#ResearchSpeak & #BrainHealth: cladribine and end-organ damage

Cladribine reduces end-organ damage in people with relapsing MS. #ResearchSpeak #BrainHealth

There are very few original ideas in the world. End-organ damage is one concept that I heard for the first time in both nephrology and cardiology. Nephrologists use it to describe the cumulative damage sustained by the kidney in people with diabetes and cardiologists in relation to the effects of hypertension on the heart. We in MSology, use the term to describe the cumulative damage to brain and spinal cord as a result of MS. The best biomarker that integrates this damage over  time is brain volume loss, or brain atrophy. We now know that the timing of atrophy is temporally out of sync with inflammatory damage, by at least 12 months and probably 24 months. In other words brain atrophy today has been primed by inflammation at least 12 months ago. So if you switch off inflammation with an effective treatment you won't really see a major change in the rate of brain atrophy until year 2 and 3. What is clear is that brain atrophy is strongly linked to the acquisition of disability and cognitive impairment and is also and indicator of loss of reserve. The large your brain the more reserve you have the better you will age. Please remember that life is a sexually-transmitted age-related neurodegenerative disease. In other words if you live long enough you will develop age-related cognitive impairment and what protects you from this is brain reserve (size) and cognitive reserve (education), which is why I am so keen on everyone living a brain healthy life. 

The study below show that oral cladribine has an impact on accelerated brain atrophy in pwMS. The fact that it has an impact on brain atrophy within a 2-year period of the trial puts it in the high-efficacy bracket of DMTs. The question that remains unanswered is does its impact on brain atrophy improve with time, particularly in year 3 and 4? Cladribine is one of the agents that enters the central nervous system and hence is likely to impact on lymphocytes within the target organ and hence may have delayed benefits that won't be seen in the initial 24 month window. Cladribine has many other attributes that will make it a very welcomed disruptor in the DMT market: 

  1.  It's a PIRT (pulsed immune reconstitution therapy) that is given as short course; you only require 10 days of treatment in year 1 and year 2.
  2. It does not have a major impact on the innate immunity, i.e. the cells that fight common infections such as Listeria, therefore the upfront risks of infection are low.
  3. It depletes lymphocytes slowly therefore there is no cell lysis syndrome that you get with the other depleting monoclonals. In practice patients don't experience any untoward symptoms from the gradual cell death that occurs.
  4. Cladribine does not deplete your CD4 and CD8 cells to zero, but by 6-80%. These surviving cells are immune competent therefore opportunistic infections should be less of a problem.
  5. Once your immune system has reconstituted post-cladribine you will be able to travel to exotic places and be exposed to novel and new infection with the knowledge your immune system should cope.
  6. Similarly, your immune system should cope well with vaccinations. I suspect the label will state that live vaccines are contraindicated, but this will be a relative contraindication. 
  7. Immune reconstitution post-cladribine is not associated with secondary autoimmunity. This fact alone will make it a very appealing alternative choice for people considering alemtuzumab. I sincerely hope, the European Medicine Agency consider this when assessing the drug and give a liberal license to allow us to offer it first line alongside alemtuzumab. 
  8. Apart from having a full blood count before your next dose of cladribine there is really no need for blood monitoring. The low burden of monitoring will make cladribine a very popular drug in over-worked MS clinics that have become pharmacovigilance units. Please note we are proposing  that redoing of oral cladribine only happens if your lymphocyte count is above 800. This is to prevent any prolonged grade 3 & 4 lymphopaenia. This alone will help derisk cladribine. 
  9. Cladribine is out of your system within in days to weeks, which will make it appealing for women with MS who are contemplating starting or extending their families. 
Against cladribine is that the relative efficacy of the drug puts it in the same ball-park as that of fingolimod and daclizumab and not natalizumab, alemtuzumab or ocrelizumab. Similarly, its brain atrophy data is not as good as the very high-efficacy drugs. Another issue is the cancer risk. The good news is that the short to intermediate term risk of cancer from cladribine looks not to be a problem. The initial risk was due to an abnormally low rate of cancers in the placebo arm of the CLARITY phase 3 trial. In the ORACLE CIS study there was no cancer signal. At present we can't comment on the long-term cancer risk as we don't have enough data. However, as cladribine is an immunosuppressive therapy it is likely to be associated with a modest increased long-term cancer risk. Please note the predicted secondary cancer risk with cladribine is a class-effect of 'immunosuppressive therapies' and occurs with all immunosuppressive treatments. The only way to define this risk is with post-marketing surveillance programmes. 

Because of cladribine's ease of use, low monitoring requirements and CNS penetration we think it is the ideal drug at the base of the pyramid to test in more advanced MS. We are pushing hard to get such a trial off the ground. Dr K will be the PI on this trial and we are keen for you to help us lobby to get this study funded. 

Finally, as cladribine is available as a generic drug for treating cancer it can be used off-label and hence has the potential to be used in resource-poor settings. This is why subcutaneous cladribine is on our Barts-MS Essential Off-Label list of drugs

De Stefano et al. Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets. Mult Scler. 2017 Jan 1:1352458517690269.

BACKGROUND: Neuroimaging studies have used magnetic resonance imaging-derived methods to assess brain volume loss in multiple sclerosis (MS) as a reliable measure of diffuse tissue damage.

METHODS: In the CLARITY study ( ClinicalTrials.gov NCT00213135), the effect of 2 years' treatment with cladribine tablets on annualized percentage brain volume change (PBVC/y) was evaluated in patients with relapsing MS (RMS).

RESULTS: Compared with placebo (-0.70% ± 0.79), PBVC/y was reduced in patients treated with cladribine tablets 3.5 mg/kg (-0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (-0.57% ± 0.72, p = 0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI = 0.571, 0.787; p < 0.001), with patients with lower PBVC/y showing the highest probability of remaining free from disability progression at 2 years and vice versa.

CONCLUSIONS: Cladribine tablets given annually for 2 years in short-duration courses in patients with RMS in the CLARITY study significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates.

CoI: multiple, I am a co-author on this paper and the PI of the CLARITY trial.

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