A number of new drugs for neurology and psychiatry are currently in review with regulatory authorities in the U.S. and Canada. The following summarizes some of the key therapies expected to be approved in 2020.
Siponimod (Novartis): This selective S1P receptor 1,5 modulator (Mayzent) was submitted to Health Canada in February 2019. A Canadian Drug Expert Committee (CDEC) meeting is scheduled for February 19, with recommendations by early March. The submitted application was for the treatment of SPMS. Mayzent received FDA approval in March 2019 for the treatment of relapsing forms of MS, including clinically isolated syndrome, RMS and active SPMS. Approval was based on the EXPAND study, which demonstrated a 21% reduction in the risk of 3-month confirmed disability progression in SPMS patients (Kappos et al. Lancet 2018;391:1263-1273). Mayzent is dose-titrated so most patients will not require first-dose observation, in contrast to its sister drug Gilenya.
Ozanimod (Celgene/Bristol-Myers Squibb): This is the second of four selective S1P modulators currently in development; the others are siponimod (see above), ponesimod (Johnson & Johnson) and amiselimod (MT-1303) (Mitsubishi Tanabe). Following a refusal-to-file notification from the FDA a year ago, ozanimod is expected to receive FDA approval in late March. In the phase III SUNBEAM trial, the annualized relapse rate (ARR) was 0.24 and 0.18 with ozanimod 0.5 mg/day and 1 mg/day versus 0.35 with interferon-beta-1a IM at 12 months (Comi et al. Lancet Neurol 2019;18:1009-1020). In the RADIANCE trial, ARR was 0.22 and 0.17 with ozanimod 0.5 mg/day and 1 mg/day versus 0.28 with interferon-beta-1a IM at 24 months (Cohen et al. Lancet Neurol 2019;18:1021-1033). A pooled analysis showed a comparable rate of 3-month confirmed disability progression with ozanimod and IFN-beta-1a (Cree BAC. CMSC 2018).
Fremanezumab (Teva): This is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP) administered monthly (225 mg) or q3monthly (675 mg) by subcutaneous injection. The drug (Ajovy) received FDA approval in September 2018 for the prevention of episodic or chronic migraine. Other drugs in this class include erenumab (Novartis; approved May 2018 in US, August 2018 in Canada) and galcanezumab (Eli Lilly; approved September 2018 in US, October 2019 in Canada). Fremanezumab was submitted to Health Canada in June 2019 and approval is expected this summer. In the recently-published FOCUS study, there was a mean reduction of four migraine days per month with fremanezumab versus placebo in patients who had previously failed four prior migraine prophylaxis agents (Ferrari et al. Lancet 2019;394:1030-1040).
Eptinezumab (Alder/Lundbeck): A fourth anti-CGRP MAb has also filed with the FDA and is expected to be approved later this month. Treatment is administered every three months by infusion. A phase IIb study reported a >75% responder rate in up to one-third of chronic migraine patients (Dodick et al. Cephalalgia 2019;39:1075-1085).
Rimegepant (Biohaven): The injectable CGRP MAbs will face competition from rimegepant, the second drug in a class of oral CGRP antagonists. Ubrogepant (Ubrelvy, Allergan) received FDA approval in December 2019 for the acute treatment of migraine. Another new player is lasmiditan (Reyvow), an oral serotonin-1F agonist approved in November for acute migraine. For rimegepant, a phase III trial reported that 21% of acute migraine patients were pain-free with rimegepant (vs. placebo 11%) and 35% were free of their most bothersome symptom (vs. placebo 27%) at two hours post-dosing (Croop et al. Lancet 2019;394:737-745). Biohaven is currently enrolling patients in a phase III trial of rimegepant for migraine prophylaxis.
Esketamine (Janssen): This N-methyl D-aspartate (NMDA) receptor blocker (Spravato) is currently in review with Health Canada. CDEC will meet to discuss it on June 17 with approval expected in July. Esketamine received FDA approval in March 2019 for treatment-resistant depression as an adjunct to an oral antidepressant. Three short-term efficacy trials have been performed; only one (TRANSFORM-2) reported a significant advantage of esketamine/antidepressant versus placebo/antidepressant (Popova et al. Am J Psychiatry 2019;176:428-438). It is unclear if the treatment effect (4-point difference in MADRS score at day 28) is clinically meaningful (Gastaldon et al. Epidemiol Psychiatr Sci 2019;29:e79). The drug is administered by intranasal spray; medical supervision is required. There are black-box warnings of sedation, dissociation, misuse and suicidal thoughts/behaviours.