Newer FDA-Approved Drugs for Multiple Sclerosis

1. Anti-CD20 Monoclonal Antibodies (High Efficacy)

Ocrelizumab (Ocrevus) - FDA approved March 2017

• Indication: RRMS, active SPMS, PPMS (first and only drug proven effective in PPMS, reducing disability progression by 25%)
• Route: IV infusion every 6 months
• Mechanism: Anti-CD20; depletes B cells via antibody-dependent and complement-mediated cytotoxicity
• Side effects: Infusion reactions (most common - flushing, fever, chills), upper respiratory infections, oral herpes reactivation, decreased immunoglobulins with long-term use, PML risk (rare), increased breast cancer signal in trials (monitor)
• Note: A new subcutaneous formulation - Ocrevus Zunovo (ocrelizumab + hyaluronidase-ocsq) - was FDA-approved September 2024, allowing a 10-minute subcutaneous injection rather than IV infusion

Ofatumumab (Kesimpta) - FDA approved August 2020

• Indication: RRMS, active SPMS
• Route: Subcutaneous injection (self-administered monthly after loading doses); notably the only self-injectable anti-CD20 for MS
• Mechanism: Anti-CD20 monoclonal antibody; fully human (unlike ocrelizumab which is humanized)
• Side effects: Injection site reactions, upper respiratory infections, headache, local skin reactions, hypogammaglobulinemia, PML risk (rare), hepatitis B reactivation
• Advantage: Can be self-administered at home without infusion center visits

Ublituximab (Briumvi) - FDA approved December 2022

• Indication: RRMS, active SPMS
• Route: IV infusion (shorter infusion time than ocrelizumab - ~1 hour)
• Mechanism: Anti-CD20 monoclonal antibody; glycoengineered for enhanced ADCC activity
• Side effects: Infusion reactions, upper respiratory and urinary tract infections, decreased immunoglobulins, PML risk, hepatitis B reactivation
• Note: Approved based on the ULTIMATE I and II trials; [PMID 36057173] includes safety data summary

2. Sphingosine-1-Phosphate (S1P) Receptor Modulators

Siponimod (Mayzent) - FDA approved March 2019

• Indication: RRMS, active SPMS (first oral drug specifically approved for SPMS)
• Route: Oral tablet daily
• Mechanism: Selective S1P1 and S1P5 receptor modulator (more selective than fingolimod)
• Side effects: Bradycardia/AV block (requires cardiac monitoring at initiation), macular edema, elevated liver enzymes, headache, hypertension, peripheral edema, PML risk
• Important: Requires CYP2C9 genotyping before use - the CYP2C9*3/*3 genotype is a contraindication due to markedly elevated drug levels

Ozanimod (Zeposia) - FDA approved March 2020

• Indication: RRMS, active SPMS; also approved for ulcerative colitis
• Route: Oral capsule daily (titrated over 7 days)
• Mechanism: Selective S1P1 and S1P5 modulator
• Side effects: Bradycardia at first dose (requires dose titration), macular edema, elevated liver enzymes, upper respiratory infections, hypertension, back pain, PML risk
• Drug interaction: Substrate of CYP2C8 - avoid strong CYP2C8 inducers/inhibitors; also interacts with MAOIs

Ponesimod (Ponvory) - FDA approved March 2021

• Indication: RRMS, active SPMS
• Route: Oral tablet daily (2-week titration schedule)
• Mechanism: Selective S1P1 modulator
• Side effects: Bradycardia/AV conduction slowing (at initiation), macular edema, elevated liver enzymes, upper respiratory infections, dizziness, peripheral edema, PML risk
• Note: Head-to-head trial (OPTIMUM) showed superiority over teriflunomide for annualized relapse rate reduction

3. Oral Fumarates

Diroximel Fumarate (Vumerity) - FDA approved October 2019

• Indication: RRMS, active SPMS
• Route: Oral delayed-release capsule twice daily
• Mechanism: Nrf2 (nuclear factor erythroid 2-related factor 2) pathway activator; prodrug of monomethyl fumarate
• Side effects: Flushing, abdominal pain, diarrhea, nausea (but significantly less GI side effects vs. dimethyl fumarate - the major advantage), lymphopenia, PML risk, elevated liver enzymes

Monomethyl Fumarate (Bafiertam) - FDA approved April 2020

• Indication: RRMS, active SPMS
• Route: Oral delayed-release capsule twice daily
• Mechanism: Direct Nrf2 activator (not a prodrug)
• Side effects: Flushing, GI disturbance (less than dimethyl fumarate), lymphopenia, PML risk

4. Purine Antimetabolite

Cladribine (Mavenclad) - FDA approved March 2019

• Indication: RRMS, active SPMS (for patients with inadequate response to or intolerant of other DMTs)
• Route: Oral tablets - short annual "courses" (2 weeks/year for 2 years, then no treatment for 2 years)
• Mechanism: Purine nucleoside analog; selectively depletes lymphocytes (both B and T cells); incorporated into DNA of dividing lymphocytes causing cell death
• Side effects: Lymphopenia (most common, dose-dependent), increased infection risk (herpes zoster, oral herpes), nausea, headache; teratogenic (contraindicated in pregnancy and within 6 months of last dose); potential oncogenic risk (black box warning)
• Regulatory bodies also approved cladribine for active SPMS, per Harrison's 22e

5. Emerging / Pipeline: BTK Inhibitors

• Tolebrutinib (Sanofi): Oral BTK inhibitor; received FDA Breakthrough Therapy designation (December 2024) for non-relapsing secondary progressive MS (nrSPMS) - a population with no currently approved oral agents. PDUFA date was September 2025.
• Fenebrutinib (Genentech): Phase III data in 2026 showed positive results in both relapsing MS and PPMS across three trials (FENhance 1, 2, 3)

Quick Reference Table

Cross-Cutting Safety Notes

1. PML risk: Applies to natalizumab (highest), S1P modulators, fumarates, and anti-CD20s. Risk linked to JC virus reactivation with lymphopenia.
2. Macular edema: Required ophthalmologic screening before and during all S1P modulators; risk higher in patients with diabetes or uveitis.
3. Cardiac monitoring: All S1P modulators can cause first-dose bradycardia and AV block; ponesimod and ozanimod require graduated dose titration; siponimod requires titration and ECG monitoring.
4. Pregnancy: Cladribine, teriflunomide contraindicated. Fumarates and S1P modulators require effective contraception. Anti-CD20s may cause neonatal B-cell depletion if used in 3rd trimester.
5. Immunoglobulin monitoring: Anti-CD20 agents reduce IgG levels over years of treatment; patients with levels below threshold may need IVIG supplementation.
6. Hepatitis B reactivation: Screen all patients before starting anti-CD20 agents.