In a study of how people newly diagnosed with multiple sclerosis fared on the first therapy they tried, a drug that isn’t even approved for the disease came out on top. Rituximab, sold by Roche as Rituxan to treat non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis, outperformed newer MS drugs from Biogen and Novartis.
The study used medical records, and falls short of the certainty given through randomized controlled clinical trials, the gold standard of medical evidence. But it is likely to raise new questions about why Roche did not develop Rituxan for MS, choosing instead to focus on a newer drug, Ocrevus. It also means it’s possible that newer drugs, like Biogen’s Tecfidera and Novartis’ Gilenya, could face competition from off-label Rituxan, depending on whether insurers decide to cover it.
“Our early studies in MS Phase II rituximab trials provided proof of concept for the central role of CD20-positive B-cell targeted medicines in MS,” Roche said in a statement. “At that time, we had a number of anti-CD20 targeted molecules in our portfolio with a range of different features. We advanced Ocrevus, a humanised anti-CD20 antibody, into late stage development because we believed it had the best potential efficacy and safety profile for patients with MS, a disease where long-term treatment is warranted.”
Drugs to treat MS have proliferated as more effective treatments have been approved, with some half dozen options now available. But it’s still difficult for patients and doctors to choose the right first treatment in the crucial early days after diagnosis, when the autoimmune disease that attacks the nervous system hasn’t yet caused irreparable damage.
Researchers in Sweden looked back on the records of nearly 500 MS patients receiving treatment in two different counties to see whether patients kept taking the first drug they tried, and if their disease progressed while they were on it. “Collectively, if you look at efficacy, safety, and tolerability, patients did best when they started on rituximab,” says lead study author and neurologist Fredrik Piehl of the Karolinska Institutet in Stockholm, Sweden. The results were published in JAMA Neurology Monday.
Patients that started on rituximab stopped taking the drug at a rate of 0.03 per year. Those on first-generation therapies including the interferon-betas (Biogen’s Avonex and EMD Serono’s Rebif) and glatiramer acetate (Teva’s Copaxone) stopped at a rate of 0.53 per year; dimethyl fumarate (Biogen’s Tecfidera) 0.32 per year, fingolimod (Novartis’ Gilenya) 0.38 per year, and natalizumab (Biogen’s Tysabri) 0.29 per year. Patients on rituximab also had fewer relapses and new brain lesions seen on MRI, though the difference didn’t reach statistical significance for fingolimod and natalizumab.
In a statement, Teva pointed out “there are many caveats when attempting to draw conclusions across multiple data sources without replication through well-controlled head-to-head trials for confirmation.”
“The comparison of drugs which are commonly administered to patients who are early in the disease-course and whose disease was relatively inactive at that time to drugs which are used to treat patients with very active disease and approved as 2nd line are subject to bias,” Novartis said in a statement. “Adding to this, a drug which has not been approved by regulatory authorities for the treatment of MS in a dose which has not been clearly defined is doubtful regarding any derived conclusions.” The sample size of patients taking Gilenya in the study was too small to provide “any meaningful statistical significance,” Novartis said, and show approximately 90% adherence to the therapy.
“Head-to-head, blinded, controlled, randomized studies are the best way to evaluate the safety and effectiveness of therapies,” Biogen said in a statement. “In the absence of such studies, comparative-effectiveness analyses are a valid approach, provided they are adjusted to account for the baseline characteristics of the populations under study.”
“The standard measures of effectiveness of MS treatments include annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS), and safety,” Biogen continued. “Discontinuation rates are relevant, but it is important to fully understand and evaluate the reasons for discontinuation.” Biogen jointly markets Rituxan in the U.S. with Genentech, which is owned by Roche.
“The results from this small real world evidence study do show the significant potential of anti-CD20 therapies for the treatment of MS patients,” Roche said in its statement, “both in terms of clinical efficacy and drug discontinuation rate, which indicates the patient preference of anti-CD20 treatments versus the other [disease modifying therapies] currently marketed.”
Rituximab decreases the body’s amount of B-cells, a type of immune cell implicated in MS, by targeting the CD-20 protein on the outside of these cells. Genentech received FDA approval for ocrelizumab, another drug in the same class, last March. Roche’s patent on rituximab expires in the U.S. this year, and Sandoz has a biosimilar version under review at the FDA, it announced last September.
“We can’t cure brain injuries, so I think there’s a strong case growing stronger by the year to start with highly effective treatments early,” Piehl says. In most cases, anti-CD20 therapies such as rituximab and ocrelizumab are “the most logical choice.”