Future look: Drug approvals pending for 2020


Three drugs for use in neurology or psychiatry have filed with Health Canada and are expected to be approved in 2020. All have received FDA approval in the U.S. Here is a summary of what is waiting in the wings.

Esketamine for treatment-resistant depression (Janssen):

The N-methyl D-aspartate (NMDA) receptor blocker filed in January 2019 for the treatment of treatment-resistant depression. In the U.S. (marketed as Spravato), the approved indication is for patients who have not responded adequately to at least two antidepressants and is intended as an adjunct to an oral antidepressant. The drug is a nasal spray with each device containing half the usual dose (28 mg). Recommended dosing is 56 mg twice per week for the first four weeks, 56 mg or 84 mg once-weekly for four weeks, then 56 mg or 84 mg once or twice a week thereafter. Treatment must be administered with the supervision of a healthcare professional. Blood pressure must be assessed before and after dosing. A two-hour observation period is required due to a risk of sedation and dissociation. Black-box warnings include a potential for abuse (Schedule III drug in the U.S.) and an increased risk of suicidal thoughts in younger patients.

U.S. approval was based on the results of five phase III trials. In TRANSFORM-1, the 84-mg dose failed to meet the primary endpoint of a change from baseline to day 28 in the MADRS total score; the 56-mg dose was not formally tested (Fedgchin et al. Int J Neuropsychopharmacol 2019;22:616-630). The treatment effect was considered by investigators to be clinically meaningful. A maintenance trial reported a reduction in relapses with esketamine + antidepressant versus antidepressant alone in patients who were prior responders to esketamine (Daly et al. JAMA Psychiatry 2019; epublished June 5, 2019). Other studies have not yet been published. A recent editorial sounded a note of caution about esketamine, noting that it has not been determined how long the drug can be maintained and whether discontinuation will be problematic (Schatzberg AF. Am J Psychiatry 2019;176:422-424).

Siponimod for secondary-progressive MS (Novartis): The sphingosine-1 receptor 1,5 modulator filed with Health Canada in February 2019. In the U.S. (marketed as Mayzent), the approved indication is for relapsing forms of MS, including CIS, RRMS and SPMS. The oral drug is titrated over six days to a dose of 1 mg or 2 mg per day; the dose depends on the results of CYP2C9 genotyping. Patients with CYP2C9 polymorphisms (*1/*3 and *2/*3 genotypes) have >50% reduction in siponimod metabolism and require a lower dose. Titration eliminates the need for first-dose observation except in patients with pre-existing heart disease. There are no black-box warnings. An assessment for macular edema is recommended.

FDA approval was based on the results of the phase III EXPAND trial, which reported a 21% reduction versus placebo in three-month confirmed disability progression in SPMS patients (Kappos et al. Lancet 2018;391:1263-1273). There was a trend to improved three-month CDP in the subgroup without superimposed relapses. There were also significant reductions in the cumulative number of Gd+ and new T2 lesions, T2 lesion volume and brain atrophy rate.

Fremanezumab for migraine prophylaxis (Teva): This humanized monoclonal antibody targets the calcitonin gene-related peptide (CGRP) ligand and an application was filed with Health Canada in June 2019. In the U.S. (marketed as Ajovy), the approved indication is for migraine prophylaxis. The drug is administered subcutaneously either 225 mg once-monthly or 675 mg every three months. The most common adverse effect is injection site reactions. Potential hypersensitivity reactions include rash, pruritus and urticaria. There are no black-box warnings.

FDA approval was based on one trial in episodic and one in chronic migraine. In episodic migraine, the treatment effect of fremanezumab versus placebo was about 1.5 fewer migraine headache days/month (reduction of -3.7 vs. -2.2) (Dodick et al. JAMA 2018;319:1999-2008). The proportion of patients with >50% reduction in mean monthly migraine days was 44-48% with fremanezumab versus 28% with placebo. In chronic migraine, the net treatment effect with fremanezumab versus placebo was about two fewer headache days/month (-4.5 vs. -2.5) (Silberstein et al. N Engl J Med 2017;377:2113-2122). The proportion of patients with >50% reduction in mean monthly headache days was 38-41% with fremanezumab versus 18% with placebo. The FDA concluded that fremanezumab is an important addition to the migraine prophylaxis armamentarium.

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