Voxelotor: novel drug for sickle cell disease

Sickle cell disease (SCD), is an autosomal recessive disorder caused by mutation in the ??chain of haemoglobin (Hb) that leads to production of sickle haemoglobin (HbS). The disease has a profound negative impact on health-related quality of life with increased propensity for complications. Current treatment options include drugs like hydroxyurea and L-glutamine that are currently on the market. However, none of these therapies target the underlying mechanism and have potential safety concerns. As oxygenated Hb is a potent inhibitor of HbS polymerization, increasing the proportion of oxygenated HbS may provide a disease?modifying approach to SCD. Voxelotor is a novel therapy developed for the treatment of SCD by modulating the Hb affinity for oxygen. By forming a reversible covalent bond with the N?terminal valine of the ??chain of Hb, the drug results in an allosteric modification of Hb and thereby leading to an increase in oxygen affinity. Moreover, voxelotor prevents sickling of red blood cells (RBCs) and possibly interrupts the molecular pathogenesis of the disease. The drug is available in oral formulation with a recommended dosage of 1500 mg once daily. The onset of voxelotor is fast, shows rapid absorption and linear pharmacokinetics. Most common adverse reactions seen are headache, diarrhea and abdominal pain. Clinical trials for voxelotor have been positive, and results suggest that the drug may be a new safe and effective option for SCD treatment. With global blood therapeutics having already received US FDA approval in November 2019, voxelotor may soon be an addition to the mounting armoury of drugs against SCD.

Lefamulin: novel pleuromutilin drug for community acquired bacterial pneumonia

The advent and spread of antimicrobial resistance has led to a global public health emergency necessitating development of new antimicrobial drugs. Community acquired bacterial pneumonia (CABP) contributes a major portion of societal burden with increasing morbidity due to evolution of drug resistant strains. Lefamulin is a novel pleuromutilin antibiotic with unique mechanism of action through inhibition of protein synthesis by binding to the peptidyl transferase center of the 50s bacterial ribosome. The drug displays activity against Gram positive and atypical organisms associated with CABP (i.e., Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumonia, Legionella pneumophila, and Chlamydophila pneumoniae), with an expanded Gram-positive spectrum including Staphylococcus aureus (i.e., methicillin-resistant, vancomycin-intermediate, and heterogeneous strains). Lefamulin is available in both intravenous (IV) and per oral (PO) formulation, exhibits high nonlinear plasma protein binding with low unbound concentrations, higher concentrations in lung epithelial lining fluid (ELF) than in plasma, and a half-life of approximately 10 hour. The recommended IV dose is 150 mg twice daily over 1 hour or a PO dose of 600 mg twice daily. Most common adverse drug reactions injection site reactions, hepatic enzyme elevation, nausea, diarrhoea, hypokalemia, insomnia, and headache. Clinical trials for lefamulin have been positive and Phase 3 data suggest similar efficacy when compared to moxifloxacin with or without linezolid in CABP. Also, the documented resistance and cross-resistance with other Gram-positive antibacterials remains low. With Nabrivia Pharmaceuticals having already received US FDA approval in August 2019, lefamulin may soon be a new addition to the mounting armoury of drugs against CABP.

Prucalopride: novel drug for chronic idiopathic constipation

Chronic Idiopathic Constipation (CIC), defined as constipation in which the underlying cause is unknown, is a common medical illness with a profound negative impact on health-related quality of life and increased propensity for life threatening complications. Current treatment for CIC includes lifestyle modifications, over-the-counter medications, and prescription medications. Presently, the only approved, prescription products for CIC in the US are prosecretory agents. However, the current knowledge that serotonin plays an important role in colonic motility has opened new horizons in the treatment of CIC promoting use of prokinetic agents with a different mechanism of action. Prucalopride is a highly selective 5-hydroxytryptamine type 4 (5-HT4) receptor agonist that enhances propulsive motor patterns in the large intestine due to a high affinity for 5-HT4 receptors in gastrointestinal (GI) tissues. The onset of action of Prucalopride is fast, shows rapid absorption, oral bioavailability of 93% and linear pharmacokinetics. Most common adverse reactions seen are headache, nausea, diarrhea, and abdominal pain. Clinical trials for Prucalopride have been positive, and results suggest that the drug may be a new safe and effective option for CIC treatment, especially for patient’s refractory to prosecretory agents. As a prescription drug for the management of constipation and given the virtual demise of other prokinetic agents for this indication, prucalopride competes primarily with another class of agents: those that stimulate secretion. With Shire Pharmaceuticals having already received US FDA approval in Dec 2018, Prucalopride may soon be a new addition to the mounting armoury of drugs against CIC.

Lasmiditan: new drug for acute migraine

Migraine is ranked by the World Health Organization as the world’s second leading cause of disability. The current state of knowledge suggests that migraine is a neuronal process involving activation and sensitization of the trigeminal nociceptors and the trigeminocervical complex, as well as cortical spreading depression and abnormal brainstem activity. The present non vascular etiological basis has opened a new horizon in the treatment of acute migraine targeting the trigeminal pathways. Lasmiditan, a highly selective 5-HT1F receptor agonist, acts on the trigeminal system without causing vasoconstriction because of its low a?nity for 5-HT1B receptors. The compound belongs to a new class of drugs “ditans” and its mechanism of action is neuronal without evidence of vasoactive effects as seen with triptans. It lowers plasma protein extravasation decreasing the neurogenic inflammation of the dura and suppress neuronal firing within the trigeminal nucleus caudalis. Also, 5HT1F agonists have shown to decrease c-fos activity within trigeminal nucleus thereby reducing the level of synaptic activation. The onset of action of lasmiditan is fast, shows rapid absorption, oral bioavailability of 40% and linear pharmacokinetics. Most common adverse reactions seen are dizziness, paresthesia, somnolence, nausea, fatigue and lethargy with dizziness being the most recurrently reported adverse event. Clinical trials for lasmiditan to date have been positive, and maiden results suggest that lasmiditan may be a new safe and effective option for acute migraine treatment, especially for patients refractory to or unable to tolerate triptans, and/or for patients with pre-existing cardiovascular disease. With Eli Lilly and Co. having already applied for US FDA approval in Nov 2018, lasmiditan may soon be a new addition to the mounting armoury of drugs against migraine.