Plegridy™ Approved for Relapsing Forms of MS
On August 15, 2014, Biogen Idec announced that the United States Food and Drug Administration (FDA) had approved Plegridy™ (peginterferon beta-1a) for the long-term treatment of relapsing forms of multiple sclerosis (MS). Manufactured by Biogen Idec, this new medication is the 11th disease-modifying therapy (DMT) to be approved for MS since the early 1990s. Plegridy is given once every two weeks through a subcutaneous self-injection.
Medication Description and Dosing
Plegridy is a pegylated version of interferon beta-1a. Pegylation is a chemical modification of a molecule (in this case the interferon beta-1a molecule) that extends its half-life, which refers to how long a drug stays active in the body before it is metabolized or eliminated. Given the longer half-life, Plegridy does not need to be taken as often as the presently approved self-injected DMTs for MS, which range from once daily to once weekly. This is the first pegylated drug to be approved for the treatment of MS.
Interferons appear to reduce inflammation by modulating a favorable balance between cells that increase inflammation and cells that decrease inflammation. They also reduce the transport of damaging lymphocytes into the brain. Lymphocytes are immune-system cells produced to fight infection and disease.
This new medication has been studied in two groups – with injections given either every two weeks or every four weeks; the two-week dosing was submitted and selected for approval. Additionally, the 125-mcg dose is administered subcutaneously, which is easier and more comfortable than intra-muscular injections, using either the Plegridy Pen (a ready-to-use autoinjector) or a prefilled syringe.
Study Results and Side Effects
Plegridy was submitted to the FDA based on the results from the first year of the two-year ADVANCE study. This Phase III clinical trial is an international multi-center study, which is placebo-controlled and double-blinded (so neither the patients nor the treating professionals know who is getting the active treatment). During the first year of this two-year study, the 1,512 participants with relapsing-remitting MS (RRMS) were randomized to receive either the active drug or the placebo, given either once every two weeks or once every four weeks. After the first year of the study, those given a placebo were switched to the active drug.
According to MSAA’s 2014 edition of its MS Research Update (written by Stephen Krieger, MD and reviewed by MSAA Chief Medical Officer Jack Burks, MD), “Plegridy dosed every two weeks significantly reduced MS disease activity versus placebo. Relapses [the annual relapse rates] were reduced by 36 percent, and new brain lesions by 67 percent, compared to placebo at one year. Disability outcomes were also positive in this one-year trial. In total, the proportion of disease activity-free patients over one year was significantly higher in the two treatment groups compared to placebo.”
According to Biogen Idec’s press release issued on August 15th, Plegridy reduced the risk of 12-week confirmed disability progression, as measured by the Expanded Disability Status Scale (EDSS), by 38 percent compared to placebo. In addition to reducing the new or newly enlarging T2-hyperintense lesions by 67 percent (as noted in the prior paragraph), Plegridy also reduced the number of new gadolinium-enhancing lesions by 86 percent compared to placebo.
According to Biogen Idec’s press release, in addition to injection-site reaction and flu-like illness, more specific common adverse reactions included fever, headache, muscle pain, chills, injection-site pain, weakness, injection-site itching, and joint pain. The
pharmaceutical company also notes that the two-year safety data from the ADVANCE study were consistent with safety results
observed in year one.
For more information, please see MSAA’s full online article at http://mymsaa.org/news/plegridy-approved/ (or by going to MSAA’s website at mymsaa.org and selecting this article under “News from MSAA”). Readers without internet access may call MSAA at (800) 532-7667 to request a copy of the online article.
Written by Susan Wells Courtney
Reviewed by Jack Burks, MD, MSAA Chief Medical Officer
Highlights from the 2014 Joint ACTRIMS-ECTRIMS Meeting
Every three years, two international organizations come together to discuss the most recent research findings in the area of MS. The sixth joint conference of ACTRIMS (Americas Committee for Treatment and Research in Multiple Sclerosis) and ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) took place in Boston in September. This summary focuses on topics of particular interest to the MS community. Only a fraction of the more than 1,700 scientific papers and almost 200 presentations will be addressed in this article.
Lemtrada® (alemtuzumab, formerly Campath), is given intravenously each day for five days, and again one year later, daily for three days. Lemtrada has been submitted to the United States Food and Drug Administration (FDA) for approval; a decision is expected in late 2014. The majority of patients treated with Lemtrada (alemtuzumab) in the CARE-MS I study (a Phase III comparison of alemtuzumab and Rebif in treatment-naïve patients) were free of new brain lesions and MRI activity at year three. Although the majority of the patients did not receive treatment after the first two yearly courses of Lemtrada, most continued to experience a slowed yearly rate of brain volume loss over three years.
Laquinimod is an oral medication taken once daily under investigation for the treatment of RRMS. In the Phase III BRAVO trial, treatment with laquinimod resulted in a significant reduction in brain atrophy (a reduction in both grey matter and white matter in the brain) compared to placebo. Using pooled data from the ALLEGRO and BRAVO trials, researchers determined that laquinimod demonstrated significant benefits in relapse rate, disability, walking, and MRI outcomes in patients with RRMS with EDSS (Expanded Disability Status Score) scores more than 3, which is a level where the individual is able to walk but experiences difficulties in other areas.
