fixed-dose compound formulation cabpirin (vornorazan fumarate/acetylsalicylic acid) developed by Takeda was approved for marketing in Japan last year. This product is limited to patients with a history of gastric ulcer or duodenal ulcer, and is suitable for reducing the risk of thrombosis/embolism in patients suffering from the following diseases or undergoing the following operations: Angina (chronic stable angina, unstable angina), myocardial infarction, ischemic cerebrovascular disease (transient ischemic attack, cerebral infarction), coronary artery bypass graft (CABG) or percutaneous coronary angioplasty (PTCA). Single-tablet Cabpirin contains potassium ion-competitive acid blocker Vonolazan and NSAID drug acetylsalicylic acid. The product was jointly developed by Japan’s Takeda and Otsuka Pharmaceutical.
Hypovolemic shock is caused by severe body fluid loss. The most common cause is bleeding (traumatic injury, gastrointestinal bleeding, postpartum hemorrhage, etc.) or body fluid loss caused by vomiting/diarrhea, which leads to reduced stroke volume, poor blood circulation and organ failure. Severe hypovolemic shock is associated with high mortality, so there is a significant clinical need for new therapies. Last year, the α2B-adrenergic ligand centhaquine citrate (Lyfaquin; Pharmaz) was approved for marketing in India as a new treatment for hypovolemic shock. Centhaquine improves hypovolemic shock through blood redistribution, thereby protecting organ function and reducing mortality. The drug can be used as a first-line treatment and can be used in combination with standard treatments. A key phase III study of Centhaquine in patients with hypovolemic shock in India showed that Centhaquine can significantly increase blood pressure and reduce blood lactic acid levels compared to standard treatment. These two indicators were key indicators to improve blood flow and increase blood perfusion in organs. In this study, Centhaquine also significantly reduced mortality. Centhaquine is well tolerated, and its characteristic is that it does not need to act on β-adrenergic receptors, thereby avoiding severe toxic reactions such as myocardial dysfunction.
Hutchinson-Gilford premature aging syndrome (HGPS) is an extremely rare genetic disease. About one in every 20 million people in the world suffers from the disease. The prevalence in time is equivalent to 350 children in the world. Presenile lamina disease is another extremely rare and fatal hereditary Progeria associated with HGPS. Approximately 200 children worldwide are affected by the disease. Progeria is caused by a point mutation in the lamin A (LMNA) gene, which produces a farnesylated abnormal protein, that is, progeria. Presenile lamina disease is caused by a series of mutations in the LMNA and/or Zmpste24 genes, which can produce farnesylated proteins that are different from progeria. Children with HGPS and Progeria-like laminopathy have normal mental development, but the deposition of progeria or progeria-like defective protein in the cells will accelerate the progression of cardiovascular disease in children. The manifestations of the disease include growth retardation, body fat loss and hair loss, skin aging, joint stiffness, hip dislocation, systemic arteriosclerosis, cardiovascular disease and stroke, which lead to premature death. The average life expectancy of children is only 14.5 year old. At the end of 2020, the U.S. FDA approved the farnesyltransferase inhibitor Lonafarnib (Zokinvy; Eiger BioPharmaceuticals) as a disease-modifying therapy for the treatment of HGPS and presenile laminopathy. Two single-arm trials involving 62 patients demonstrated the effectiveness of Lonafarnib in the treatment of HGPS and compared these patients with matched and untreated patients in another independent retrospective study of the natural history of the disease. Compared with untreated patients, the life expectancy of patients treated with Lonafarnib was extended by an average of 3 months in the first 3 years of treatment. Among patients with the longest follow-up period of 11 years, the life span was extended by an average of 2.5 years. Lonafarnib obtained orphan drug and breakthrough therapy qualifications and priority review qualifications. The approval of the drug enabled Aiger to obtain a priority review voucher for rare pediatric disease products.