Genzyme’s Lemtrada Approved by the FDA

Cambridge, Massachusetts based Genzyme announced Friday that the U.S. Food and Drug Administration (FDA) has approved the company’s new drug Lemtrada (alemtuzumab) for treatment of people with relapsing forms of multiple sclerosis, which includes people who experience periodic MS attacks, such as those who have relapsing-remitting MS or secondary-progressive MS with relapses.

“The FDA approval is the culmination of more than a decade of work by Genzyme to develop Lemtrada,” says Genzyme President and CEO, David Meeker. “Lemtrada demonstrated superior efficacy over Rebif on annualized relapse rates in the two studies which were the basis for approval. A comprehensive risk evaluation and mitigation strategy (REMS) will be instituted in order to help detect and manage the serious risks identified with treatment.”

The road to FDA approval in the United States has been a daunting one for Genzyme, who has worked tirelessly to secure the approval and make the drug available in the U.S. Lemtrada has been approved in other major health markets worldwide and has seen continued use in patients with the relapsing-remitting form of the disease. With recent reports about Lemtrada making headlines, such as the news of approvals in Scotland and Argentina, both Genzyme and multiple sclerosis patients in the U.S. have had to wait for word from the FDA after the company resubmitted an application for the drug in June, after what appeared to be concerns that Lemtrada might not be approved after all.

However, in light of the new announcement, the MS patient community is heralding the news, as it gives those suffering from the disease a new therapeutic option, particularly for those patents who have not responded to first- and second-line therapies. “The FDA approval of Lemtrada is a significant milestone for people living with relapsing MS in the United States,” says Dr. Timothy Coetzee, Chief Advocacy, Services and Research Officer at the National MS Society. “We are pleased that the voices of the MS community have been recognized and that people with relapsing MS will now have access to a new, needed treatment option.”

The following sections outline key information about the approval of Lemtrada in the U.S.

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Lemtrada’s Administration, Dosage Fosters Patient Compliance

Lemtrada has a unique dosing and administration schedule of two annual treatment courses. The first treatment course is administered via intravenous infusion daily on five consecutive days, and the second course is administered one year later with individuals receiving one infusion per day for three days. The administration of Lemtrada is part of what it makes it attractive to certain MS patients, as its ease of use fosters improved patient compliance, which is turn allows the medication to work optimally. Lemtrada is administered clinically as an infusion into a vein. Each infusion delivers 12 mg of Lemtrada, and there is no Lemtrada treatment between the two courses. Each infusion takes approximately four hours.

Risks And Risk Management

As a result of the announcement, Genzyme is now working to disseminate information about the drug so that patients and physicians can make informed decisions about prescribing Lemtrada. According to the company’s own press release, due to risks associated with it as a treatment, Lemtrada can only be administered in certified healthcare settings that have on-site access to equipment and personnel trained to manage anaphylaxis and serious infusion reactions. Lemtrada may be associated with an increased risk of malignancy, including thyroid cancer, melanoma and lymphoproliferative disorders. Lemtrada is only available through a restricted distribution program, the Lemtrada REMS (Risk Evaluation and Mitigation Strategy) — a comprehensive risk management program with frequent monitoring, is being implemented to help mitigate these serious risks.

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 is intended to help educate healthcare providers and patients on the serious risks associated with Lemtrada and the appropriate periodic monitoring required to support the detection of these risks for 48 months after the last infusion. The REMS is based on a developmental risk management program that was successfully implemented in the Phase 2 and Phase 3 trials and allowed for early detection and management of some of the serious risks associated with Lemtrada.

