Oral and monoclonal antibody treatments for relapsing forms of multiple sclerosis: Effectiveness and value

DISCLOSURES: Ms McKenna, Dr Lin, Dr Whittington, Mr Nikitin, Ms Herron-Smith, Dr Campbell, and Dr Peterson report grants from Arnold Ventures, grants from Blue Cross Blue Shield of MA, grants from California Healthcare Foundation, grants from The Commonwealth Fund, and grants from The Peterson Center on Healthcare, during the conduct of the study; other from America's Health Insurance Plans, other from Anthem, other from AbbVie, other from Alnylam, other from AstraZeneca, other from Biogen, other from Blue Shield of CA, other from CVS, other from Editas, other from Express Scripts, other from Genentech/Roche, other from GlaxoSmithKline, other from Harvard Pilgrim, other from Health Care Service Corporation, other from Kaiser Permanente, other from LEO Pharma, other from Mallinckrodt, other from Merck, other from Novartis, other from National Pharmaceutical Council, other from Premera, other from Prime Therapeutics, other from Regeneron, other from Sanofi, other from United Healthcare, other from HealthFirst, other from Pfizer, other from Boehringer-Ingelheim, other from uniQure, other from Envolve Pharmacy Solutions, other from Humana, and other from Sun Life, outside the submitted work.

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system, with symptoms that vary over time, including muscle weakness, fatigue, trouble with coordination and balance, numbness or tingling in the limbs, and problems with vision. 1 Periodic relapses occur that lead to progressive disability and shortened life expectancy. Nearly 1 million Americans are affected by MS; the disease is more common in women and is typically diagnosed in young adulthood. 2 Because symptoms of MS most commonly appear in the third decade of life and treatment may last for decades, MS has a high economic burden, estimated in 2019 to be $85 billion, which is accounted for by $63.3 billion in direct medical costs and $22.1 billion in indirect and nonmedical costs. 3 Access and cost of medication were mentioned as barriers to treatment by people with MS. 3 There is no known cure for MS, but a range of treatments can help manage symptoms and slow the progression of the disease. These treatments include medications that modify the immune system (disease-modifying therapy [DMT]), medications that manage specific symptoms, and physical therapy. There are more than 20 DMTs available for the treatment of relapsing forms of MS, which include relapse remitting MS (RRMS) and secondary progressive MS.
Ublituximab, an anti-CD20 monoclonal antibody, is the latest DMT to have gained regulatory approval in the United States. The Institute for Clinical and Economic Review (ICER) evaluated ublituximab alongside 4 other monoclonal antibodies (natalizumab, ofatumumab, ocrelizumab, and rituximab) and 5 oral therapies (dimethyl fumarate, fingolimod, ozanimod, ponesimod, and teriflunomide) as first-line DMTs for relapsing forms of MS. This report presents the summary of our systematic literature review and cost-effectiveness analysis and highlights the key policy recommendations discussed at the New England Comparative Effectiveness Public Advisory Council (CEPAC) public meeting on January 20, 2023. The detailed report is available at https://icer.org/wp-content/ uploads/2022/04/ICER_MS_Final_ Evidence_Report_022123.pdf

CLINICAL EFFECTIVENESS
We evaluated the comparative clinical effectiveness of first-line DMTs for relapsing forms of MS with a particular focus on ublituximab, the latest entrant to the market. Direct evidence on ublituximab was obtained from 2 identical phase 3 randomized controlled trials (RCTs) that evaluated the efficacy and safety of ublituximab vs teriflunomide in patients with relapsing forms of MS (ULTIMATE 1 and 2). 4 Patients treated with ublituximab had a significant reduction in the rate of relapse (rate ratio: ULTIMATE 1 = 0.41, 95% CI = 0.27-0.62; ULTIMATE 2 = 0.51,

Author affiliations
Oral and monoclonal antibody treatments for relapsing forms of MS: Effectiveness and value incidence of both serious adverse events and discontinuation because of adverse events with ublituximab vs teriflunomide. Similar to other agents in the monoclonal antibody class, ublituximab carries an increased risk of serious infections because of its B-cell depletion mechanism of action. Other common side effects include infusion and injection-related reactions.

