The path to approval for MS
In June 2012, Genzyme submitted supplemental Biologics License Applications to the US Food and Drugs Administration and the European Medicines Agency for the regulatory approval of Campath-1H (trade named Lemtrada) for the treatment of relapsing MS. This was based on the data from the CARE MS-1 and MS-II trials.
On August 27 2012 Genzyme received a 'Refuse to File' letter from the FDA asking the company to modify the presentation of the data sets it had submitted in its original application to help the agency better navigate the application. While the FDA did not request any additional data or further studies, which would have been a major setback, the letter gave an edge to the company's competitors, who were forging ahead in the development of treatments for the fast-growing multi-billion dollar MS market.
Just over a year later, on 17 September 2013, the European Commission granted marketing authorisation for Lemtrada to treat adult patients with relapsing remitting MS with active disease defined by clinical or imaging features. Lemtrada is to be administered through five infusions over a 5 day period, and then again one year later over 3 days. Significantly, the European approval indicated that Lemtrada could be given to patients newly diagnosed with MS, not just those who had previously tried other treatments. This gave Lemtrada a significant advantage over Biogen Idec's Tysabri, the drug's key rival in the marketplace, which can only be given to patients whose MS symptoms have continued to progress even after taking other treatments. Lemtrada has since been approved for the treatment of MS in 30 countries, including Canada, Australia, Argentina and all members of the European Union. European regulators called the drug a 'step change' in MS treatment. Other marketing applications are currently under review for Lemtrada by regulatory authorities in other countries around the world.
The drug was to be given a further boost when on April 4 2014 the British National Institute for Health and Care Excellence (NICE) recommended Lemtrada for the treatment of adults with active relapsing-remitting MS. NICE concluded Lemtrada to be a more clinically effective treatment than the beta-interferon drug Rebif and that it has a beneficial impact on sustained accumulation of disability at 6 months. Moreover, it noted, the drug's treatment effect persisted for many years after the last treatment. This was based on weighing up evidence from the CAMMS223 and CARE-MS I and II trials and from clinical specialists who acknowledge there is uncertainty regarding the effectiveness of Lemtrada in the long term, specifically for periods exceeding the duration of the follow-up studies to the clinical trials and that the drug is not appropriate for everyone. While clinicians highlighted Lemtrada could cause side effects, they indicated these could be managed.
NICE is of the view that Lemtrada is a cost-effective treatment. The drug's indicative price is £7,045 ($9,722) per 12 mg vial, which equates to £56,360 for the full course of treatment consisting of five daily consecutive 12mg doses in year one, followed by three daily consecutive 12mg doses 12 months later in year two. This price has not yet been confirmed by the Department of Health. The advantage of Lemtrada is the fact that the recommended time for it to be administered is much less than other available treatments which need to be taken either orally as tablets on a daily basis or injected several times a week. Like other MS treatments Lemtrada is not recommended for use during pregnancy. The shorter period that Lemtrada has to be administered, however, makes it more attractive than other treatments for women planning to have a baby. Overall, NICE has recommended Lemtrada be provided by the National Health Service for selected patients with varying types and stages of active relapsing-remitting MS.
In contrast to other regulators, on 27 December 2013, the FDA rejected approval of Lemtrada for the treatment of relapsing-remitting MS and called for more clinical trials to demonstrate its benefits over its side effects. This came after an FDA advisory panel voted 14 to 0 on 13 November 2013 the drug be approved for MS patients who failed other therapies.
The major reason given for the FDA's decision was that the drug's trials did not conform with the agency's standard requirement of double-blind, placebo controlled drug trials, whereby some patients receive placebo treatments without their or the doctor's knowledge. Some FDA reviewers expressed concern that some of Lemtrada's trial data could have been skewed because patients had known which medicine they were given. This was published in a report in November 2013. Click here to see the PDF report.
