Thursday, 11 October 2018

ECTRIMS2018.La La La La, Alemtuzumab neutralizing antibodies are not important

As Greg Winter from Cambridge got the Nobel Prize for his part in the making of antibodies, notably humanizing antibodies, we can celebrate his work on the production of the world's first humanised antibodies (CAMPATH-1H) that was designed to stop anti-antibody responses , which were common when rodent antibodies were used.

Although it achieved its aim somewhat....It is in fact probably one of the Worlds worse antibodies for inducing an anti-drug response.
Did these stop the drug working?
The antibody depletes most T and B cells from the blood, but also it depletes regulatory cells and when the immune system reconstitutes, it is amazing that there is a massive anti-drug response. However this does not seem to matter because the drug is gone by the time it arrives and it generally wanes by 12 months. So these do not interfer with the next round of treatment. In addition to binding antibodies there are neutralizing antibodies that can stop the drug working.

However, the presence of neutralizing antibodies was not mentioned in the European licence, until after we identified them. 

Alemtuzumab depletion failure can occur in multiple sclerosis.
Dubuisson N, Baker D, Kang AS, Pryce G, Marta M, Visser LH, Hofmann WE, Gnanapavan S, Giovannoni G, Schmierer K.
Immunology. 2018;154(2):253-260.

In the MS-CARE I and MS-care II trials binding antibodies occurred in about 60% of people within the first month of infusion and these were boosted by repeat injections. It meant that over 60% of people had an antibody binding response after 23-23months. Of these about 30% of people had neutralizing antibodies at the end of the second treatment cycle. This  may suggest that some people may not deplete properly and so the drug would not work.

We approached the manufacturer for the data over and over again and none was forth coming. 

So to shut me up at ECTRIMS we have

P611 - Minimal impact of anti-alemtuzumab antibodies on the pharmacodynamics and efficacy of alemtuzumab in RRMS patients from the CARE-MS studies
A. Jacobs, L. Chung, Q. Yu, I. Firmino Sanofi, Cambridge, MA, United StatesIntroduction: MS patients (pts) on biologic therapies develop anti-drug antibodies (ADA) that may affect the treatment pharmacodynamic (PD) profile and/or efficacy. Alemtuzumab, a humanized, anti-CD52 monoclonal antibody approved for RRMS pts, is administered as 2 initial courses (12 mg/day; baseline: 5 consecutive days; 12 months later: 3 consecutive days) with up to 2 additional courses (3 consecutive days; ≥12 months apart) as needed for disease control. In the CARE-MS studies (NCT00530348, NCT00548405), 2 courses of alemtuzumab significantly improved clinical/MRI outcomes vs SC IFNB-1a; efficacy was maintained in a 4-year extension (NCT00930553), wherein pts could receive additional courses as needed. 
Aims: To determine the effect of alemtuzumab ADA on PD and efficacy in CARE-MS pts. 
Methods: Alemtuzumab-binding ADA status (ever positive or always negative) was evaluated in pts receiving Course 2 (C2; all pts) and Course 3 (at any time point; median interval from C2, 2.2 years). Other assessments for correlation: lymphocyte counts (total, CD4+ T cells), annualised relapse rates (ARR), and new Gd-enhancing lesions. 
Results: Of 811 pts from the pooled CARE-MS studies, 87.8% were positive for binding ADA at any time point during the 2-year alemtuzumab treatment period; 292 (90.4%) pts who received C3 were ADA positive. Median ADA titres peaked 1 month after C2 and C3, and decreased 100-fold 12 months later (defined treatment interval); titres were higher post-C3 vs post-C2. No discernible difference was detected in total or CD4+ lymphocyte depletion and repopulation patterns or efficacy measures after C2 between pts who were ADA positive or negative. The mean total lymphocyte count nadir was lower post-C2 vs post-C3. The ADA effect was minimal on CD4+ T cell depletion after C3, with limited non-significant changes in pts in the highest titre quartile. ADA had no effect a year after C3 on ARR (ADA negative: 0.19; titre quartiles 1-4: 0.16, 0.15, 0.26, and 0.15) or the percentage of pts free of Gd-enhancing lesions (ADA negative: 89%; titre quartiles 1-4: 87%, 90%, 90%, and 82%). There was no consistent trend for an ADA impact on efficacy through Year 5 post-C3. 
Conclusion: Although the incidence of ADA was high at mid-course determinations with marked reduction prior to each course, it had minimal impact
This study implies there is no consequence of the antibodies from the third infusion.  I say come on guys....we know that already. At the population level Cambridge showed that most people deplete after the third and for that matter the forth cycle. 
Yet again the potential problem is hidden for the individual. Again there is no mention of antibody neutralisation in this poster and they do not show the critical data.  
This is to show what happened to the individual
What was the before (month 24) and after (month 25) level of lymphocytes in relation to their neutralizing response? 
In the those that did not delete, because there will be some individuals, what was their titre (antibody level)? 
In  the phase III trial there was about 5 people with pre-existing antibody neutralization level and one person had a poor depletion and  they had a high titre of antibody. It would be so easy to present this data and this would show if there was no value or some value in determining if the pwMS would respond to treatment based on their neutralizing response. It could be lost in poster land and put me off the scent. 
Is there anything been hidden, maybe not but why show red rag to a bull?

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