More evidence for the value of Generic Cladribine

In 2011 Merck decided to terminate development of oral cladribine (movectro €20,000/year) and we thought that it may be an opportunity to develop generic cladribine (€1000. Which delivers twice as much cladribine to oral cladribine) and as you may know we posted on this quite a few times and kept interest in the drug alive. Maybe so much so that Merck revived their interest in oral cladribine and they are at the regulators as i write.

Therefore ECTRIMS 2016 was awash with oral cladribine posters that were regurgitated from the original studies reported 4-6 years ago, with a bit of follow up.

Oral cladribine was licenced for use in MS in Australia in 2010 before it was withdrawn in 2011. What was their experience?

Kalincik et al. Australian cladribine experience
Background: In 2011, 144 patients with multiple sclerosis (MS)
were treated with cladribine through the Australian patient familiarisation program (PFP).
Objective: To characterise the Australian MSBase cladribine
Methods: Longitudinal data from 90 patients who received oral
cladribine (1mg per kg, initial treatment consisting of 2 courses
completed in 2 weeks) were captured in MSBase, including 66 patients with disability information before and after cladribine.
Descriptive evaluation of the demographic and clinical information
was carried out.
Results: Characteristics of the MSBase cladribine PFP cohort:
72% female, mean age 47 years (SD 12), mean MS duration 13
years (SD 9), 77% relapsing-remitting, 20% secondary progressive
and 3% active primary progressive MS, median baseline EDSS 5 (quartiles 3-6), EDSS trajectory +0.3 step per year (quartiles 0.2-0.6) and annualised relapse rate 1 (quartiles 0.5-1.9). In 62 (69%) patients exposure to another disease modifying therapy (DMT) was recorded after cladribine, including 16 patients treated within a year of commencing cladribine. Most commonly, these included fingolimod (42%), dimethyl fumarate (23%) and natalizumab (15%). Seventeen patients experienced relapses prior to starting the subsequent DMT. Mean on-cladribine relapse rate reached 0.6-0.75 per year (quartiles 0-1). Median time to the first post-cladribine relapse was 3.3 years. The proportions of patients reaching 6-month confirmed EDSS progression were 12% and 20% at years 1 and 2, respectively. EDSS trajectory post-cladribine was increasing at +0.1 stepper year (quartiles 0-0.2). In contrast to the pre-cladribine EDSS trajectory, the post-cladribine trajetory stabilised for approximately 18 months, after which the EDSS has resumed its ascending trajectory. Nineteen adverse events (of which 6 were reported as unrelated to cladribine) were recorded in 15 patients (17%). These included moderate cephalalgia that was likely retated to cladribine, and severe gastrointestinal symptoms and moderate arterial hypertension in which the relationship to cladribine was not suggested. During the treatment with the subsequent DMTs, 12 adverse eventsin 10 (11%) patients were recorded. It should be noted that the records of adverse events in MSBase are likely to be incomplete.
Conclusion: The Australian cladrbine PFP suggested temporary
amelioration of disability accrual in a cohort that was enriched for
patients with progressive MS forms.

In the trials people were given 3.5mg/kg or 5mg/kg which was repeated 1 year later to give a relapse rate of about 0.15, so in this cohort apparently getting 1mg/kg once there was perhaps no induction, but inhibition of relapse for 3 years which is not bad compared to having to take drugs daily/weekly/monthly etc.

So a bit more data indicating that a short course of generic cladribine could be useful and worth study and this was the case and we have been examining this.

Alvarez-Gonzalez et al. Treating multiple sclerosis with generic cladribine……British Experience.

Background: Trial evidence suggests Cladribine, a purine analogue licensed for treatment of people with hairy cell leukaemia, is also an effective, safe and convenient disease modifying therapy (DMT) for people with multiple sclerosis (pwMS)1-4. Cladribine appears to exert its effect through selective long-term suppression of lymphocytes and reduction of pro-inflammatory cytokines and chemokines whilst leaving other cell types relativelyunaffected.