UNCERTAINTIES DUE TO LIMITATIONS IN THE CLINICAL EVIDENCE
Because of the limited head-to-head data on these agents, we used indirect analyses to compare ublituximab with the other DMTs, and thus there is more uncertainty in the results than if therapies could be compared directly. Furthermore, uncertainty in the data on disability progression limits how informative this outcome is in distinguishing between DMTs, despite its importance to patients. We were also unable to compare agents on other patient-important outcomes (eg, quality of life) because of data limitations. Furthermore, the data on ublituximab are limited to shortterm follow-up from clinical trials; given that MS treatment is expected to span decades, long-term data on the efficacy and safety are needed to fully compare ublituximab with older DMTs. Lastly, although it does not have a labeled indication for MS, rituximab was included in our analysis because of support from clinical experts, robust data on its effectiveness, and increasing use inside and outside of the United States. [5][6][7][8]

LONG-TERM COST-EFFECTIVENESS
We evaluated the cost-effectiveness of ublituximab vs dimethyl fumarate (a commonly used and generically available oral treatment) in adults with relapsing forms of MS from a US health care sector perspective using a Markov model informed by key clinical inclusion criteria. The trials ranged in size (N = 104-1,133) and duration (48-120 weeks), enrolling a predominately young, white, female population with relapse remitting MS with active disease (baseline relapses in prior 12 months = 1-1.5; baseline EDSS = 1.6-3). NMA results showed that all DMTs significantly decreased relapse rates compared with placebo, with the monoclonal antibodies having a greater impact on this outcome compared with oral medications (Table 1). All monoclonal antibodies, including ublituximab, had similar effectiveness in reducing relapse rates. Monoclonal antibodies also had numerically greater effects on disability progression than oral DMTs, although there was more uncertainty in the results (see Table 1). Rituximab was not included in the disability progression NMA because of a lack of high-quality evidence on this outcome.
Using a Bayesian network metaanalysis (NMA), we compared all the DMTs with placebo and with each other on annualized relapse rate and CDP-3/6 outcomes. MRI outcomes were reported inconsistently, and therefore, DMTs were not quantitatively compared on this outcome. We identified 23 RCTs that met our

KEY UNCERTAINTIES IN THE MODELING OF LONG-TERM COST-EFFECTIVENESS
The differences between each monoclonal antibody's modeled health outcomes were largely driven by small point estimate differences in each treatment's ability to slow disability progression estimated from the NMA. These small point estimate differences were not statistically significant, and thus the differences in the modeled health outcomes may not be clinically meaningful. The model structure uses health states defined by EDSS, which is a scale that has been critiqued for missing important quality-of-life impacts of MS beyond physical disability, but this scale remains the most widely used measure for MS disease progression. Additionally, there was a wide variation in utility scores reported in the literature for high EDSS levels.

