Yesterday some asked about the third cycle of alemtuzumab and if they had break through.
If you live in England you may want to view this document
It says
In May 2014 NICE published the Technology Appraisal (TA312): Alemtuzumab
for treating relapsing-remitting multiple sclerosis and recommended that
alemtuzumab is a treatment option, within its marketing authorisation (MA), for
that indication.
The MA for alemtuzumab at the time recommended a dosage of 12 mg/day
administered by intravenous infusion for two treatment courses. The initial
treatment course lasts five consecutive days, followed 12 months later by the
second treatment course of three consecutive days.
However, the MA also stipulated that in an open-label follow-up of alemtuzumab
clinical trials, some patients received additional “as needed” treatment with
alemtuzumab upon documented evidence of resumed multiple sclerosis (MS)
disease activity. The additional course(s) were administered at 12 mg/day for
three consecutive days (36 mg total dose) at least 12 months after the prior
treatment course. (Based on Cambridge data the to doses controlled disease in about 50% of people but three doses controlled disease in about 85% of people..so seems to have merit as an option)
If additional treatment courses are to be given they must be
administered at least 12 months after the prior course. (Wonder why? Could have something to do with the neutralizing antibodies that the company have recently reported to occur with high frequency)
In December 2017, the European Medicines Agency approved a revision in the
licence which includes the following statement:
Up to two additional treatment courses, as needed, may be considered:
Third or fourth course: 12 mg/day on three consecutive days (36 mg total
dose) administered at least 12 months after the prior treatment course in
patients with MS disease activity defined by clinical or imaging features.
NHS England has started to receive requests for a third cycle of alemtuzumab. Evidence to support this along with additional information from NICE within the
published TA presented below would suggest this is a cost effective use of this
medicine and may be cost saving against other options.
Clinical commissioning position
Based on a limited scoping of the evidence, NHS England has concluded that
there is sufficient evidence to support for the routine commissioning of this
treatment for the indications and clinical criteria listed.
Initial treatment of two courses:
- First treatment course: 12 mg/day on 5 consecutive days (60 mg total dose)
- Second treatment course: 12 mg/day on 3 consecutive days (36 mg total dose) administered 12 months after the first treatment course. Up to one additional treatment course, as needed, may be considered:
- Third course: 12 mg/day on 3 consecutive days (36 mg total dose) administered at least 12 months after the prior treatment course in patients with MS disease activity defined by clinical or imaging features.
NHS England will reimburse activity undertaken within the terms of this policy
statement, as follows:
Delivery of alemtuzumab will be at providers who are currently
commissioned specialised neurology centres and also within those
providers where outreach clinics for MS Disease Modifying Therapies
prescribing are held.
All patients will need to be registered on NHS England’s web based
registration system for the third cycle. This must be done using the same
reporting system as applies to all disease modifying therapies for multiple
sclerosis.
The policy statement is effective from 17 August 2018
So you are eligible to get the third course of alemtuzumab if it is needed, if delivered by specialised neurology centre. They have the infrastructure for the monitoring that is required which entails monthly blood tests for 4 years after the last dose
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Although humanization of CAMPATH-1H was designed to reduce the occurrence of anti-drug antibodies, alemtuzumab is one of the worst in class and most people make binding and neutralizing responses. These typically take a year to disappear and the 3 day course is probably designed with the view that there are less lymphocytes to deplete and that the antibody can be administered before a significant anti-drug response generates. That by the end of month 24, that over 70% of people have binding antibodies and over 30% have neutralizing antibodies is the reason for the original dosing schedule developed by Cambridge and the Manufacturers.
Based on the two doses. For people who have high titre neutralizing antibodies, there are some people who won't deplete or won't deplete very well. So if people have three doses there will be more people who don't deplete or don't deplete well as only 0.6% had neutralizing pre-second dose and 31% had neutralizing antibodies pre-second dose. The manufacturer has now published the data that we reported over a year ago.
We have asked for the data on the titre (level of antibody) before and one month after the third alemtuzumab infusion coupled with their lymphocyte number before and after infusion. We have asked until we are blue in the face and over and over and nothing has been forthcoming. This suggests that something is being hidden
The data could show if you have titre above a certain level that you may not deplete and therefore the value of the third infusion would be limited. This looses a sale for the manufacturer but would save money for NHS England and may help mitigate the risks of infusion reactions to the person being treated.
However instead they fudge the data and show the anti-drug antibody (ADA) responses at the population level, most people deplete on the third cycle.
A. Jacobs, L. Chung, Q. Yu, I. Firmino ECTRIMS
P611 - Minimal impact of
anti-alemtuzumab antibodies on the pharmacodynamics and efficacy of
alemtuzumab in RRMS patients from the CARE-MS studies
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.
Conclusion: Although the incidence of ADA was high at mid-course determinations with marked reduction prior to each course, it had minimal impact on long-term alemtuzumab PD/efficacy in CARE-MS pts. Peak ADA titres dropped precipitously by 12 months, the required treatment interval post-alemtuzumab.
However, we know people deplete on the third cycle from the phase II extension data. Furthermore we know that ater the third cycle that antibody response is boosted, we showed this in an individual.
Dubuisson N, Baker D, Kang AS, Pryce G, Marta M, Visser LH, Hofmann WE, Gnanapavan S, Giovannoni G, Schmierer K.
Immunology. 2018; 154:253-260
The question is not how good it was the majority of people, but how bad was it for a few individuals, where it didn't work. They need to be switched to something that does work. In the 2 year trial we could see that at least 1/5 people with pre-existing antibodies (Dubuisson et al. 2018) did not deplete well, so as the frequency of neutralizing antibodies is 60 times worse for the third cycle (0.6% verses 31.2%) so will there be 60 sixty more drug failures. (as there are 60 time more people with pre-existing neutralising antibodies).
The manufacturers have a test for these antibodies and have the data from the trial it would take a few minutes to deal with this.
A quick test could determine whether the next course is worth it.
However, the manufactures don't seem to want to acknowledge this possibility and so like a ferret locking its jaws we should see if anything is being hidden. If is was reported properly and then the result would probably have been ignored as a small problem.
Show me the data and I'll shut up.