How Lemtrada Works

Lemtrada is a recombinant humanized monoclonal antibody that is a recombinant humanized monoclonal antibody and a selective immunomodulator that targets CD52, a protein abundant on T and B cells. Treatment with alemtuzumab results in the depletion of circulating T and B cells thought to be responsible for the damaging inflammatory process in MS. Lymphocyte counts then increase over time with a reconstitution of the lymphocyte population that varies for the different lymphocyte subtypes. Alemtuzumab has minimal impact on other immune cells. The acute anti-inflammatory effect of alemtuzumab is immediately followed by the onset of a distinctive pattern of T and B cell repopulation that continues over time, altering the immune system in a way that potentially reduces MS disease activity.

Clinical Testing Of Lemtrada

Lemtrada is supported by a comprehensive and extensive clinical development program that involved 1,188 patients, resulting in 2,363 patient-years of safety follow-up. The FDA approval of Lemtrada is based on two pivotal randomized Phase III open-label rater-blinded studies comparing treatment with Lemtrada to Rebif (high-dose subcutaneous interferon beta-1a) in patients with relapsing remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II).

Significantly More Effective Than Interferon Beta-1a

In CARE-MS I, data were evaluated for 563 people with early, active relapsing-remitting MS, who had never received disease-modifying therapy to treat their MS and were randomly assigned to receive Lemtrada or Rebif. Lemtrada was shown to be significantly more effective than interferon beta-1a at reducing annualized relapse rates; the difference observed in slowing disability progression did not reach statistical significance. After two years the relapse rate for those on Lemtrada was reduced by 55% compared to those on Rebif. Also after two years, 8% of those on Lemtrada experienced an increase (worsening) in their EDSS score (a standard scale of physical disability) compared to 11 % on Rebif – a difference that was not statistically significant. After two years 78% of those on Lemtrada remained relapse-free, which was significantly more than the 59% who remained relapse-free on Rebif

In CARE-MS II, a two-year trial comparing Lemtrada to the standard subcutaneous dosing of Rebif, Data were evaluated for 628 people with relapsing-remitting MS who had already been treated with another MS therapy but had experienced at least one relapse on that previous therapy. Lemtrada was significantly more effective than interferon beta-1a at reducing annualized relapse rates, and accumulation of disability was significantly slowed in patients given Lemtrada vs. interferon beta-1a. After two years, the annual relapse rate for those on Lemtrada was 0.18 compared to 0.39 for those on Rebif, representing a 49% lower risk of relapses. In addition, on average fewer people on Lemtrada had an increase (worsening) in their EDSS score compared to those on Rebif (13% for Lemtrada vs. 21% for Rebif) — a 42% difference that was statistically significant. After two years, 65 percent of those on Lemtrada remained relapse-free compared to 47 percent.The clinical development program for Lemtrada involved nearly 1,500 patients with more than 6,400 patient-years of safety follow-up.

According to a Multiple Sclerosis Society Of Canada (MSSoC) drug profile, findings from a separate study assessing the safety and efficacy of alemtuzumab compared with interferon beta 1a in people with relapsing-remitting MS who have relapsed despite first-line treatment (interferon beta or glatiramer acetate) suggest that alemtuzumab was more effective in reducing relapse rate and disability progression compared with interferon beta 1a.

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Success Rates

Genzyme reports that more than 90 percent of patients participating in the Phase III pivotal trials enrolled in the extension study. Patients who originally received Lemtrada were eligible to receive additional treatment in the extension study if they had experienced at least one relapse or at least two new or enlarging brain or spinal lesions.

These interim results are from the first year of the extension study for patients who previously received Lemtrada in the two-year studies. Findings cited are based on patients who enrolled in the extension study:

More than half of patients (67 percent in CARE-MS I and 55 percent in CARE-MS II) who received Lemtrada in the pivotal trials and enrolled in the extension study were still relapse-free through the first year of the extension study.

In the first year of the extension phase, the annualized relapse rate for patients who received Lemtrada in the pivotal trials was 0.24 and 0.25, comparable to the annualized relapse rate for those patients in CARE MS I and CARE-MS II, respectively.

Through year three, 72.4 percent of patients in CARE MS I and 70.0 percent in CARE MS II had improved or stable disability as measured by EDSS.

