Extension Alemtuzumab Data Show Stable Effect in MS

San Diego, California — An interim analysis of extension data from phase 3 trials of alemtuzumab (Lemtrada, Genzyme/Sanofi) shows that relapse rates and sustained accumulation of disability remained low after 1 year in patients with multiple sclerosis (MS), and disability levels remained stable or improved.

During the trials, patients received alemtuzumab in 2 annual courses: at the start of the study and then 1 year later. This analysis shows that 80% of patients who participated in the extension did not require retreatment during the third year.

These findings are important because they suggest that the benefits of alemtuzumab observed in the phase 3 studies are maintained, even though most patients did not receive further dosing, said Edward Fox, MD, director of the Multiple Sclerosis Clinic of Central Texas, Round Rock.

In addition, no new safety signals were identified. The safety profile was consistent with the previous trials, but Dr. Fox emphasized that patient education and participation in monitoring for any potential autoimmune disorders will be critical.

Although it's not a cure, these results do introduce the idea of long-term remission for patients with MS, he told Medscape Medical News.

"What I think that 'long-term remission' has meant to oncologists and now to us, is going to be the concept that there are those patients — and we've seen this historically from the open-label experience many years ago and beyond with the phase 2 trial — who have gone many, many, many years without retreatment after an initial dose or 2, or more depending on the trial."

Dr. Fox presented the results here at the American Academy of Neurology (AAN) 65th Annual Meeting.

CARE-MS Trials

Alemtuzumab is a monoclonal antibody that targets CD52, present on T and B cells. It is already approved for the treatment of chronic lymphocytic leukemia (CLL) under a different brand name (Campath, Genzyme). On the strength of the CARE-MS findings, using a lower dosage and frequency in MS, the drug has been submitted to the US Food and Drug Administration (FDA) for review for an MS indication.

In September 2012, Genzyme announced that the FDA had issued a "Refuse to File" letter on its supplemental Biologics License Application, asking for a revision in the presentation of the data so that regulators might "better navigate" the application. In the meantime, the company said it has limited access to the Campath alemtuzumab product in the United States and the European Union to prevent off-label use of it in MS before approval.

Main results of phase 3 trials of alemtuzumab confirmed that treatment was associated with reductions in relapse rates in patients with relapsing-remitting MS, and 1 trial found reduced sustained accumulation of disability (SAD) vs standard treatment with interferon beta-1a (Rebif, Serono Inc).

In the phase 3 Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS II) trial, alemtuzumab significantly reduced relapse rates and SAD when used as a first-line therapy compared with standard therapy with interferon-β1a in 840 patients with relapsing-remitting MS.

Results from CARE-MS I, a phase 3 comparison of alemtuzumab and interferon-β1a in 581 treatment-naive patients, showed a significant reduction in relapse rates at 2 years, but there was no significant effect on SAD with alemtuzumab in this trial.

CARE-MS I and CARE-MS II trials were published online November 1 in The Lancet. They were funded by Genzyme (Sanofi) and Bayer Schering Pharma.

Three-Year Data

At this year's AAN meeting, researchers presented interim results from the first year of the extension study. During the trials, the first course of alemtuzumab was given intravenously on 5 consecutive days, and the second on 3 consecutive days 12 months later. When starting the extension phase of the trial, patients who had received alemtuzumab during the trials but showed disease activity (defined as at least 1 clinical relapse or 2 new or enlarging brain or spinal lesions on imaging) were treated with an additional course of alemtuzumab once daily for 3 days.

Interferon-β1a was given subcutaneously at a dose of 44 μg 3 times per week during the study in the interferon group. Those who took interferon-β1a during the trials and crossed over to receive alemtuzumab during the extension phase received alemtuzumab once daily for 5 days and then once daily for 3 days 1 year later. Use of other disease-modifying therapies was allowed if investigators chose.

In all, more than 90% of patients in the trials agreed to participate in the extension study. From CARE-MS I, 144 of the interferon-treated patients and 349 of the alemtuzumab patients entered the extension; from CARE-MS II, 145 and 392 patients entered, respectively. A total of 1.8% of those previously receiving alemtuzumab and 3.8% previously receiving interferon therapy dropped out during follow-up.

Annualized relapse rates in the first year of the extension phase were similar to those seen with alemtuzumab treatment during the main trials.

