Growing number of MS drugs brings challenges
By Kerry Dooley Young
Major federally funded studies are underway to help neurologists better assess a growing array of multiple sclerosis treatments, including competing tablets.
But in the near term, physicians and people with MS will continue to have to make certain educated guesses when choosing medications.
“Over the last decade, there has been a ramp-up of a lot of new therapies,” said Scott D. Newsome, DO, of John Hopkins University, Baltimore. “It’s been a game changer for people living with MS. Now they don’t have to necessarily go to a self-administered injectable therapy.”
The Food and Drug Administration this year alone approved three MS tablets; diroximel fumarate (Vumerity), siponimod (Mayzent), and cladribine (Mavenclad). And it is reviewing a fourth, ozanimod from Bristol-Myers Squibb’s Celgene unit. The FDA may make its decision whether to approve ozanimod by March 2020.
Another newer MS treatment, ocrelizumab (Ocrevus) has had a fairly rapid uptake. The first drug to get FDA approval for primary progressive multiple sclerosis (PPMS), ocrelizumab also is used for the relapsing forms of the disease. More than 130,000 people have been treated with infusion(s) of ocrelizumab in clinical trials and real-world settings, according to Roche.
Dr. Scott D. Newsome
“As neurologists we’re faced with having to pick between 18 medications,” said Daniel Ontaneda, MD, of the Cleveland Clinic’s Mellen Center for Multiple Sclerosis. “The people whom we think are going to do poorly, we start on stronger medications. But to be honest, it’s an imperfect science. Many times we’re picking somewhat haphazardly what medications people will be starting.”
Both Dr. Newsome and Dr. Ontaneda are part of efforts to provide more scientific grounding for these choices. They are principal investigators for two of the studies of MS treatments being funded by the Patient-Centered Outcomes Research Institute (PCORI). Created through the Affordable Care Act of 2010, PCORI is intended to spark a movement toward studies that provide a better understanding of a broad landscape of treatments work for a disease.
There is very little evidence at this time that shows which MS treatment might be best for an individual patient, said Hollie Schmidt, vice president of scientific operations at the nonprofit Accelerated Cure Project for Multiple Sclerosis. In a March video done for PCORI, Schmidt discussed how the program has worked in drawing more MS patients into research programs.
Dr. Daniel Ontaneda
PCORI is unique in the types and numbers of comparative effectiveness research it funds, and in its patient-centered approach to research.
“PCORI is unique in the types and numbers of comparative effectiveness research it funds, and in its patient-centered approach to research,” Ms. Schmidt said in a subsequent email exchange.
Drugmakers tend to fund more narrowly focused studies, looking at how their medicines work against placebo or a single competitor, while PCORI-funded studies are examining entirely different approaches to treatment.
Biogen, for example, funded a study that compared the annualized relapse rate and risk of relapse in MS patients who taking its dimethyl fumarate (Tecfidera) versus two other tablets: fingolimod (Gilenya) and teriflunomide (Aubagio). This research found dimethyl fumarate to have similar effectiveness to fingolimod and a lower risk of relapse, compared with teriflunomide, according to a January 2019 paper in the journal Multiple Sclerosis and Related Disorders. Dr. Ontaneda is the lead author of this paper.
With PCORI funding, Dr. Ontaneda is leading the DELIVER-MS trial that will study how well patients fare if given “early highly effective” therapy or an “escalation” approach is used, using measurements of loss of brain volume. The target date for the study’s completion is September 2023, according to ClinicalTrials.gov.
The trial, which started in January 2019, aims to recruit 800 patients. In one group, patients will take medicines judged to be “early highly-effective” treatments: natalizumab (Tysabri), alemtuzumab (Lemtrada), ocrelizumab (Ocrevus), or rituximab (Rituxan).
In the “escalation” arm, patients will receive other approved MS medicines as their initial disease-modifying treatment. The choices for this group include teriflunomide, fingolimod, dimethyl fumarate, beta-interferons, and glatiramer acetate (Copaxone). The study also includes an observational group for people who are not comfortable with randomization or not eligible to receive any of the options in a randomized arm, according to the ClinicalTrials.gov site.
PCORI has made MS one of its major points of focus. In 2017, it announced five substantial awards, including $10.6 million project for the DELIVER-MS trial.
The largest award in that tranche was $13.5 million for the TREAT-MS study that also compares strategies. Led by Dr. Newsome and Ellen M. Mowry, MD, also with Johns Hopkins, the TREAT-MS study is intended to recruit 900 patients. The target date for the study’s completion is October 2022.
The TREAT-MS study intends to evaluate whether an “early aggressive” approach may do more to help patients avoid disability than a more moderate one. Akin to the DELIVER-MS trial, patients in the “early aggressive” therapy group of TREAT-MS can take natalizumab, alemtuzumab, ocrelizumab, or rituximab.
In the traditional therapy arm, patients can take glatiramer acetate, interferons, teriflunomide, dimethyl fumarate, or fingolimod. This study is intended to track how well medications stave off the progression of disability in people with MS.
“Having more treatment options for people with MS is a great thing,” Dr. Newsome said.
But clinicians treating people with MS do not have access to biomarkers that may help determine a patient’s treatment response like those used for some cancers, Dr. Newsome said. There are biomarkers in oncology that help steer treatment choices and gauge people’s responses to them.
Without having these kinds of biomarkers for MS, “it really is like a flip of the coin with choosing an initial therapy and when a switch in therapy is needed,” Dr. Newsome said.
