The beneficial effects of treatment of relapsing-remitting multiple sclerosis (MS) with alemtuzumab (Lemtrada, Genzyme/Sanofi) are maintained as far out as 7 years, with significant reductions in brain atrophy even among those who received no additional treatment after the first two courses, results from the latest extension phase data on the drug suggest.
“It is remarkable and encouraging that patients can receive two doses of alemtuzumab 1 year apart and have sustained benefit for 7 or more years,” said Corey C. Ford, MD, a professor of neurology and director of the Multiple Sclerosis Specialty Center at the University of New Mexico in Albuquerque, in commenting on the study to Medscape Medical News.
“That result is similar to observations after autologous stem cell transplant and obviously of great significance for MS patients.”
The findings, presented here at the Consortium of Multiple Sclerosis Centers (CMSC) 2018 Annual Meeting, reflect the latest updates on patients 7 years after starting in the phase 3, 2-year CARE-MS II trial of alemtuzumab, a humanized anti-CD52 monoclonal antibody.
Treatment with the intravenous drug includes a course of 12 mg per day for 5 consecutive days, followed by a second course of three doses 12 months later.
In the original CARE-MS I trial of 376 treatment-naive patients with relapsing-remitting MS, alemtuzumab was superior to subcutaneous interferon β-1a in various clinical measures, with 78% of patients in the alemtuzumab group relapse-free after 2 years, compared with only 59% of patients with interferon β-1a.
The CARE-MS II trial, which included 435 patients with relapsing-remitting MS who had an inadequate response to prior therapy, also showed significant improvements in clinical and MRI outcomes compared with interferon β-1a treatment over 2 years.
That trial was followed by a 4-year extension in which patients could receive alemtuzumab retreatment or other disease-modifying therapies (DMTs) as needed for relapse. The durability of the original treatments was demonstrated, with approximately half of patients not requiring further treatment following the first two courses of the drug.
The latest findings reflect the first year of the subsequent five-year TOPAZ study, designed to continue to evaluate the efficacy and safety of the alemtuzumab, with patients given the option of receiving alemtuzumab retreatment 12 or more months apart or any other DMT at any time.
As many as 73% of alemtuzumab recipients from the core CARE-MS II baseline remained through year 1 of TOPAZ (representing year 7 in the full study) and 47% received neither alemtuzumab retreatment nor another DMT through year 7.
Of the 336 patients who entered the TOPAZ trial, 67% showed no MRI disease activity at the end of year 7, 90% had no new gadolinium-enhancing lesions on MRI, 67% had no new or enlarging T2 lesions, and 88% had no new T1 hypointense lesions.
The median annual change in brain volume, as measured by the relative change in brain parenchymal fraction (BPF), from baseline, was –0.62 in the alemtuzumab group at the end of the 2-year CARE II-MS trial, compared with –0.81 in the interferon β-1a group (P = .01).
Changes since then remained low, at less than 0.19% annually (–0.10% in year 3, –0.19% in year 4, –0.07% in year 5, –0.10% in year 6, and –0.14% in year 7).
“We saw not even a 1% change from baseline in terms of brain volume loss over 7 years,” said senior author Daniel Pelletier, MD, from the Keck School of Medicine of University of Southern California, Los Angeles, in presenting the results.
“If this isn’t close to normal aging, I don’t know what is.”
In terms of the 40% of patients who did receive one or more additional courses of alemtuzumab but did not receive another DMT, and had at least 12 months of follow-up after the third course, the mean percentage of patients who were free of MRI disease activity increased from 51% before the third course to 63% 12 months after (P = .001). This percentage remained increased, at 69% 24 months after the third course and 61% at 36 months.
Pelletier noted that in addition to brain volume loss, preliminary imaging data from pilot studies suggest further neuroprotective effects with alemtuzumab, including significant increases in retinal nerve fiber layer (RNFL) thickness in patients with or without optic neuritis and maintenance of RNFL thickness in patients without optic neuritis.
In addition, an increase in myelin water fraction in normal white matter and lesions, suggesting remyelination, has also been observed, and patients have shown a stabilization of magnetization transfer ratio, which is a measure of tissue structural integrity in normal-appearing gray and white matter and lesions, Pelletier explained.
“These findings, along with improved clinical outcomes, suggest alemtuzumab may provide a unique treatment approach for relapsing-remitting MS patients, remaining efficacious in the absence of continuous treatment,” Pelletier said.
A separate analysis of the findings of the CARE-MS II trial through year 7 (year 1 of TOPAZ) further showed an annualized relapse rate of just 0.14, and 51% of patients were relapse-free from year 3 to year 7.
As many as 73% of core patients had Expanded Disability Status Scale (EDSS) scores that were improved or stable at year 7 compared with baseline, with 22% improved and 51% stable, with a mean change in EDSS score from baseline of 0.17.
Nearly 70% of patients at year 7 were free of 6-month confirmed disability worsening, while 44% had 6-month confirmed disability improvement.
In 60% of patients, there was no evidence of disease activity in year 7 and as many as 88% did not receive another DMT following their initial two courses.
Ford, in further commenting on the research, noted that an important caveat is the risk for secondary autoimmune dysfunction affecting the thyroid, platelets, and kidneys.
The study did show an incidence of thyroid-related adverse events reaching the highest point in year 3 (17%); however, the incidence subsequently declined.
As recently reported by Medscape Medical News, new reports of potentially life-threatening adverse events associated with alemtuzumab, published in March, include eight cases of acute acalculous cholecystitis, two cases of hemophagocytic lymphohistiocytosis, and one occurrence of acute coronary syndrome.
An accompanying editorial, published at that time along with the three papers in Neurology, noted that other rare adverse reactions have also emerged in postmarketing reports on the drug.
Ford commented that such potential adverse events need to be taken seriously and weighed carefully against the potential benefits for individual patients.
“More efficacious disease-modifying therapies often have more serious potential toxicities or adverse events,” he said.
“That is always a concern in a disease much more likely to cause disability rather than shorten life. For that reason, a patient’s risk tolerance must be balanced against disease severity and their prognosis for disability.
“There are effective drugs with risk benefit profiles that virtually preclude their use, for example mitoxantrone. For a lifelong disease like MS, the right DMT is ideally both effective and safe.”
The study received support from Sanofi and Bayer HealthCare Pharmaceuticals. Pelletier’s disclosures include relationships with Biogen, Merck Serono, Novartis, Roche, and Sanofi (consulting and/or speaking fees, grant/research support). Corey Ford has received research funding from Genentech/Roche and Genzyme/Sanofi Aventis but has not done any recent consulting work with either and is not on any speaker’s bureaus.
Consortium of Multiple Sclerosis Centers (CMSC) 2018 Annual Meeting. Abstracts DX65 and DX07. Presented June 1, 2018.
