FDA Committee Recommends Lemtrada for Approval
November 14, 2013
On November 13, 2013, the United States Food and Drug Administration (FDA) held a meeting to discuss Lemtrada® (alemtuzumab, also known as Campath), a new treatment that has been submitted for approval to treat relapsing forms of multiple sclerosis (MS). Despite concerns over the drug’s safety as well as study design, the FDA’s committee voted to recommend the drug for approval. The committee also recommended that the treatment be approved as a second-line therapy, when other treatments previously approved by the FDA as disease-modifying therapies fail or are not tolerated well by a patient. The FDA usually, but not always, follows their independent advisory committee’s recommendations. The FDA is expected to make a decision about the drug’s approval by the end of the year.
The November 13 meeting was attended by members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, an external group of medical professionals. Also attending were representatives from the pharmaceutical company that submitted the drug for approval (Genzyme Corporation, a Sanofi company), as well as members of the MS community, including representatives from MS organizations, medical professionals, and individuals with MS. MSAA was among those MS organizations advocating for patients at the meeting. The committee members discussed and voted upon questions such as: whether or not the drug trials for Lemtrada were adequate and well-controlled; if the pharmaceutical company had provided substantial evidence of Lemtrada’s beneficial effects; if safety concerns preclude approval; if approved, whether or not Lemtrada should be a first-line therapy; and what types of monitoring programs and administering facilities would be needed.
One challenge with study design is that this experimental treatment is given via intravenous (IV) administration, once daily for five days, and then one year later, once daily for three days. Although most studies have one treatment arm receiving a placebo (a similar-appearing treatment with no active ingredients), having a placebo group in studies with Lemtrada would have been difficult. In place of a placebo group, the studies compared the effectiveness and adverse events of Lemtrada to individuals treated with Rebif® (interferon beta-1a), an approved disease-modifying therapy for MS, given three-times weekly via subcutaneous (under the skin) injections. As mentioned in the section to follow, a Phase II study comparing Lemtrada to high-dose Rebif (44 mcg) was notable, as Lemtrada-treated patients had the lowest relapse rate ever reported for an MS drug in an FDA-approved, comparative trial.
Lemtrada was originally approved in 2001 for the treatment of a certain type of leukemia (B-cell chronic lymphocytic leukemia), using “Campath” as the trade name. It works by depleting or suppressing T and B cells – the body’s disease-fighting cells that may become misdirected and cause harm to one’s own body. Misdirected T and B cells are believed to play a major role in the MS disease process.
Based on a review of the data available, MSAA’s Chief Medical Officer Dr. Jack Burks believes that Lemtrada, with its ability to reduce relapses and possibly improve disability as well as prevent disease progression, has the potential to be a major contributor in the fight to manage MS. According to Dr. Burks, “Efficacy data from Phase II and Phase III FDA trials with Lemtrada were significant and impressive. However, adverse events such as thyroid problems, low platelet counts, and infusion reactions were seen in some MS patients. These types of events may be discovered early and are manageable. The FDA is also evaluating other potential adverse events. Another effect of the drug is a decrease in the white-blood-cell count, although this is expected and is the mechanism of action for how the drug works. If this treatment is approved by the FDA, a risk-management strategy and monitoring system will need to be implemented, although details about any type of patient-safety program are still to be determined.”
MSAA President and CEO Doug Franklin was among those who spoke at this meeting in support of individuals with MS and their families. During his brief presentation, Mr. Franklin supported the benefits of having more treatment options, expressing Dr. Burks' position that Lemtrada has the potential to be a highly effective treatment for MS. Mr. Franklin also noted that the risk of adverse events often increases with an increase in a medication’s efficacy, and that the determination of risk versus benefit is best to be considered between the treating physician and the informed patient. He also pointed out that robust monitoring programs with other treatments have proven effective in mitigating some adverse events. Mr. Franklin concluded by stating that MSAA is committed to supporting both the MS patient and healthcare communities in their understanding of all MS medications.