At three years, 88 percent and 80 percent of patients who received Lemtrada in the pivotal trials, respectively, did not experience six-month confirmed sustained accumulation of disability.

During an extensive, ongoing clinical development program, 80 percent of RRMS patients who received two treatment courses of Lemtrada required no further therapy, and 55 percent remained relapse-free through the first year of the extension study. Unlike other current disease modifying therapies (DMTs) in which stopping treatment usually results in resumed disease activity, Lemtrada continues to have a durable effect far beyond the two annual treatment courses. In fact, in more than 70 per cent of clinical trial patients, disability scores improved or remained stable over three years.

Results Underscore Tremendous Promise Lemtrada Holds For MS Patients

“These results underscore the tremendous promise that Lemtrada holds for MS patients,” commented Genzyme’s Dr. Meeker. “We’re pleased to be able to present these three-year results that provide us with important new information about Lemtrada and are consistent with the published results from our Phase II extension study.”

Genzyme says safety results from the first year of the extension study were reported for patients who received Lemtrada in the Phase III pivotal studies. No new risks were identified. The frequency and type of common and serious adverse events in the first year of the extension study were generally similar to those in the Phase III pivotal studies. The most common adverse events during this period of time were infections, including predominantly mild to moderate upper respiratory and urinary tract infections.

There were two deaths. One, as previously reported, was from sepsis. The other death was presumed accidental and deemed unrelated to study treatment. The cumulative incidence of autoimmune thyroid disease over three years was 29.9 percent, as expected based on the Phase II study experience. Additionally, over three years, approximately 1 percent of patients developed immune thrombocytopenia (ITP) and 0.3 percent developed nephropathy, all of whom responded to treatment. These cases were detected early through routine monitoring. Patient monitoring for autoimmune disorders is incorporated in all Genzyme-sponsored trials of Lemtrada.

Side Effects And Warnings

As with all medications, there are always some side effects associated with administration, and Genzyme has laid out those potential effects for Lemtrada. The company reports that the most common side effects are infusion-associated reactions (headache, rash, fever, nausea, hives, itching, insomnia, chills and flushing) pyrexia, nasopharyngitis, nausea, and infections (nasopharyngitis, urinary tract and upper respiratory tract), fatigue, insomnia, herpes viral infection, urticaria, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting.

The Lemtrada label includes a boxed warning noting a risk of additional potential serious risks, including serious infections and autoimmune conditions, including thyroid disease, autoimmune cytopenias (decreased white blood count), pneumonitis, immune thrombocytopenia (ITP) and anti-glomerular basement membrane disease, and kidney disease that can occur in people receiving Lemtrada, which also may cause increased risk of malignancies including thyroid cancer, melanoma and lymphoproliferative disorders.

Comprehensive Risk Management Program

Consequently, a comprehensive risk management program incorporating education and monitoring to support early detection and management of these identified risks is in order, and prior to starting Lemtrada treatment, patients will require blood and urine tests, and an EKG. Blood and urine tests will continue for 4 years after an individual’s last Lemtrada infusion, and it is important to get this testing done according to the recommended schedule in order for physicians to watch for signs of autoimmune side effects so that treatment can occur quickly, if needed. Indeed, Because of its safety profile, Lemtrada will not be a treatment of first or even second resort, but generally reserved for patients who have had an inadequate response to two or more other drugs indicated for the treatment of MS.

Nevertheless, “The unmet need in MS remains high,” says Edward Fox, M.D., Ph.D. , Director of the Multiple Sclerosis Clinic of Central Texas. “It is a great day for people living with relapsing forms of MS in the United States, who will now have access to this new meaningful treatment.” Multiple sclerosis, which involves immune system attacks against brain and spinal cord tissues, is estimated to affect more than 2.3 million people globally, including approximately 410,000 people living with MS in the United States, and 100,000 in Canada. MS symptoms can include: blurred or loss of vision, poor coordination, slurred speech, extreme fatigue, diminished mobility of the arms or legs, problems with memory and concentration, and bladder and bowel dysfunction.

