Alemtuzumab exposes lots of interesting biology. #MSCOVID19 The macrophage is important for getting rid of SARS-CoV-2

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Yesterday we (MD1&MD2) and others (MS researchers) were accused of being responsible for the downfall of alemtuzumab with the regulators. This is because they (other MS researchers) have drip-fed reported adverse events like these:

Immune-mediated hepatitis induced by therapy with alemtuzumab in a patient with Multiple Sclerosis. Bolte FJ, Schmidt HH, Schlevogt B.Hepatology. 2020 Jun 24. doi: 10.1002/hep.31435.

Acquired hemophilia A and other autoimmune diseases after alemtuzumab therapy for multiple sclerosis: A report of two cases.Comini-Frota ER, Campos APF, Neto APG, Christo PP.Mult Scler Relat Disord. 2020 May 21;44:102181.

I may do a post on haemophilia A, shortly but that’s for another day. But that new usual things continue to occur accounts for the case-reports that are there to provide a warning. This type of vigilence created the monitoring for an autoimmune platelet issue and this has been sucessful as witnessed by the few cases occurring (see below).

However, it suggests that alemtuzumab as used, must block a fundemental mechanism of auto-antibody (antibody that causes autoimmunity) formation. We have suggested it is in part loss of a regulatory balance. But there does not appear to be much interest/effort in investigating and treating this. Although immune check-point inhibitors have been used, we (ProfG) suggested a transient B cell depletion to inhibit the hyper-repopulating immature/naive B cells such that they return after regulatory T cells have recovered from their depletion. However, as regulatory cells continue to be viewed to increase after alemtuzumab there is not much interest and we can’t do studies of this nature if it is not part of a funded trial.

Yesterday ProfG was having his epiphany about how well people treated with alemtuzumab do and perhaps forgot to cite this paper, which reports on the long-term benefit of alemtuzumab. So if we could deal with the side-effect issues alemtuzumab would be see to be less risky.

Long-term efficacy and safety of alemtuzumab in patients with RRMS: 12-year follow-up of CAMMS223.Steingo B, Al Malik Y, Bass AD, Berkovich R, Carraro M, Fernández Ó, Ionete C, Massacesi L, Meuth SG, Mitsikostas DD, Pardo G, Simm RF, Traboulsee A, Choudhry Z, Daizadeh N, Compston DAS; CAMMS223, CAMMS03409, and TOPAZ Investigators.J Neurol. 2020 Jun 24. doi: 10.1007/s00415-020-09983-1

Background: In the phase 2 CAMMS223 trial (NCT00050778), alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over 3 years in treatment-naive patients with relapsing-remitting MS. Here, we assess efficacy and safety of alemtuzumab over 12 years in CAMMS223 patients who enrolled in the CAMMS03409 extension (NCT00930553), with available follow-up through the subsequent TOPAZ extension (NCT02255656).

Methods: In CAMMS223, patients received 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days); 22% received a third course. In the open-label, nonrandomized extensions, patients could receive as-needed additional alemtuzumab or other disease-modifying therapies.

Results: Of 108 alemtuzumab-treated patients in CAMMS223, 60 entered the CAMMS03409 extension; 33% received a total of 2 alemtuzumab courses, and 73% received no more than 3 courses through Year 12. Over 12 years, annualized relapse rate was 0.09, 71% of patients had stable or improved Expanded Disability Status Scale scores, and 69% were free of 6-month confirmed disability worsening. In Year 12, 73% of patients were free of MRI disease activity. Cumulatively throughout the extensions (Years 7-12), 34% of patients had no evidence of disease activity. Adverse event (AE) incidence declined through Year 12. Infusion-associated reactions peaked at first course and declined thereafter. Cumulative thyroid AE incidence was 50%; one immune thrombocytopenia event occurred, and there were no autoimmune nephropathy cases.

Conclusions: Alemtuzumab efficacy was maintained over 12 years in CAMMS223 patients, with 73% receiving no more than three courses. The safety profile in this cohort was consistent with other alemtuzumab clinical trials.

However importantly in the COVID-19 era alemtuzumab suggests that the macrophages are the important cells in getting rid of the virus

Alemtuzumab in multiple sclerosis during the COVID-19 pandemic: A mild uncomplicated infection despite intense immunosuppression.Carandini T, Pietroboni AM, Sacchi L, De Riz MA, Pozzato M, Arighi A, Fumagalli GG, Martinelli Boneschi F, Galimberti D, Scarpini E.Mult Scler. 2020 May 28:1352458520926459. doi: 10.1177/1352458520926459.

A person got COVID-19 within 2 weeks of alemtuzmab, meaning there were essentailly no T cells, no B cells and there was lower levels of neutrophils in the blood and they recovered pretty well. This supports the view we made in: The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.Baker D, Amor S, Kang AS, Schmierer K, Giovannoni G.Mult Scler Relat Disord. 2020 May 12;43:102174

Now I am sure the low dose (36-60mg) means that the lymph glands and bone marrow aren’t cleared with alemtuzumab and so many immune cells remain. Unfortunately antibody-responses were not measured, but I suspect that one could be made as we can see with the anti-drug antibody responses.

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