Research News
Written by Susan Wells Courtney
Reviewed by Jack Burks, MD
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Changes Made to Tecfidera’s Label
Lemtrada™ Receives FDA Approval for Relapsing Forms of MS
Phase II Primary-Progressive MS Study Does Not Meet Primary Endpoint
Changes Made to Tecfidera’s Label
In December 2014, the United States Food and Drug Administration (FDA) made some changes to the product labeling for Tecfidera® (dimethyl fumarate). These changes instruct physicians on how to best prescribe the drug for their patients to minimize the potential for certain side effects and adverse events.
To follow is a general overview of the changes to Tecfidera’s labeling:
- Temporary dose reductions (to half the dose) may be used for individuals unable to tolerate the drug, for up to four weeks before returning to the full dose
- Discontinuation should be considered for patients unable to return to the maintenance dose after four weeks of a reduced dose
- Non-enteric, coated aspirin (up to a dose of 325 mg), 30 minutes prior to Tecfidera dosing, may be given to help reduce the potential side effect of flushing
- This medication is contraindicated in patients with known hypersensitivity to dimethyl fumarate or to any of Tecfidera’s ingredients
- New warning that anaphylaxis and
angioedema (allergic reactions) may occur after the first dose or at any time during treatment; symptoms have included difficulty breathing, urticaria [hives], and swelling of the throat and tongue; Tecfidera should be discontinued and immediate medical care sought if experiencing these symptoms - A fatal case of Progressive Multifocal
Leukoencephalopathy (PML) occurred in one patient with MS who received Tecfidera for four years while enrolled in a clinical trial; the patient experienced prolonged lymphopenia (reduction in circulating lymphocytes) while taking Tecfidera - New warning that Tecfidera may decrease
lymphocyte counts; a CBC (complete blood count), including lymphocyte count, should be obtained before initiating treatment, after six months of treatment, every six to 12 months thereafter, and as clinically indicated
Please note that these are only highlights of the labeling changes for Tecfidera. For full drug and prescribing information, please visit Tecfidera’s website at www.tecfidera.com.
Lemtrada™ Receives FDA Approval for Relapsing Forms of MS
On November 14, 2014, the United States Food and Drug Administration (FDA) announced that Lemtrada™ (alemtuzumab) had been approved for the long-term treatment of relapsing forms of multiple sclerosis (MS). Lemtrada is a humanized monoclonal antibody that targets a protein present on the surface of mature lymphocytes, and results in a rapid depletion/suppression of T and B cells. By doing so, researchers believe that the immune system may be reset, and the new immune-system cells may behave differently than those that previously attacked the nerves.
Given via intravenous (IV) infusion for a course of five days and followed one year later by a second three-day course, Lemtrada has been approved as a second-line therapy. This classification refers to a drug that may only be prescribed when other FDA-approved treatments fail or are not tolerated well by a patient. Because of the medication’s safety profile, Lemtrada should generally be prescribed for patients who have had an inadequate response to two or more of the disease-modifying therapies.
In clinical trials, Lemtrada was shown to significantly reduce the relapse rate for individuals with relapsing-remitting MS, as well as significantly reduce the risk of sustained disability accumulation. In a multi-year extension study of the 334 individuals who participated in the original Phase II study (comparing Lemtrada to an approved long-term treatment for MS), Lemtrada reduced the risk for sustained accumulation of disability by 73 percent, while 77 percent of Lemtrada-treated patients were relapse-free. A five-year assessment showed that 87 percent were free of sustained disability accumulation, 72 percent were relapse-free, and 65 percent were free of clinical-disease activity.
Adverse events from Lemtrada can include infusion reactions to the medication, an increased risk of infection, and emergent autoimmune diseases. In the two Phase III studies – CARE-MS I and II respectively – approximately 18 percent and 16 percent of Lemtrada patients developed an autoimmune thyroid disorder, and 0.8 percent and 1 percent developed a potentially severe bleeding disorder called immune thrombocytopenic purpura (ITP). In ITP, the blood does not clot as it should, and this can result in internal bleeding.
Because of its potential adverse events, Lemtrada is only available through the Lemtrada REMS (Risk Evaluation and Mitigation Strategy) program. This program has been developed to ensure that access to Lemtrada in the U.S. is only through certified prescribers, healthcare facilities and specialty pharmacies and to also ensure that patients are enrolled in the REMS program. The program helps to educate healthcare providers and patients on the serious risks associated with Lemtrada and the appropriate periodic monitoring required.
For more information, readers may call the MS One to One® line at (855) MSOne2One [(855) 676-6326]. Information and support are also available at www.MSOnetoOne.com.
Phase II Primary-Progressive MS Study Does Not Meet Primary Endpoint
On December 1, 2014, Novartis announced that their Phase III INFORMS trial with Gilenya® (fingolimod) for individuals with primary-progressive multiple sclerosis (PPMS) did not meet its primary endpoint. Presently, this disease-modifying therapy, taken orally (by mouth), is approved for the long-term treatment of relapsing forms of MS.