 FDA Screening And Monitoring Recommendations

The FDA recommends that before starting treatment:
• it should be determined whether the individual has been vaccinated for varicella zoster virus, and if not, tested for antibodies and vaccinated if needed 6 weeks prior to beginning treatment with Lemtrada;
• thyroid function tests such as thyroid stimulating hormone level should be obtained before treatment and every 3 months until 48 months after the last infusion;
• full blood count with differential should be obtained prior to treatment and monthly thereafter until 48 months after the last infusion;
• serum creatinine levels should be obtained prior to treatment and monthly thereafter until 48 months after the last infusion;
• urinalysis  with urine cell counts be obtained prior to treatment and monthly thereafter until 48 months after the last infusion;
• skin exam should occur at start of treatment and yearly thereafter to monitor for melanoma;
• people with active infections should consider delaying treatment until the infection is controlled.
• People should not have live-virus vaccines after a course of Lemtrada.

Potential Benefits Vs. Risks

“The approval of Lemtrada provides an important and immunologically powerful new therapeutic option for people with relapsing MS,” observes Bruce A. Cohen, MD, Professor, Davee Department of Neurology and Clinical Neurosciences at Northwestern University’s Feinberg School of Medicine, and Chair of the National MS Society’s National Medical Advisory Committee. “Its long-lasting effects may profoundly influence the course of relapsing MS, but will require careful and sustained monitoring for side effects which people receiving the medicine must follow. Individuals with MS who are considering treatment with this medicine should thoroughly educate themselves on its potential benefits and risks.”

As a Sanofi company, Genzyme benefits from the reach and resources of one of the world’s largest pharmaceutical companies, with a shared commitment to improving the lives of patients. Genzyme holds worldwide rights to alemtuzumab and has responsibility for its development and commercialization in multiple sclerosis. Bayer Healthcare receives contingent payments based on global sales revenue. First approved in September 2013 in the European Union, Lemtrada is approved in more than 40 countries. Additional marketing applications for Lemtrada are under review by regulatory agencies around the world.

“Médicament d’exception” In Quebec

Lemtrada was approved by Health Canada in December 2013 — the approval based on the data from the Lemtrada clinical development program comparing treatment of Lemtrada to high-dose subcutaneous interferon beta-1a (Rebif). In September, Genzyme announced that the Canadian province of Québec’s Institut national d’excellence en santé et services sociaux (INESSS) has recommended that Lemtrada 12 mg be included on the provincial drug formulary under “Médicament d’exception” as a second-line treatment for people living with relapsing-remitting multiple sclerosis (RRMS). This announcement follows decisions by international Health Technology Assessment Agencies, such as NICE in the UK in May and PBAC in Australia in August 2014.

The FDA approval of Lemtrada marks Genzyme’s second MS treatment approval in the United States. Genzyme received FDA approval of its once-daily, oral Aubagio (teriflunomide) for the treatment of relapsing forms of MS in September 2012. Aubagio is approved in more than 50 countries, and is under review by additional regulatory agencies. Between clinical trials and commercial use, approximately 30,000 patients have been treated with Aubagio.

As part of its commitment to those living with MS, Genzyme has developed the MS One to One program which provides comprehensive and effective support, particularly with regard to the procedures for reimbursement and administration, as well as providing educational resources. Staffed by dedicated MS nurses and highly trained representatives, MS One to One provides support for individuals living with MS, their healthcare providers, family and loved ones. Information and support are available at:
https://www.MSOnetoOne.com

For more information, visit:
https://www.genzyme.com

Sources:
Genzyme
The National Multiple Sclerosis Society
Multiple Sclerosis Society Of Canada
U.S. Food and Drug Administration