Both Sanofi's executives and the team in Cambridge defended the trials on the basis that it was difficult to keep the process entirely blind due to the fact that the administration of Lemtrada is very different from that of Rebif, the comparator drug. Unlike Rebif, which is administered as an injection 3 times a week, Lemtrada is given as an infusion over a few days. The other complication was patients would have known what drug they were on because of the side effects. One of the reasons the investigators opted for an open study as opposed to a blind one was also the fact that Lemtrada had known safety concerns. The investigators, therefore, argued that ethically the only way to justify Lemtrada's use in a trial was to compare it with an active drug already routinely used. This method contrasted with other trials for MS drugs which used a placebo. To have used a placebo would have involved patients being given a sham infusion for several days. This would not only have proven impractical, but also unethical. In addition, they point out that it was difficult to keep the process completely blind because Lemtrada, like many established MS treatments, has immediate side effects easily detectable by doctors and patients. One particular complication, immune thrombocytopnic purpura (ITP), known from 2005 to be associated with alemtuzumab, would be quickly obvious to treating clinicians. This would have been difficult to hide, let alone unethical, to hide. Overall, a completely blinded trial was impossible to achieve. The investigators also stress that while patients and treating physicians were aware of who received Lemtrada or Rebif during the trials, physicians who conducted the examinations of patients for the drug's efficacy outcomes were not told which treatment patients had received or of the patients' adverse effects. In addition, they state that from the start the FDA was consulted about the design of the trials and it was overseen by a steering committee that included specialists from many different countries which established an international consensus on the study design.
In addition to questioning the clinical trials, the FDA rejected Lemtrada on account of its potential for serious adverse reactions. These include ITP, an increased susceptibility to infection and Grave's disease as well as lifelong hyperthyroidism and the possibility of melanoma and other malignancies. Yet, as many point out, these risks were well known for decades and in almost all cases where disorders occur are much less severe and more easily treated than MS itself. Moreover, other drugs approved for MS carry serious side effects. Biogen Idec's Tysabri, for example, which is viewed as Lemtrada's key competitor, can trigger progressive multifocal leukoencephalopathy, a potentially fatal brain infection. Similarly, Gilenya, the first oral MS drug to be approved for market, can cause fatal heart rate abnormalities after the first dose. The advantage of Lemtrada is that, unlike older MS drugs, which have to be injected daily or weekly, it only needs to be administered once a year for two years.
The FDA's refusal to approve Lemtrada greatly disappointed many neurologists and patients in the US who petitioned the FDA to reconsider its decision on the grounds that patients in the US should not be deprived of access to a treatment available in other countries. Many MS experts expressed concern that the FDA's rejection would lead patients to travel abroad to gain access to the drug which could result in unsupervised use. Importantly, it would make it more difficult to monitor patients after treatment, which is vital given the drug's possible side effects.
On November 24 2014 the FDA finally approved Lemtrada for the treatment of patients with relapsing forms of MS. This came after Sanofi resubmitted an application in May 2014 aimed at getting a new analysis of their clinical data. The FDA recommended Lemtrada be generally reserved for those patients who had experienced poor responses to two or more previous drugs.
The FDA's reversal of its earlier decision has come as a major relief to the 400,000 MS patients in the US. In accordance with the FDA's approval, these US patients are to access the drug through a restricted distribution programme known as the Risk Evaluation and Mitigation Strategy (REMS). Modelled on the management programme successfully implemented during the drug's phase 2 and 3 trials, the REMS has mechanisms for the early detection and management of the potentially serious risks associated with Lemtrada. Patients are expected to have monthly blood and urine tests to screen for side effects. The REMS also put in place a programme to educate healthcare providers and patients about the potential dangers associated with the drug. The distribution of Lemtrada can only be done by prescribers, healthcare facilities and specialty pharmacies certifiied by the REMS programme.
How far the drug will penetrate the MS market remains to be seen. The emergence of new forms of MS treatments, particularly those that can be taken orally, has made the market extremely competititve. This and the regulatory setbacks in the US are all tempering expectations that Lemtrada will achieve the peak annual sales of $3.5 billion once predicted by Genzyme. In the first nine months of its approval in Europe, 2013, drug sales reached $22.54 million.