According to a press release from Novartis, the INFORMS study is the largest clinical trial ever conducted in PPMS, enrolling 970 people aged 25-69 years with PPMS. The double-blind, randomized, and placebo-controlled study was conducted at 148 sites across 18 countries.
Patients were treated for at least three years and the primary endpoint was to evaluate the effect of Gilenya versus placebo on reducing the risk of three-month sustained disability progression. Unfortunately, the initial results of the study did not show a significant difference between the group taking Gilenya and the placebo group. However, additional analysis of the data will reveal if any sub-groups of individuals with PPMS experienced positive effects from this medication over the three years.
Stem-Cell Research Update
Even though it is still in early stages of study, the topic of stem-cell research in MS has been growing in popularity within the MS community. According to MSAA’s 2015 edition of the MS Research Update, stem-cell approaches are based on three different classes. To follow is an overview of these approaches, along with a few recent study results:
Hematopoietic Stem-Cell Transplantation (HSCT)
This form of stem-cell therapy first requires a wiping out or “ablation” of the immune system, typically with high-dose chemotherapy. This destroys most blood cells as well as the bone marrow, where blood cells are formed. Then a patient’s own hematopoietic stem cells can be transplanted, in an effort to completely reset the immune system in the hopes of abolishing the autoimmunity responsible for MS.
One trial of this technique is the High-Dose Immunosuppression and Autologous (stem cell) Transplantation for Multiple Sclerosis (HALT MS) Study, for poor prognosis multiple sclerosis. The two-year follow-up results of this Phase II study with 25 patients reported that the treatment induced profound immune suppression and a high rate of sustained remissions at two years.
Further interim results covering three years of the study reported that 78 percent of subjects had no new disease activity; however, treatment failed in five subjects and two deaths occurred. There have been 130 adverse events that were severe or life-threatening, most relating to low blood counts induced by the treatment approach.
A Swedish study of 41 patients with aggressive, relapsing forms of MS, found that a high proportion were free from disease activity following hematopoietic stem-cell transplantation (HSCT). With a mean average follow-up time of nearly four years after receiving the HSCT procedure, 89 percent of the participants were relapse-free and 77 percent of the participants had no disability progression. Serious side effects included sepsis, fever, and other adverse events. These included a reactivation of herpes zoster in seven patients and thyroid disease in four patients; no deaths occurred in this trial.
Therapy Utilizing Mesenchymal Stem Cells
These stem cells can be derived from tissues other than bone marrow and do not require a “wiping out” of the immune system. In a Phase IIa study, 10 patients with SPMS with involvement of the visual system were infused with self-derived (autologous) mesenchymal stem cells. Researchers found an improvement in visual and other measures of optic-nerve function. There were no serious adverse events or deaths. The results of this study were suggestive of a more generalized neuroprotective effect.
Therapy Utilizing Stem Cells to Directly Regenerate Myelin
This third approach is perhaps the one most in-line with the notions about the potential uses of stem cells. This approach requires multiple complex steps in order to be successful. Techniques must be employed to: harvest a patient’s stem cells; grow and multiply them; administer them to the patient; ensure that they get into the central nervous system; ensure that they are not destroyed by the body’s own immune system; ensure that they grow to become the correct type of cell (for instance, to restore myelin); and to ensure that they do not overgrow or cause damage to the nervous system.
This approach to stem-cell therapy is being investigated in an open-label Phase I clinical trial announced in fall 2013. The design of this single-center trial includes enrolling 20 patients with progressive MS, and infusing doses of stem cells harvested from the patients’ own bone marrow directly into the cerebral spinal fluid (CSF). This is typically done via lumbar puncture, repeatedly over six months.
For more information about stem-cell research in MS, as well as references to these studies mentioned above, please see MSAA’s 2015 MS Research Update. Please also watch for updates on MSAA’s website at mymsaa.org. For current stem-cell studies, including those that are still recruiting, please visit clinicaltrials.gov and search for stem cells and MS.
Phase III Study Data Added to Aubagio’s Labeling
In November 2014, the United States Food and Drug Administration (FDA) approved adding the data from two Phase III studies to Aubagio®’s (teriflunomide) product label. These studies are the TOWER and TOPIC studies, which provide additional study results for Aubagio’s efficacy and safety.
The addition of this study data informs medical professionals that this medication has been shown to (1) reduce the relative risk of sustained disability progression (along with reducing the annual relapse rate), as found in the Tower study, and (2) prevent or delay a second clinical attack (relapse), as seen in the TOPIC study, in individuals who were not yet diagnosed but experienced their first neurological symptoms suggestive of MS. Individuals in this latter group, who have not yet been diagnosed with MS but have experienced symptoms, are referred to as having clinically isolated syndrome (CIS).