Unmet Needs for All and Most Vulnerable Secondary Progressive MS Patients
Thomas P. Leist, MD, PhD, shares the unmet needs for patients with SPMS, and for the average patient likely to have MS.
Thomas P. Leist, MD, PhD, shares the unmet needs for patients with SPMS, and for the average patient likely to have MS.
Thomas P. Leist, MD, PhD, says one of the things secondary progressive multiple sclerosis professionals struggle with is making the most effective treatment available to patients, very early on, most likely due to financial reasons.SHOW MORE
Secondary progressive multiple sclerosis (SPMS) is an advanced form of multiple sclerosis (MS) thought to be caused by neurodegeneration within the central nervous system and involves steadily increasing neurologic dysfunction and disability without clear recovery or stability periods. (1,2) It develops from relapsing remitting multiple sclerosis (RRMS), typically 10 to 15 years after a diagnosis of MS. (3) Among patients with RRMS, up to 80% may progress to SPMS within 20 years. Additionally, among those who do not receive disease-modifying therapies for MS, 33% progress to SPMS within eight years. (2)
Treatment of SPMS is associated with many challenges, perhaps most significantly the historical lack of treatment options developed specifically for the condition. The therapeutic armamentarium has evolved significantly since 2019, however, with the approval of 2 oral therapies with indications for the treatment of SPMS. Additionally, many therapies already approved for RRMS have seen their labels broadened to include SPMS. Given these recent and significant shifts, health plans are challenged with selecting appropriate therapies for coverage for SPMS while offsetting the broadly escalating costs of MS treatment. (4)
Diagnosis — Diagnosing SPMS can be difficult because it relies entirely on clinical judgement. (1) There are no clear diagnostic criteria, and patients may not notice a symptomatic change during the early stages of SPMS because of the brain’s ability to compensate for the loss of neurons. For this reason, diagnosis may be delayed up to three years and is often given retrospectively.(2)
Efforts have been made to improve SPMS diagnostics. Screening tools, including the MS Progression Discussion Tool, the MS prediction score and the SPMS nomogram have been developed to leverage data to predict the risk of progression and diagnose early-stage SPMS accurately. Newer imaging technologies, such as unconventional MRIs and optical coherence tomography, may provide higher sensitivity biomarker measurements to aid in detecting disease risk and progression. (2) Emerging biomarkers, measured by either images or tests of cerebral spinal fluid or blood, include neurofilament light chain levels in serum or cerebrospinal fluid (CSF), CSF sCD27, chemokine (C-C motif) ligand 18 plasma levels, the MS risk allele HLA-DRB1*15 and chitinase-3-like protein (1). Larger-scale trials are needed for further data generation before these markers can be used clinically. (1,2)
Once diagnosed, SPMS is further categorized into active and nonactive disease states. First established in 2013, the term “active” is defined as relapses, acute or subacute episodes of new or increasing neurologic dysfunction followed by full or partial recovery, in the absence of fever or infection and/or the occurrence of contrast-enhancing T1 hyperintense or new or unequivocally enlarging T2 hyperintense lesions. A clinical assessment for disease activity is recommended annually. (5)
Disability and comorbidities — With SPMS, patients experience cognitive and physical decline, such as sleep changes, fatigue, incontinence, sexual dysfunction, and spasticity. Spasticity typically increases with disease progression and can eventually become refractory. (6) Disability associated with MS, which is primarily measured by the ability to walk, can substantially affect patient quality of life and socioeconomic status. (6) Disability progression is typically influenced most by the duration of disease; this differs from the disability progression associated with other diseases, which is often most influenced by patient age. (7) Adjusting to disability and other decline can be difficult and stressful for patients. Key determinants for a successful adjustment involve developing healthy coping strategies, participating in patient support networks and maintaining appropriate activity levels.(8)
In addition to dealing with physical and psychological burdens, patients with MS also experience a higher prevalence of comorbid conditions. Results from a recent study demonstrated that approximately 62% of patients with MS had comorbidities; the most common conditions included depression (24%), anxiety (23%), hypertension (13%), migraine (12%), smoking or history of smoking (10%) and obesity (9%). (9) Comorbidities may affect MS severity and outcomes, which implicates the importance of screening and monitoring for comorbidities.