Table 1. CARE-MS I and CARE-MS II: Annualized Relapse Rates

Trial	Year 1	Year 2	Year 3
CARE-MS I	0.22	0.13	0.24
CARE-MS II	0.28	0.25	0.25

Through the first year of the extension study, more than half of the patients in each trial who elected to continue were still relapse-free. More than 80% in each group were still free of 6-month SAD.

Table 2. CARE-MS I and CARE-MS II: 3-Year Disease Activity

Endpoint	Year 2 (%)	Year 3 (%)
CARE-MS I
Relapse-free	78	67
SAD-free	92	88
CARE-MS II
Relapse-free	65	55
SAD-free	87	80

Similarly, disability measured by using the Expanded Disability Status Scale (EDSS) was stable or improved during the extension phase in 72.4% of those in CARE-MS I and 70.0% of those in CARE-MS II. Mean EDSS values remained below pretreatment values through year 3, the authors note.

Table 3. CARE-MS I and CARE-MS II: 3-Year Disability

Trial	Worsened (%)	Remained Stable (%)	Improved (%)
CARE-MS I
Years 0 to 2	24	37	39
Years 0 to 3	28	33	40
CARE-MS II
Years 0 to 2	24	30	46
Years 0 to 3	30	25	45

More than 80% of patients treated with alemtuzumab in the studies did not require re-treatment. In CARE-MS I, 62 patients (18%) met re-treatment criteria and in CARE-MS II, that number was 79 patients (20%). Less than 3% of patients received another disease-modifying therapy during the extension year.

Safety Similar

Safety results from the first year of the extension study were reported for patients who received alemtuzumab in the phase 3 pivotal studies, and no new risks were identified, the authors note.

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 main trials. The most common adverse events were infections, including predominantly mild to moderate upper respiratory and urinary tract infections.

Two patients died during the 3 years. One, reported previously, died of sepsis. The other death was presumed accidental and deemed unrelated to study treatment.

The cumulative incidence of autoimmune thyroid disease over 3 years was 29.9%, similar to the incidence seen in the phase 2 studies of this agent. In addition, over 3 years, approximately 1% of patients developed immune thrombocytopenia (ITP) and 0.3% developed nephropathy; all responded to treatment. These cases were detected early through routine monitoring.

Table 4. Autoimmune Events During Year 3

Event	Year 3, n (%)	Cumulative Years 0 to 3, n (%)
Thyroid	180 (19.4)	291 (29.9)
ITP	4 (0.4)	13 (1.3)
Nephropathy	1 (0.1)	3 (0.3)

Patient monitoring for autoimmune disorders is incorporated in all Genzyme-sponsored trials of alemtuzumab, and patient monitoring is likely to be part of any approval for this agent, Dr. Fox speculated. In the phase 2 trials, a case of ITP was fatal because it was unanticipated; had the diagnosis been made earlier, he said, the case might not have been fatal.

"Every single case of ITP since that original one has resulted in a complete resolution of the ITP and noral platelet counts long-term," he said.

"For patient safety, you have to adhere to a risk-management program," he added. "If I had a patient that I did not trust to come back in and do the safety evaluations, this would not be the medicine for them."

The current plan calls for patients to be monitored monthly for 4 years after the last dose of alemtuzumab.

"Enticing" Idea

Asked for comment on these results, Lily Jung-Henson, MD, a neurologist at the Swedish Medical Center, Seattle, Washington, and a CARE-MS II investigators, pointed out this treatment option may be an attractive option for patients.

"This is exciting news because the idea that you can 'cool down' the disease activity and therefore limit disability and relapses is pretty enticing," she told Medscape Medical News. "And at a time when most established MS patients are tired of being reminded that they have a chronic disease that affects them daily to be able to treat the condition and then theoretically not have to think about their condition for several years is also quite attractive."

Genzyme's applications for marketing approval for the treatment of MS are currently being reviewed by the European Medicines Agency and the FDA, a release notes. The company expects action on both applications this year.

Dr. Fox reports receiving consultancy fees, honoraria, travel, and research support from Bayer Healthcare, Novartis, Ono, sanofi-aventis, Biogen Idec, EMD Serono, Genzyme, Opexa Therapeutics, Pfizer, Roche, Teva Neuroscience, and Eli Lilly.

American Academy of Neurology (AAN) 65th Annual Meeting. Abstract S41.001. Presented March 21, 2013.