Sanofi's Lemtrada likely to see strong physician uptake in MS patients with active disease, long-term side-effects on watch – neurologists
2012-06-06 BioPharm Insight
Sanofi's (EPA:SAN) Lemtrada (alemtuzumab) is likely to see strong physician uptake and become the "go-to" treatment for patients with active multiple sclerosis, neurologists said.
The France-based drugmaker recently presented final results of two pivotal Phase III trials CARE-MS I and CARE MS-II. CARE-MS II, comparing the investigational drug alemtuzumab to Merck (ETR:MRK) and Pfizer's (NYSE:PFE) Rebif in patients with relapsing-remitting multiple sclerosis (RRMS) who had relapsed while on prior therapy, announced that co-primary endpoints of the trial were statistically significant.
Consistent with the CARE-MS II results, CARE MS- I showed a benefit on relapse one co-primary endpoint; however, only a trend was shown on the second co-primary endpoint sustained accumulation of disability.
In CARE-MS I, the disability progression for patients in the Rebif group was not as rapid as we had predicted it would be, a spokesperson said. Therefore, while fewer patients in the Lemtrada arm experienced a worsening of disability, the difference between the groups was not significant, he added. Treatment with Lemtrada resulted in 55 % reduction in relapse rate compared to Rebif, he said.
One investigator said Lemtrada will become a "go-to" drug for physicians more and more as they become familiar with it.
Of note and in contrast to patients on interferon-beta, overall disability was improved in Lemtrada patients over two years, said Dr Mathias Buttmann, senior consultant neurologist, University Hospital of Würzburg, Germany. Although by design of CARE-MS II a lot of interferon non-responders were included, which may represent a bias favouring alemtuzumab, these results are very exciting, he said.
Lemtrada has the potential to be the first approved "super potent" MS drug, Dr Stephen Krieger, said assistant professor of neurology, Corinne Goldsmith Dickinson Center for MS, Mount Sinai Medical Center, New York. However, he noted that this will likely be utilized for second- to third-line treatment, as this has been a major unmet need for MS patients with severe disease course that has not been responsive to other agents.
This news service previously reported the drug is likely to be used as a second- or third-line treatment.
It is very likely it will be used in aggressive cases where patients are not responding to treatment, said Dr Jeffery Dunn, clinical associate professor, Neurology & Neurological Sciences, Stanford University, California. The general importance of the drug is that it is very potent, he added.
While CARE-MS I did not demonstrate a significant reduction of disability progression in Lemtrada versus interferon-beta patients, this could possibly be due to the low disease activity already in the interferon group, said Buttmann.
CARE-MS II, which in contrast to CARE-MS I was not conducted in treatment-naive patients but in those experiencing break-through disease activity on ABCR (approved injectable treatments), now demonstrated an impressive difference regarding disability progression, favouring Lemtrada over interferon-beta, Buttman said.
Injectable products approved for MS include Biogen Idec's Avonex, Bayer's (ETR:BAYN) Betaseron, Rebif, Novartis's (VTX:NOVN) Extavia and Teva's (TLV:TEVA) Copaxone.
Taking the Lemtrada clinical trial program as a whole, Lemtrada seems to be the most effective agent available to date for patients with RRMS, although no head-to-head comparisons (e.g. with natalizumab) were performed to be absolutely sure about this, Buttman noted.
Results from CARE-MS I (naive patients) were not as impressive as in CARE-MS II (patients who experienced relapses under first-line treatment i.e. INFb or Copaxone) and so far data are in favour of using Lemtrada as a second-line treatment, Dr Georgios Hadjigeorgiou, associate professor of neurology University of Thessaly, and Elias Zintzaras, associate professor of biomathematics University of Thessaly, said jointly in an email.
There could be issues with the data during the approval process as a first-line treatment as combination therapies have been found to be very promising in MS, Hadjigeorgiou and Zintzaras wrote.
In CARE-MS II, Lemtrada used soon after INFb or Copaxone failure and the question of whether results from CARE-MS II are the result of the usage of consecutive treatments may be asked because this could explain differences between the results of the two trials, Hadjigeorgiou and Zintzaras wrote.
Yet, Dr Joseph Berger, chairman of the University Of Kentucky Department of Neurology, said that his most important concern is often disability, as this can have a considerable and profound effect on quality of life.
The lack of benefit seen on the CARE MS-I trial could be due to the fact that even the control group did not progress much on this measure, said Dr Jai Perumal, assistant professor, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York. She explained that if patients are not progressing very much it is difficult to demonstrate a difference between groups.
Side-effects
The safety profile of Lemtrada is well established, consistent in all in studies, and manageable, the spokesperson said. Both pivotal studies included a risk management program, and we do expect that the FDA will require a REMS program for Lemtrada, as it has for other newer MS treatments, he added.
Autoimmune effects need to be watched with Lemtrada and the very low levels of lymphocytes; however, so far there have not been any instances of "terrible infection." Lemtrada will be used over a short-term duration due to a lack of long-term data, Perumal added.
Five-year data is required in order to fully understand the carcinogenicity potential of the drug, Perumal added.
Lemtrada significantly reduces the number of lymphocytes, and this is why the extension trials will be very important, one neurologist said. Additionally, there has been some carcinogenicity associated seen on the clinical trials to date, he added.
Side-effects of this drug need to be watched very carefully, Dunn said. He added that long-term side-effects such as malignancy could be an issue, he added.
Overall, Lemtrada was safe over a two-year duration in CARE-MS II, Buttmann said, adding that, nevertheless, Lemtrada is a very strong immunosuppressant with unknown long-term adverse effects.
Buttmann said he would place Lemtrada as a third-line treatment in patients with very high disease activity on the general notion that this is a very strong immunosuppressant which might be harmful over a long-term duration (e.g. potential carcinogenicity). However, there is no data on this so far, he added.
Immunogenicity long-term follow-up studies will determine whether the drug is used as a short-term or chronic treatment, Hadjigeorgiou and Zintzaras wrote.
There need to be three to five year follow-up trials conducted to fully understand the risks associated with the drug, Berger said.
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