PCORI also is funding a major study focused on rituximab. In 2016, PCORI awarded $8.4 million for the COMBAT-MS study, which has an estimated completion date of December 2022. This observational trial is intended to enroll 3,700 patients, which the ClinicalTrials.gov site describes as the “largest real-world population-based structured prospective follow-up cohort of relapsing-remitting multiple sclerosis (RRMS) patients.”
COMBAT-MS looks at rituximab in comparison to commonly used approved medicines: natalizumab, fingolimod, alemtuzumab, interferon-beta, glatiramer acetate, and dimethyl fumarate. The COMBAT-MS study is being led by researchers at Sweden’s Karolinska Institute and Annette Langer-Gould, MD, PhD, of Southern California Kaiser Permanente Medical Group, Los Angeles.
Credit: U.S. Army
Research released in 2016 found rituximab demonstrated superior drug survival (i.e., the proportion of patients remaining on a drug over time), compared with fingolimod and natalizumab. The likelihood of relapse-free survival also appeared greater with rituximab than with fingolimod or natalizumab.
In a study published in JAMA Neurology in January 2018, rituximab was associated with a lower drug discontinuation rate versus all other commonly prescribed medicines used as initial therapy for RRMS in a retrospective study of patient data from a Swedish multiple sclerosis registry.
Researchers have shown greater interest in studying rituximab for MS than has the company that developed it. Some years back, Roche’s Genentech chose not to further pursue investigations of rituximab in MS and instead proceeded with a focus on ocrelizumab.
Rituximab failed to demonstrate significant clinical benefits for MS in previous testing, noted Justin Hurdle, a Genentech spokesman, in an email exchange.
The off-label use of rituximab is part of a recent shift in MS treatment. Scientists have long focused on T cells as the primary culprit in the malfunction in the immune system that leads to attacks on myelin. Phase 2 research work on rituximab did provide proof of concept for the central role of CD20-positive B-cell targeted medicines in MS, Mr. Hurdle said. Genentech has looked at a number of potential candidates to serve as B cell-targeted investigational medicines.
“Ocrevus was selected because it had the most favorable efficacy and safety profile with the potential to provide the greatest benefit for MS patients,” Mr. Hurdle said.
Genentech has been losing sales of rituximab to an approved copycat versions known as a biosimilar. The FDA in 2018 approved Teva’s version of rituximab.
Dr. Annette Langer-Gould
The FDA also in 2019 approved new MS medicines for two companies that are fighting U.S. generic competition for their established treatments for the disease.
Biogen is seeking to thwart generic competition for dimethyl fumarate, one of its top-selling products with quarterly sales topping $1 billion. At the same time, Biogen and its partner Alkermes are seeking to position the newer, similar drug diroximel fumarate at an advantage to the older drug. In announcing the FDA approval of diroximel fumarate in October, the two companies said the new drug “offers the well-characterized efficacy” of dimethyl fumarate “and has been studied for improved patient-reported gastrointestinal tolerability.”
The FDA approved diroximel fumarate for the treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. The approval rested in part on pharmacokinetic bridging studies comparing diroximel fumarate and dimethyl fumarate, the two companies said.
In March, the FDA said it approved siponimod, citing a study in which the drug compared well to placebo. Siponimod is similar to Novartis’ older drug fingolimod, with both medicines acting as sphingosine-1-phosphate receptor modulators. Novartis this year won a legal victory delaying generic competition for its older drug. Although the FDA approved three generics for fingolimod on Dec. 5, the ruling stops them from going to market for now.
Credit: Liderina/Getty Images
An influential group has suggested insurers stick with the older Novartis drug in anticipation of savings from generics. The Institute for Clinical and Economic Review (ICER) reviewed the data for both medicines and argued against paying more for siponimod. Instead, insurers can consider granting preferential formulary status to fingolimod when its generic versions reach the U.S. market, ICER said.
“Given its similarities to fingolimod, siponimod should be considered amongst a group of highly effective disease modifying therapies (DMTs) for relapsing forms of MS, including fingolimod, alemtuzumab, natalizumab, and ocrelizumab,” ICER wrote in May.
In many cases, physicians and their patients confront challenges in getting insurers to cover preferred medicines. In an email exchange, Dr. Langer-Gould wrote of a Kaiser policy that recommends starting “a highly effective DMT (our preferred agents are natalizumab and rituximab, initially, but not anymore, fingolimod) in patients with relapsing-MS at high risk of disability.”
“For these patients we do not require a fail-first policy,” Dr. Langer-Gould wrote.
Often, though, patients may face hurdles with other insurers in getting access to treatments they and their physicians want them to have. Formulary preferences may reflect secret price negotiations between pharmacy-benefit managers and companies, Dr. Langer-Gould said. This can prevent patients with highly active MS from getting highly effective therapies soon enough, she said.
Dr. Newsome also said his patients may not agree with the preferred treatment of choice of the insurance companies.
“Insurance companies will often deny what my patient and me collectively decide to start because it isn’t on their formulary, or the therapy is not first line based on whatever metrics the insurance company is using,” Dr. Newsome said. “If we are not comfortable with the insurance company’s decision, then I go to bat for what I feel my patient needs and deserves.”
Dr. Newsome also stressed the need to listen to patients’ concerns and preferences in selecting among MS treatments.
“What I usually say to patients is that the best medication is the one that they feel comfortable taking,” he said. “Being on an MS disease-modifying therapy – regardless of what it is – is better than not being on a medication. We have plenty of data to support this.”