Two new disease-modifying therapies — siponimod (Mayzent, Novartis) and cladribine (Mavenclad, EMD Serono) — were approved by the U.S. Food and Drug Administration (FDA) for use in active secondary progressive multiple sclerosis (SPMS) in the last week of March/early April. The vast majority of treatments for multiple sclerosis are approved for relapsing, rather than progressive, forms of the disease.
“Multiple sclerosis can have a profound impact on a person’s life,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, in the press release from the FDA announcing the approval of siponimod. “We are committed to continuing to work with companies that are developing additional treatment options for patients with multiple sclerosis.”
In the FDA’s announcement of the approval of the use of cladribine in these cases, Dr. Dunn said that the government agency is “committed to supporting the development of safe and effective treatments for patients with multiple sclerosis.”
“The approval of Mavenclad represents an additional option for patients who have tried another treatment without success.”
These approvals should enhance treatment options for SPMS patients, says Timothy West, M.D., associate professor of neurology at the University of California San Francisco School of Medicine, San Francisco.
“The big advancement here, and the cause for enthusiasm and hope, is that now we have medication that has demonstrated beneficial effects within this underserved population,” Dr. West says. “As such, I suspect there will be an increased interest in identifying active secondary progressive MS and treating it.”
What is Secondary Progressive Multiple Sclerosis?
MS manifests in various forms, which can be divided into three broad categories: relapsing MS, progressive MS, and clinically isolated syndrome.
Relapsing forms of the disease include relapsing-remitting MS and active secondary progressive MS with relapses. Progressive forms of the disease include primary progressive MS and secondary progressive MS without relapses. Clinically isolated syndrome is, in effect, the first clinical attack of a demyelinating disease that resembles and could potentially develop into MS.
A portion of people whose disease starts out with the relapsing-remitting form may go on to develop secondary progressive MS, which is characterized by steadily increased disease progression with fewer significant relapses. Disease-modifying therapies prescribed for relapsing MS are partially intended to delay or prevent the transition to secondary progressive MS.
The majority of disease-modifying therapies approved for MS are aimed at relapsing forms of the disease. However, the approved use of some therapies has been expanded to include secondary progressive MS with relapses and clinically isolated syndrome. Few therapies are aimed specifically for progressive forms of MS, with ocrelizumab (Ocrevus, Genentech) being the first approved for primary progressive MS in 2017.
How is Secondary Progressive Multiple Sclerosis Diagnosed?
The diagnosis of secondary progressive MS is retrospective. People who begin with relapsing-remitting MS experience an up-and-down cycle of clinical relapses with partial or complete recovery. Some residual neurological damage can remain with incomplete remissions.
When a patient has begun to experience more disease progression and fewer relapses over a period of years — basically their disease has become more neurodegenerative rather than inflammatory — the suspicion of SPMS may arise.
I am aware of some people living with MS who may have transitioned to SPMS, but who (on paper) remained diagnosed with RRMS, primarily to maintain access to treatment. And I’ve known people with SPMS who have become discouraged by lack of treatment options.
I asked Dr. West if, as patients with SPMS have historically had limited treatment options (which may have been partly due to insurance company formularies and strictness with diagnoses and FDA labeling), if he thought that the approval of disease-modifying therapies (DMTs) specific to active SPMS will encourage neurologists to be more accurate in documenting the transition from RRMS to SPMS in patients who remain good candidates for DMT treatment.
“It is true that insurance has and will be a limiting factor in the usage of medication to treat MS. However, it’s important to realize that a large part of the reason why medicines were not used in secondary progressive MS is that there was a lack of data for demonstrated efficacy. Why use a medication if it doesn’t help?”
But these approvals should bring positive possibilities to SPMS patients.
“While doctors will continue to work hard to diagnose and treat patients correctly, my hope is that the largest change we will see with the FDA approval of this medication for active secondary progressive MS is that patients who had previously given up hope on treating this later stage of disease may return to clinic with renewed enthusiasm that we may be able to intervene on their behalf,” Dr. West says.
What Else Should You Know About New Treatments?
It’s always an exciting time when new therapies are approved for MS. As of April 2019, siponimod and cladribine mark the sixteenth and seventeenth new treatment options that have been approved by the FDA for multiple sclerosis since 1993. I remember when there were only four options the year I was diagnosed.
Siponimod is the first oral treatment specifically approved for patients with active secondary progressive MS. It’s also approved for use in relapsing-remitting MS and clinically isolated syndrome. The drug is what’s called a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator.
The approval of siponimod was based on data from the Phase III EXPAND trial (n=1,651), a randomized, double-blind, placebo-controlled study, comparing the efficacy and safety of siponimod versus placebo in people living with SPMS. This trial showed patients using siponimod experienced a 21 percent relative risk reduction of disease progression, including impact on physical disability and cognitive decline, compared to those who received a placebo.
Siponimod is an oral medication produced by Novartis that is taken once daily. Its safety profile was similar to that of other S1P modulators, such as fingolimod (Gilenya, Novartis).
The other drug approved, cladribine oral tablets, treats relapsing forms of MS and active SPMS. Cladribine is not recommended for people diagnosed with clinically isolated syndrome. Because of its safety profile, cladribine will be recommended for patients who’ve had an inadequate response to, or are unable to tolerate, an alternative drug indicated for the treatment of MS, according to the FDA. Due to increased risks, cladribine should not be used in people with prior malignancy or increased risk of malignancy, or in patients who are pregnant or plan to become pregnant within six months.
Cladribine is a purine antimetabolite — a type of therapy that interferes with DNA synthesis in certain types of cells. The approval of cladribine was based on data from the Phase III CLARITY trial in 326 patients with relapsing forms of MS who had at least one relapse in the previously 12 months before joining the trial. Cladribine reduced the annual relapse rate by 58% compared to placebo when given as an oral treatment (3.5 mg/kg) for a maximum of 20 days during a two-year period. Cladribine also reduced the progression of disability compared to treatment with placebo.
Cladribine is given in two courses: five consecutive days of daily medication followed by the same one month later, with this procedure repeated one year later. Cladribine is produced by EMD Serono, whose MS treatment line currently includes Rebif (interferon beta-1a) and previously included Novantrone. Prior to approval by the FDA, cladribine had already been approved for use in 50 countries worldwide.
As with any decision regarding treatment options, please talk to your neurologist to assess the risk/benefit profile for your specific situation living with MS.