Economic impact — MS has the second-highest all-cause medical costs associated with chronic conditions (after congestive heart failure), with total all-cause per-patient healthcare costs — direct and indirect — of up to $54,244 annually. (10) As the disease progresses and disability increases, costs also escalate. For a patient with severe disability, average annual healthcare costs can reach $100,000 or more. (11) Direct costs associated with MS, comprising, on average, 77% of costs, can be primarily attributed to prescription medications, (10) which are taken by 57.5% of people with MS in the United States. (12) Although high, the cost of medications may be offset by medication efficacy in preventing relapse and disability. (4,13) Use of certain therapies may also relate to improved rates of employment among patients with MS, according to a study conducted in Australia. (14) Unemployment related to MS disability is higher than for any other reason, and loss of productivity contributes to up to 44% of MS costs in the United States and Europe. (15) According to results from a case report form questionnaire, 38.5% of 437 patients with MS were underemployed or unemployed because of MS. The most common reason was fatigue. (16)
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)
The managed care challenges associated with the MS care spectrum have become increasingly complicated with the influx of new therapies, particularly in relation to determining a benefits design for SPMS that balances patient access to the right treatment while accounting for high treatment costs — which are growing more rapidly than those of most other disease states. Prior to 2009, many health plans’ formularies included all MS therapies with adequate accessibility. When several new drugs were introduced to the market after 2009, pharmacy and therapeutics committees (groups responsible for determining which drugs to include in the formularies) became more selective. Agents are now chosen based on clinical trial data regarding safety, efficacy and cost/value. (4) Designated efficacy outcomes, which have evolved over time, must be evaluated against the safety of the agent. Short- and long-term safety are particularly important for consideration; however, long-term safety in newer therapies has not yet been established. Health plans must also make accommodations, as some of these therapies are associated with serious safety concerns that necessitate monitoring with administration. (25)
Regarding the increasing costs of SPMS therapy, in addition to selecting SPMS agents with a favorable cost-effectiveness ratio, health plans may offset the costs by developing formulary tiers that incentivize providers to prescribe the most affordable therapies, using generic medication, establishing arrangements with drug manufacturers to fix costs or offer discounts in exchange for a top placement in the formulary and requiring that therapy initiation or switching is preceded by authorization. (25)
Recent labeling inconsistencies among newer, approved treatments have also contributed to the complexities experienced by health plans when determining appropriate patient access. As discussed earlier, the active and nonactive designations for SPMS were established in 2013. (5) They were first included in FDA-approved indications in 2019 when siponimod, cladribine and other disease-modifying therapies entered the market. All therapies for MS have since adopted this terminology for their labeling and all are now indicated for the treatment of active SPMS. A treatment for nonactive SPMS has not yet been developed. (25) Including the active/nonactive terminology in labels can be useful for treatment selection, but standardized definitions do not exist; regulatory authorities have established differing definitions. Although U.S. regulators defined activity based on clinical relapses, European regulators required inclusion of imaging results, indicating inflammation. In addition, product labels have not been required to include a time frame within which patients experienced disease activity. Because all patients with SPMS have experienced activity at some point, any could receive an active status. This challenge may be alleviated if U.S. labels for approved MS therapies included the full definition of activity. (26)
Substantial personal and economic burdens are associated with MS. (6,10) As the second most common and debilitating form of MS, 2 SPMS necessitates attention and collaboration from health plans, healthcare providers and the health community to establish tailored, standardized management strategies and evidence-based treatment options. (4) Emerging biomarkers and screening tools may improve clinicians’ abilities to promptly and accurately diagnose SPMS, and newer therapies approved for SPMS may offer a more tailored treatment approach for patients with this condition. There are still opportunities, however, for improvement regarding SPMS diagnosis and treatment. (2,18,19) As health plans navigate an increasingly complex and costly treatment landscape, individualized care approaches and shared decision-making should be prioritized.