Historically, drug development and approval within the MS treatment spectrum have been focused toward RRMS. However, the treatment spectrum for SPMS in particular is rapidly expanding. As of 2019, 34 randomized trials have evaluated 21 therapies for SPMS, most of which already received approval for RRMS. Of the trials, only 38% achieved the primary endpoint. At that time, the intravenous immunosuppressant mitoxantrone was the only approved therapy for SPMS. Although evidence supported its efficacy for treating disability, adverse effects (AEs) included cardiac complications and malignancy risk. In addition, patients could only receive a total of 140 milligrams (mg) which limited the therapeutic value of mitoxantrone for SPMS to approximately a two-year period. (17) In 2019, the oral therapies Mayzent (siponimod) and Mavenclad (cladribine) were approved for the treatment of active SPMS, (18,19) warranting consideration for inclusion in health plan formularies.
Cladribine is indicated for the treatment of relapsing forms of MS to include relapsing-remitting disease and active secondary progressive disease in adults. It is administered for two weeks per year for two years. (19) In CLARITY — a phase 3, randomized, double-blind, placebo-controlled clinical trial — patients with relapsing forms of MS were randomized to receive cladribine 3.5 mg/kg (n = 433), 5.25 mg/kg (n = 456), or placebo (n = 437). At 96 weeks, 81% of patients receiving cladribine were relapse-free compared with 63% receiving placebo (nominal P < .05), and 87% of patients receiving cladribine had no confirmed three-month Expanded Disability Status Scale progression compared with 81% on placebo. (20) In addition, cladribine significantly reduced the median number of lesions across MRI endpoints versus placebo (P < .001). The most common AEs (n = 440) were upper respiratory tract infection (38%), headache (25%) and lymphopenia (24%). (19) In a post hoc analysis, 44% of patients receiving cladribine achieved no evidence of disease activity versus 16% receiving a placebo (P < .0001). (21)
Siponimod is indicated for treatment of relapsing forms of MS to include clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease in adults. (18) The phase 3, randomized, double-blind EXPAND trial evaluated siponimod, at 2 mg, for SPMS-related disability progression in patients with moderate to advanced disability. Results demonstrated a 21% relative risk reduction in disability progression for patients receiving siponimod (n = 1105) versus those receiving placebo (n = 546; P = .013). In addition, the T2 lesion volume changed from baseline 184 mm3 for patients on siponimod and 879 mm3 for patients on placebo. (22) The most common AEs were headache (15%), hypertension (13%), and increased transaminase (11%).18 Results from an analysis presented at the 2019 conference for the European Committee for Treatment and Research in Multiple Sclerosis showed the clinically relative benefits of siponimod were highest regarding disability progression, cognitive processing speed and MRI inflammatory disease activity. (23)
In 2019, the Institute for Clinical and Economic Review’s (ICER’s) Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC) reviewed the clinical and cost effectiveness of siponimod for active and nonactive SPMS. The clinical effectiveness of siponimod was compared to that of best supportive care, which was estimated based on the placebo group in EXPAND. Midwest CEPAC panel members voted 15-2 that adequate evidence demonstrated clinical superiority of siponimod compared to best supportive care for patients with active SPMS. However, they voted unanimously that there was not enough evidence to make this case for patients with nonactive SPMS. (24)
Regarding long-term cost effectiveness, ICER evaluated siponimod versus best supportive care using a Markov model that estimated confirmed disability progression, patient survival, ambulation time, quality-adjusted survival, and lifetime healthcare costs. The model used the initial wholesale acquisition cost of siponimod. Results from the Markov model showed that, for the entire SPMS patient population, the incremental cost-effectiveness ratios were more than $1 million per quality-adjusted life year. For those with active SPMS, the ratios were $433,000 per quality-adjusted life year. (24)