Glatiramer acetate

Medical uses

A 2004 Cochrane review concluded that glatiramer acetate "did not show any beneficial effect on the main outcome measures in MS, i.e. disease progression, and it does not substantially affect the risk of clinical relapses."

A trial of 251 patients, after two years failed to show any advantage in halting disability progression. As a result, it is approved by the FDA for reducing the frequency of relapses, but not for reducing the progression of disability.

A 15-year followup of the original trial compared patients who continued with glatiramer to patients who dropped out of the trial. Patients with glatiramer had reduced relapse rates, and decreased disability progression and transition to secondary progressive MS, compared to patients who did not continue glatiramer. However, the two groups were not necessarily comparable, as it was no longer a randomized trial. There were no long-term safety issues.

In two recent studies, both reported at the 2007 ECTRIMS meeting, the efficacy of glatiramer acetate was compared to high-dose/high-frequency interferon beta. In the REGARD study, Rebif was compared to glatiramer, and in the BEYOND study, Betaseron was compared to glatiramer. In both trials, there was no significant difference between interferon and glatiramer in the primary endpoints (time to relapse) or in any clinical endpoints, although some differences in MRI measures of disease activity have been claimed.

A double-blind 3-year study found no effect of glatiramer acetate on primary-progressive multiple sclerosis.

It has FDA approval for clinically isolated syndrome, based on the PreCISe trial, which showed that glatiramer delayed the progression from the first clinical event to clinically definite multiple sclerosis with a risk reduction of 45%. 43% of patients in the placebo group converted, compared to 25% in the glatiramer group.

Adverse effects

According to MediGuard, side effects may include a lump at the injection site (injection site reaction) in approximately 30% of users, and aches, fever, chills (flu-like symptoms) in approximately 10% of users. Side effect symptoms are generally mild in nature. A reaction that involves flushing, shortness in breath, anxiety and rapid heartbeat has been reported soon after injection in up to 5% of patients (usually after injecting directly into a vein). These side effects subside within thirty minutes. Over time, a visible dent at the injection site can occur due to the local destruction of fat tissue, known as lipoatrophy, that may develop.

More serious side effects have been reported for glatiramer acetate, according to the FDA's prescribing label, these include serious side effects to the cardiovascular, digestive (including the liver), hematopoietic, lymphatic, musculoskeletal, nervous, respiratory, and urogenital systems as well as special senses (in particular the eyes). Metabolic and nutritional disorders have also been reported; however a link between glatiramer acetate and these adverse effects has not been established.

It may also cause Jessner lymphocytic infiltrate.

Mechanism of action

Glatiramer acetate is a random polymer (average molecular mass 6.4 kD) composed of four amino acids found in myelin basic protein. The mechanism of action for glatiramer acetate is unknown. Administration of glatiramer acetate shifts the population of T cells from proinflammatory Th1 cells to regulatory Th2 cells that suppress the inflammatory response. Given its resemblance to myelin basic protein, glatiramer acetate may also act as a decoy, diverting an autoimmune response against myelin. The integrity of the blood brain barrier, however, is not appreciably affected by glatiramer acetate, at least not in the early stages of treatment. Glatiramer acetate has been shown in clinical trials to reduce the number and severity of multiple sclerosis exacerbations.

The mechanism(s) by which glatiramer acetate exerts its effects in patients with Multiple Sclerosis (MS) is (are) not fully elucidated. However, it is thought to act by modifying immune processes that are currently believed to be responsible for the pathogenesis of MS. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a condition induced in several animal species through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery.

History

Glatiramer acetate was originally discovered by Michael Sela, Ruth Arnon and Dvora Teitelbaum at the Weizmann Institute of Science in Rehovot, Israel. Three main clinical trials followed to demonstrate safety and efficacy: The first trial, led by Murray Bornstein, was performed in a single center, double-blind, placebo controlled trial and included 50 patients. The second trial was a two-year, multi-center, randomized, double-blind, placebo controlled trial and was performed in eleven United States centers involving 251 patients. This study was led by Kenneth Johnson at University of Maryland Medical Center. The third trial, a double-blind, multi-center, multi-country MRI study, involved 29 MS Centers in six European countries and Canada, with the participation of 239 patients. This study was led by G. Comi at the Department of Neuroscience, San Raffaele Hospital, the University of Milan.

Marketing

Glatiramer acetate has been approved for marketing in numerous countries worldwide, including the United States, Israel, Canada and 24 European Union countries. Approval in the U.S. was obtained in 1997. Glatiramer acetate was approved for marketing in the U.K. in August 2000, and launched in December. This first approval in a major European market led to approval across the European Union under the mutual recognition procedure. Iran is proceeding into domestic manufacture of Glatiramer acetate.

Patent status

Novartis subsidiary Sandoz has marketed Glatopa since 2015, a generic version of the original Teva 20 mg formulation that requires daily injection.

Teva developed a long-acting 40 mg formulation, marketed since 2015, which reduced required injections to three per week. Sandoz is also developing a generic long-acting version, Momenta Pharmaceuticals M356, which is yet to be approved by the FDA and has been subject to a technical FDA warning letter. In parallel with the development and approval processes, the generic competitors have disputed Teva's newer patents, any of which if upheld, would prevent marketing of long-acting generics.

While the patent on the chemical drug expired in 2015, Teva obtained new US patents covering pharmaceutical formulations for long-acting delivery. Litigation from industry competitors in 2016-2017 has resulted in four of the five new patents being judged invalid, and the fifth remains under challenge. The case reflects the larger controversy over evergreening of generic drugs.

Research

Glatiramer acetate has been found to be protective in a mouse model of cerebral malaria.

In 2015 researchers presented results of a small, uncontrolled study of glatiramer acetate given to girls with Rett syndrome, showing association with improvement in symptoms.

Copaxone was the subject of a phase 1 clinical trial (2008-2013) of its potential therapy for dry age-related macular degeneration (AMD).