Physician calls for "radical new approach" to MS after positive Alemtuzumab Phase II 5-Year review
This article was originally published in Scrip
A lead investigator in the Phase 2 CAMMS223 trial of Genzyme's alemtuzumab (CamPath-H1) has called for " a radical new approach" to treatment of multiple sclerosis on the basis of 5-year follow up data presented on 14 October at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) International Conference in Goteborg, Sweden. Dr Alasdair Coles from the Department of Clinical Neurosciences, University of Cambridge hopes that MS physicians will look at the data from the study and move quickly to aggressive treatments such as alemtuzumab before overt and severe disability emerges, rather than adopting the "wait-and-see" approach with MS patients.
His comments came as Genzyme reported five-year follow-up data from its completed Phase 2 multiple sclerosis (MS) trial and a separate Phase II study that examined the impact of alemtuzumab on patients with highly active relapsing-remitting MS.
The CAMMS223 Phase 2 trial compared alemtuzumab to Merck-Serono's approved MS therapy Rebif (high dose interferon beta-1a) in early, active, relapsing-remitting multiple sclerosis (RRMS) with no prior therapy. Alemtuzumab was given in two or three annual cycles of not more than five days per cycle, while Rebif was given three times per week, every week for three years.
The 5-year follow-up analysis looked at patients with relatively mild MS (mean disability (EDSS) score <3) who="" had="" been="" treated="" in="" the="" first="" year="" of="" the="" study="" either="" with="" alemtuzumab="" or="" rebif.="" the="" analysis="" showed="" that="" the="" annualized="" relapse="" rate="" was="" 0.11="" in="" those="" patients="" receiving="" alemtuzumab,="" compared="" with="" 0.35="" in="" patients="" receiving="" rebif.="" at="" the="" same="" time,="" the="" edss="" score="" for="" alemtuzumab="" patients="" improved,="" but="" worsened="" for="" patients="" receiving="" rebif:="" over="" the="" 5="" years="" of="" the="" follow="" up,="" only="" 13%="" of="" alemtuzumab="" patients="" experienced="" a="" sustained="" increase="" in="" disability="" compared="" with="" 38%="" rebif.="" the="" data="" from="" the="" study="" was="" somewhat="" complicated="" by="" the="" pragmatic="" need="" to="" continue="" to="" treat="" patients="" during="" the="" follow-up="" period,="" so="" that="" some="" of="" the="" patients="" in="" both="" arms="" of="" the="" study="" received="" not="" only="" alemtuzumab="" or="" rebif="" but="" other="" disease-modifying="" treatments.="" however,="" dr="" coles="" maintains="" that="" "even="" with="" the="" dirtiness="" of="" the="" data,="" we="" still="" demonstrate="" a="" clear="" case="" for="" sustained="" benefit="" for="" alemtuzumab.="" these="" long-term="" patient="" follow-up="" data="" suggest="" that="" alemtuzumab="" may="" have="" a="" significant="" disease="" modifying="" effect="" in="" patients="" in="" this="" study="" with="" early,="" active,="" relapsing-remitting="" multiple="" sclerosis,”="" he="">
Coles is now calling for the MS physician community to embrace what he calls a radical new approach to MS. "The old paradigm is to wait until patients start to suffer worsening disabilities before shifting to more effective treatments," he explained. "I would propose that we should treat the disease very seriously, very early on." Traditionally, he said, the approach is to be rather gentle at the beginning, perhaps even not giving any treatment. When the condition worsens, physicians will start the patient on beta-interferons or Tysabri, and only after further debilitation will they move patients to a more powerful drug. "That is doing a disservice to patients," Dr Coles claims, "because they are missing out on the opportunity to make a substantial recovery."
Of the three potential barriers to the adoption of this radical new approach – patient resistance, regulatory authority concerns, and the physician community, Dr Coles believes that conservativeness of the MS specialists is likely to be the greatest obstacle. "Some colleagues will, like me, start aggressive treatment as early as possible, but the more conservative of them will want to continue to progress slowly through the no-treatment, mild-treatment, aggressive treatment pathway." The obvious fourth barrier to use – the cost of the treatment if approved – was not something that Dr Coles was in a position to comment on.
The data needed to make that case for aggressive early treatment with alemtuzumab more convincingly will probably only arise from the continuing phase III studies. The phase II study reported at ECTRIMS dealt only with patients with a disability of score of less than 3, a narrow segment of the MS population wherein the physical signs of disease are manifest but relatively slight. The Phase III study includes a wider range of patients including many with more overt disease so that comparisons can be made between early and late intervention in the disease. Genzyme is conducting two pivotal Phase 3 trials with alemtuzumab in MS. CARE-MS I, a randomized trial comparing alemtuzumab to Rebif, is studying early, active RRMS patients who have received no prior therapy. CARE-MS II also compares alemtuzumab to Rebif but studies RRMS patients who relapsed while on other MS therapies. Data from the Phase 3 trials are expected to be available in 2011.
highly active RRMS trial
A second set of data presented at ECTRIMS involved patients from the original CAMMS223 Phase 2 trial who have highly active RRMS: this group represented 55-56% of the total patient number and included those subjects who had had two relapses in the year before the trial, and had at least one gadolinium enhancing brain lesion identified through magnetic resonance imaging (MRI). In this group, patients on alemtuzumab had a significantly reduced annualized relapse rate compared to those on Rebif: 0.09 on alemtuzumab, compared with 0.47 on Rebif. Furthermore, 91 percent of alemtuzumab-treated patients were free of sustained accumulation of disability, compared to 75 percent of patients taking Rebif.
“Alemtuzumab was significantly more effective than Rebif at reducing relapses and the accumulation of disability in patients with highly active disease, a population at a typically higher risk for poor MS outcomes,” said Dean Wingerchuk of the Department of Neurology at the Mayo Clinic.
New mechanism of action
Alemtuzumab is a humanized antibody that targets the CD52 antigen on lymphocytes. The antibody acts by selectively knocking out T and B lymphocytes and therefore reduces the damage that autoreactive lymphocytes inflict on the myelin sheath that protects nerve cells. Now, new data on its molecular mechanism (also presented at ECTRIMS) suggests that in addition to lymphocyte reduction, alemtuzumab also shifts the balance of immune cells to produce an increased percentage of suppressive regulatory T cells (Treg). “This in vitro study showed that these important cells represent a much larger percentage of the lymphocyte population following alemtuzumab treatment,” said Johanne Kaplan, Genzyme Vice President for MS research.