There is no evidence to support the idea that previous autoimmunity before or after alemtuzumab treatment predicts subsequent rare but serious and possibly life-threatening autoimmune events that have recently been linked to the drug, a new study has shown.
These latest data were reported by Alasdair J. Coles, MD, University of Cambridge, England, at the recent 8th Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
Coles, who led the initial research to develop alemtuzumab in partnership with Genzyme, explained that autoimmune disease is a well-described and common adverse event with the drug, manifesting mainly as autoimmune thyroid events that can occur in up to 40% of patients.
But as post-marketing experience has grown, it has become clear that there is a low frequency of more serious autoimmune disease, he noted. In an effort to understand these better, regulators have suggested that the presence of non-MS autoimmune disease before alemtuzumab treatment and the emergence of autoimmune disease after alemtuzumab treatment may define a group that is at higher risk of one of the rare but serious autoimmune events for those on the drug.
To investigate if this was the case, Coles and colleagues analyzed data on 1216 patients who received alemtuzumab in the clinical development program. Of these, 96 had pre-existing non-MS autoimmunity.
Results showed that up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) vs without (35.3%) pre-existing autoimmunity.
Similar percentages of patients with vs without pre-existing autoimmunity had ≥ 2 new autoimmune events (5.2% vs 8.2%, respectively). And most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab.
In addition, treatment-emergent thyroid autoimmunity after alemtuzumab course 1 was not associated with subsequent non-thyroid autoimmunity after course 2. Similarly, thyroid autoimmunity after course 2 did not predict non-thyroid autoimmunity after course 3.
In another analysis of the incidence of serious autoimmune events from post-marketing data on 25,292 patients treated with alemtuzumab, immune thrombocytopenic purpura was reported in 43 patients, the newly identified autoimmune hepatitis in 11 patients, and hemophagocytic lymphohistiocytosis in nine patients.
There was “no hint at all” that baseline thyroid disorders or post-alemtuzumab thyroid disorders is associated with increased risk of these serious autoimmune adverse events, Coles said.
He calculated that the incidence of serious autoimmune diseases that could be life-threatening after alemtuzumab treatment was 10.7 per 10,000 patients treated for autoimmune hepatitis and 2.7 per 10,000 patients treated for hemophagocytic lymphohistiocytosis.
“From two separate data sources — phase 2/3 trials populations combined and post marketing data — there is no evidence to support the hypothesis that pre-existing non-MS autoimmunity predisposes to the serious but rare autoimmune events that have newly been described; nor does thyroid auto-immunity following the use of alemtuzumab,” Coles stated.
“In my opinion it is not appropriate to preclude the use of alemtuzumab to patients who have had previous autoimmune disease before treatment or who develop thyroid autoimmunity after alemtuzumab,” he said.
“It remains in my view a reasonable treatment option for patients with active MS to receive this highly effective therapy in the face of well-managed, well understood thyroid autoimmunity and the very unlikely rare but serous autoimmune disease,” he concluded.
Commenting on the presentation for Medscape Medical News, Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis, Cleveland Clinic, Ohio, explained that whenever there is a serious risk of a complication, clinicians like to try to stratify that risk.
“We like to identify those at higher risk (and perhaps not use the therapy) and those at lower risk (and perhaps consider more likely the use of that therapy),” he said.
With regard to alemtuzumab, Fox noted: “We’d like to stratify the risk of autoimmune complications, which could help guide us regarding the patients in whom therapy may be safer. Unfortunately, these findings did not point to a risk stratification to help guide its use towards lower-risk patients.
“I view this as an unfortunate result, because it leaves me without a way to stratify the risks of alemtuzumab, which are quite significant and currently limit my use of that MS therapy only to those with no other treatment options,” he added.
On Cole’s view of alemtuzumab as a “reasonable” treatment option, Fox commented: “I guess it depends upon how that’s interpreted. Given the risks of serious, life-threatening immune and infectious complications, I only consider alemtuzumab when all other immune-modulating therapies have been tried or are not a reasonable treatment option. So, yes, I see it as ‘reasonable,’ but only when there are no other available treatment options.”
The current work was supported by Sanofi and Bayer HealthCare Pharmaceuticals. Coles reported sitting on advisory boards for Genzyme (Sanofi). He is credited as an inventor on several patents related to the technology on which alemtuzumab is based. Fox has disclosed no relevant financial relationships.
8th Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020: Session FC02.01. Presented September 13, 2020.