Objective: To report our clinical experience with Cladribine in
pwMS using a dosing scheme that adapts to individual lymphocyte

Methods: Cladribine was offered to pwMS with clinical and/or
MRI disease activity, but restricted choice of DMT. Treatment
consisted of 1-2 annual cycles of subcutaneous Cladribine (Litak).
During each cycle 10mg Cladribine was given for up to 7 days in
5 weeks. The number of injections was adjusted to individual lymphocyte count to avoid levels below 0.5×10*9/L. One way
ANOVA was used to analyse differences in white cell counts. We
report results after a mean follow-up of 4 months.

Results: Eighteen pwMS (10 women and 8 men) had a first treatment cycle of Cladribine. Mean age was 44 (34-60) years, median EDSS was 5 (2-8). No acute side effects or serious treatment related adverse event were observed, and neither any clinical disease activity within the follow-up period. Lymphocyte counts dropped from a mean of 1.81 (range: 0.9-3.4 x10*9) at baseline to 1.41 (0.7-3) at 4 weeks, and to 1.02 (0.6-1.6) at 8 weeks, p=0.02. Other white cells remained within normal range.

Conclusion: Cladribine was well tolerated and led to a controlled
decrease in lymphocyte counts leaving other cell lines largely
unaffected. So far no new disease activity has been detected.
Follow-up continues.

1 Stelmasiak, et al. Mult Scler J 2009;15:767-70
2 Giovannoni, et al. New Engl J Med 2010;362:416-26.
3 Giovannoni, et al. Lancet Neurol 2011;10:329-37.
4 Rice, et al. Neurology 2000;54:1145-55.

and more…

P1146: Rejdak et al. Induction therapy of relapsing secondary multiple sclerosis using generic cladribine…..Polish Experience.

Background: Evidence suggests Cladribine is an effective, safe

and convenient disease modifying induction therapy for people
with multiple sclerosis.
Objective: To report our experience using subcutaneous

Cladribine as a treatment for people with relapsing secondary progressive MS (SPMS).

Methods: Study was performed at the Department of Neurology,

Medical University of Lublin and received local ethics approval.
Cladribine (Biodribine) was offered to 45 patients with SPMS (30
women and 15 men; aged 42 years [25-56]; EDSS = 6 [2-7], disease duration= 10 years [5-15]; median, range). Cladribine was given subcutaneously at a dose of 0.07 mg/kg/day for 4-6 days.
Treatment courses were given every 5 weeks for a total of five
courses (total dose: 1.4 – 2.1 mg/kg). Blood samples were collected
before treatment initiation, before each subsequent treatment
course, and three months after the last dose. Patients were
followed-up for initial 28 weeks of treatment course, and there
was extended follow up of up to 5 years to record relapses, disability progression and adverse events.

Results: All patients completed the follow-up period. Cladribine

induced a gradual decline in the total lymphocyte count from
1.8±0.5 (x10*9/L; mean±SD) at baseline to 1.5±0.5 after the 1st,
1.3±0.5 after the 2nd; 1.0±0.4 after the 3rd; 1.0±0.4 after the 4th, and 0.9±0.3 after the 5th doses, respectively. Lymphocyte count then remained stable for 3 months after follow up (0.9±0.4). The total white cell count was also reduced however remained within the normal range throughout the observation period (6.4±1.6 x10*9/L at baseline, and 5.5±2.7 at last follow up). Other blood counts remained unaffected. In seven cases mild infections occurred during the follow-up period. No serious adverse events, relapses or disability progression were observed.
Conclusion: Cladribine induction therapy was safe and well tolerated in people with SPMS followed up for 28 weeks. Extended follow-up is underway to collect further data on safety and efficacy.

CoI: We are authors of some of the work.

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1 comment

  • Does the Aussie study suggest that cladribine be dosed for more than the currently favored 2 courses one year apart – maybe dose a course every year with safety monitoring?

    The Lublin study had different dosing than the Barts protocol. Any thoughts on that? The 5 year follow up data will be interesting.

    A good thing to note is that cladribine is easy to tolerate (personal experience) compared to the side effects from lemtrada, tecfidera and gilenya.

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