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. This agent has been approved for the treatment of B-cell leukemia, although as of 2012 it is being developed solely for MS.
A Phase II study of 334 individuals with early, active RRMS compared Lemtrada to high-dose Rebif (44 mcg) in RRMS. In this three-year safety and efficacy trial, Lemtrada was more effective than Rebif at reducing the relapse rate and the risk for six-month sustained accumulation of disability in patients with RRMS. This trial is notable as Lemtrada-treated patients had the lowest relapse rate ever reported for an MS drug [in an FDA-approved comparative trial].
In a multi-year extension study of the 334 individuals who participated in the original Phase II study, Lemtrada yielded a 73-percent reduction in risk for sustained accumulation of disability, 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. These data indicate that Lemtrada's treatment effect is durable; it halts clinical-disease activity in a significant proportion of RRMS patients through five years – even though many of those patients did not require subsequent re-treatment with the drug.
This drug was then granted Fast Track status by the FDA in June 2010. Lemtrada has since successfully completed two Phase III trials: CARE-MS I and II.The CARE-MS I study compared the clinical and MRI results of treatment with Lemtrada, to treatment with subcutaneous Rebif (interferon beta-1a) in patients with RRMS who had not received prior treatment with any disease-modifying therapies. Rebif was given according to the regular dosing of three times per week, while Lemtrada was given intravenously for five days, and then a second time one year later for three days. CARE-MS I was a multicenter international trial. Data were collected for each patient during a two-year period from the time of the first infusion.
The ARR (annual relapse rate) was 0.18 (or slightly less than one relapse every five years) for Lemtrada-treated patients. This was as compared with 0.39 (or slightly less than one relapse every two-and-a-half years) for Rebif-treated patients. This means that Lemtrada reduced the ARR by 55 percent compared to Rebif. Supportive analyses of the risk of severe relapses found that the risk was lower with Lemtrada. Individuals taking Lemtrada had a 59-percent reduction in severe relapses requiring steroid treatment. These clinical data were supported by MRI outcomes. Through year two, fewer Lemtrada patients developed new gadolinium-enhancing lesions (areas of active inflammation and myelin damage in the brain) than Rebif-treated patients (15.2 percent versus 27.2 percent).
CARE-MS II is the third study to compare Lemtrada with Rebif. It was designed to evaluate the effect of Lemtrada on relapse and disability as compared to Rebif in people with RRMS who had relapsed on prior therapy – people for whom a first-line injectible medication was insufficient. The study design was otherwise the same as that in CARE-MS I. The co-primary efficacy endpoints were the ARR and time to six-month sustained accumulation of disability as measured by the Expanded Disability Status Scale (EDSS).
Relapse data showed that 65 percent of patients treated with Lemtrada were relapse-free at two years, as compared to 47 percent with Rebif. These data also showed a 49-percent reduction in relapse rate as compared to Rebif. The group treated with Lemtrada showed a decrease in the mean disability score, versus a slight worsening of disability in those treated with Rebif. Approximately 29 percent of patients treated with Lemtrada experienced a six-month sustained improvement in disability, as compared to 13 percent with Rebif.
Several safety concerns have been raised by the above studies, including infusion reactions to the medication, and an increased risk of infection and emergent autoimmune diseases in patients treated with Lemtrada. All three studies showed a modest increase in the incidence of infections, though no opportunistic infections occurred. No treatment-related fatalities were reported in the Phase III studies. In the CARE-MS I and II studies 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). A program to monitor for the development of thyroid issues and immune thrombocytopenia was successful in early detection of these known complications from Lemtrada.
With the side effects and adverse events in mind, the significant reduction in relapses with Lemtrada compared with high-dose, high-frequency Rebif suggest that there is potential for Lemtrada to be a meaningful addition to the presently available treatment options for RRMS.
(The above information was taken from MSAA's MS Research Update).
Written by Susan Wells Courtney
|Last Updated on Thursday, 14 November 2013 14:05|