Policy Discussion
The New England CEPAC is one of the independent appraisal committees convened by ICER to engage in the public deliberation of the evidence on clinical and cost-effectiveness of health care interventions. The New England CEPAC is composed of medical evidence experts, including clinicians, methodologists, and patient advocates. The ICER report on oral and monoclonal antibody treatments for relapsing forms of MS was the subject of a CEPAC meeting on January 20, 2023.
Following the discussion, the CEPAC panel members deliberated on key questions raised by ICER's report. A majority of the panel (9-1) voted that the evidence is adequate to demonstrate a superior net health benefit of ublituximab compared with that provided by fumarates and fingolimod. However, the panel voted unanimously (10-0) acquisition cost of $59,000), the incremental cost-effectiveness ratios for ublituximab compared with dimethyl fumarate was $403,000 per equalvalue life-year (evLY) gained and $451,000 per quality-adjusted lifeyear (QALY) gained. For comparison, the incremental cost-effectiveness ratios for natalizumab, ofatumumab, and ocrelizumab vs dimethyl fumarate were $687,000, $616,000, and $267,000 per evLY, respectively. The incremental cost-effectiveness ratios for the modified societal perspective scenario for all interventions were generally lower, but all still exceeded the commonly used cost-effectiveness thresholds of $100,000-$150,000 per QALY or per equal-value of life-years gained. Differences in the incremental cost-effectiveness ratios are primarily driven by differences in the modeled health outcomes that may not be clinically significant and differences in the net prices. Net price differences and model outcomes are in Table 2. To achieve a cost per evLY threshold of $50,000, $100,000, $150,000, and $200,000 relative to dimethyl fumarate, the annual price of ublituximab would need to be $13,200, $17,800, $22,400, or $27,000, respectively. trials and prior relevant economic models. 9-14 Natalizumab, ofatumumab, and ocrelizumab were considered as interventions in the model for supporting context. We were unable to distinguish the clinical effectiveness among the monoclonal antibodies, and therefore, each monoclonal antibody was compared with dimethyl fumarate and not one another. We did not evaluate the cost-effectiveness of rituximab (because of insufficient evidence on disease progression) or the other oral therapies evaluated in the clinical assessment.
The model consisted of 20 health states scaled by the level of disability as measured by the EDSS. Relapses were modeled as events and could occur in any alive health state rather than as a separate health state. Individuals transitioned between health states during cycles of 1 year and over a lifetime time horizon. Future costs and outcomes were discounted at 3% per year. The model was informed by the results of the previously described ICER NMA, relevant economic models, published studies in MS, and stakeholder input.
Results from our analysis showed that at an annual maintenance cost of $45,651 (assuming an approximate 23% discount from the wholesale Oral and monoclonal antibody treatments for relapsing forms of MS: Effectiveness and value ublituximab. The full set of policy recommendations can be found in the Final Evidence Report on the ICER website: https://icer.org/wp-content/ uploads/2022/04/ICER_MS_Final_ Evidence_Report_022123.pdf.

Base-Case Results Over a Lifetime Time Horizon vs Dimethyl Fumarate
Select key policy recommendations are as follows: 1) Payers should ensure that savings from lower-cost biosimilars and generic formulations should be shared with patients through the alignment of copay and coinsurance charges. Specifically, all fairly priced drugs should be placed on the lowest relevant tier, and costsharing for generic drugs with a lower net price must not trigger a higher out-of-pocket cost to the patient compared with branded drugs. 2) Manufacturers should seek to set prices that will foster affordability and good access for all patients by aligning prices with the patientcentered therapeutic value of their treatments. In the setting of new interventions for MS that are similar in efficacy and safety to other treatments, manufacturer pricing should reflect these considerations in moderating launch pricing. 3) Payers should remove barriers to access to rituximab for patients with relapsing forms of MS who are appropriate candidates for this therapy. This includes coverage of biosimilar rituximab with little or no prior authorization, given the lack of concern regarding use in appropriate patients and how inexpensive it is compared with other monoclonal antibodies of equal effectiveness. 4) Patient organizations have a powerful voice and should apply it to create significant pressure for fair pricing and appropriate insurance coverage across all sectors of the health system. In particular, patient organizations should follow The culminating vote of the CEPAC panel, intended to reflect its integration of the relevant elements of the value assessment framework, was on the "long-term value for money." The panel voted that ublituximab was a low (9/10) or intermediate (1/10) value for money when compared with dimethyl fumarate.
Following the discussion of the evidence, a policy roundtable was convened to deliberate on how best to apply the evidence on oral and monoclonal antibodies for the treatment of relapsing forms of MS. The policy roundtable members included 2 patient organization representatives, 2 clinical experts, 2 payer representatives, and 1 representative from TG Therapeutics, the manufacturer of that the current evidence is inadequate to distinguish the net health benefit of ublituximab from that provided by other monoclonal antibodies.
The New England CEPAC also voted on "potential other benefits" and "contextual considerations" as part of a process intended to signal to policymakers whether there are important considerations when making judgments about the long-term value for money that are not adequately captured in analyses of clinical and/ or cost-effectiveness. They highlight several factors beyond the results of cost-effectiveness modeling that the CEPAC panel felt were particularly important for judgments of overall long-term value for money. The results for these votes are shown in Table 3.