Daclizumab (also known as Zenapax®) is given by intravenous infusion every four weeks and is also studied when given in subcutaneous injections. This medication is under investigation for the treatment of both RRMS and secondary-progressive MS (SPMS). Primary results were reported for the DECIDE study in which 1,841 RRMS patients were randomized to treatment with either Avonex (interferon beta-1a) 30 mcg every week or daclizumab HYP (high-yield process) 150 mg every four weeks, both delivered by subcutaneous injection (under the skin). Treatment with daclizumab resulted in a 45-percent reduction in annualized relapse rate (ARR), a 54-percent reduction in new and newly enlarging T2 lesions, and a 65-percent reduction in new gadolinium-enhancing lesions. Risks associated with daclizumab treatment were infections, rash dermatitis, and liver enzyme abnormalities.
Generic Disease-Modifying Therapies
A nine-month randomized, double-blind trial of 794 people with RRMS, called “GATE,” demonstrated that generic glatiramer acetate was equivalent to Copaxone® and superior to placebo in both safety and efficacy. The concept of generic versions of MS disease-modifying therapies is relatively new to the MS community, as the original drugs were protected by law to have a certain period of exclusivity. As these time periods expire, other pharmaceutical companies may look to provide similar drugs. MSAA published an online article on this topic, titled “The Issues Surrounding Generic Versions of MS Drugs.” This may be viewed by going to MSAA’s website at mymsaa.org and selecting this article below “News from MSAA.”
OCT: Optical coherence tomography (OCT), a non-invasive imaging test that uses light waves to take cross-section pictures of the retina, might help determine brain atrophy without the need for a brain MRI. Researchers found that certain changes in the retina accurately reflected grey matter atrophy in the whole brain, especially in those with progressive MS.
Parasitic Infections and MS: Parasite infection was found to be protective against MS disease activity in a group of 12 parasite-infected MS patients. Compared to those not infected, parasite-infected MS patients experienced a significantly lower number of relapses, a lower change in EDSS scores, and fewer brain lesions on MRI. Conversely, when treated with anti-parasitic drugs, the parasite-infected group experienced worsening of their disease.
Gut Microbial Environment: Studies have related gut dysbiosis (an imbalance in the micro-organisms in the gut resulting from too few good bacteria and/or too many harmful bacteria) with development or severity of many conditions including Crohn’s disease, type I diabetes, obesity, and autism. The Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Hospital in New York City and University of California San Francisco MS Center are collaborating to study whether gut dysbiosis may have an impact on MS.
Iron Deposits: Neurodegeneration (injury to nerves) is associated with the accumulation of iron in the oligodendrocytes (cells that produce and repair myelin), and appears to contribute to disability in MS. Brain tissue from individuals who died from complications of MS showed that iron was primarily stored in the oligodendrocytes.
Remyelination: Signs of remyelination (myelin repair) may be present even in cases of profound axonal (nerve) damage. Examination of brain biopsy tissue from patients with early MS (obtained to exclude diseases such as infection or cancer) revealed that signs of remyelination are sometimes present, despite the fact that these lesions were mainly demyelinated (where myelin is no longer present).
Although remyelination occurs, it is often not sufficient to prevent irreversible damage and progressive disability. Researchers are beginning to understand the steps in the remyelination process. Oligodendrocyte progenitor cells (OPC) have been identified as one of the main cell types responsible for remyelination. These cells can now be identified through the use of certain markers, allowing the process to be studied in depth.
MS Treatment with Myelin Peptide Skin Patches: MS treatments that could more specifically inhibit the inflammatory activity of the immune system would potentially represent an improvement over current medications that have a more global effect. To that end, researchers tested a myelin peptide-infused skin patch in two different doses compared to a placebo, to determine whether it could help stop the inflammatory response that can result in damage to the brain.
The patches strongly suppressed the inflammatory response and also resulted in a positive clinical effect. Compared to the placebo group, patients in the treated group had positive responses with respect to the number of brain lesions, annual relapse rate (ARR), the number of individuals who were relapse free, disability, and EDSS scores. There were no serious adverse events. Redness and itching in the local area of the patch was observed in 20 percent of the patients in the treatment group.
Stem Cells: Results of a Phase I safety study of stem cell transplantation were reported. Twenty-four patients with RRMS or SPMS, who had EDSS scores of 3.0 to 6.5, received a single IV infusion of mesenchymal stem cells that were derived from their own bone marrow. No significant safety issues resulted and no serious or severe adverse events occurred; there were minimal infusion-related side effects.
The trial was not designed to test efficacy and there was no evidence of either disease activation or improvement with respect to brain lesions or any other measures tested. The safety study was successful, but before Phase II trials are considered, many questions need to be addressed. Issues of cell dose, route of administration, number of infusions, and whether to use cells from the patient or a disease-free donor, are all questions to be resolved.
Written by Margaret M. McCormick, RN, BSN, MSCN
Reviewed by Jack Burks, MD, MSAA’s Chief Medical Officer