#IsitOK to publish ten years later..This time its cladribine

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Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis.Comi G, Cook S, Giovannoni G, Rieckmann P, Sørensen PS, Vermersch P, Galazka A, Nolting A, Hicking C, Dangond F. Mult Scler Relat Disord. 2019 Apr;29:168-174.

BACKGROUND: Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19+ B cells and T cells, followed by reconstitution of adaptive immune function.

OBJECTIVE:To characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort).

METHODS:Data from patients randomized to placebo (n = 435) or cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg; n = 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment.

RESULTS:Treatment with cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19+ B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of cladribine tablets in year 2. Median CD4+ T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of cladribine tablets in year 2). Median CD8+ cell counts never dropped below the threshold value.

CONCLUSION:These results show the dynamics of lymphocyte count changes following treatment with cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that cladribine tablets may represent a form of IRT.

If we get our hands on pharma data should we wait until they publish it or should we put it out there? Take the flack for upsetting a potential future author and potentially upsetting the company for giving it a different spin?

Now what if we see something that we think is a safety issue…stay stum, sit back and wait for the company to never properly disclose the data and you suffer the risk unknowkingly? Wait for them to put the data out but and perhaps not mention it or discuss it. #IsitOK to do this?

Now I am happy to say I don’t put this paper in the category of hiding something…it has just been plain slow in arriving.

We published the first bit of this story two years ago and I seem to remember that ProfG was saying it was being published…so we ummed and arghed about withdrawing our manuscript…..We thought publish and be dammed the students had done the work . They got the reward for their investigation and the “snooze you lose” thought sprang into our head.

We were duly chastized by someone for ruining opportunities….our response was “Get a life” as they had not been involved in the original study..the poster would have told us this…but they lived of the coat tails of pharma traveling to this or that meeting to present a poster made for them by pharma..no doubt. Should we feel sorry?

Anyway three years later the paper has surfaced from work done perhaps a decade ago, but in contrast to our tone, this study is largely descriptive, we put in some opinion about what might be happening. It seems like opinion to a scientist is like a bit of garlic or a stake to a vampire. If you haven’t proved your point by “science three ways” (you do the same experiment three ways to get the same result..a bit lhaving a vegatable cooked three different styles to tell you that you are having fine dining.

Anyway it is open access have a read.. You know that cladribine works for most for at least 4 years so you look at the depletion data and see that the depletion of T cells ins minor to modest and stays within normal lits for most of the time and the B cells are back to normal quicker than you can say “repopulation” or is it “reconstituion”. Its all normal so the way it works is “Magic”. Have a read and see what you think.

There is not one mention of memory B cells…maybe because we used the generic version and is too much opinion to suggest that the active ingredient is the same.

CoI This is one of ProfGs papers.

Who owns the data, the people with MS you too risks to do the study or pharma, who use the data when it suits them?

Safety of cladribine tablets in the treatment of patients with multiple sclerosis: An integrated analysis.Cook S, Leist T, Comi G, Montalban X, Giovannoni G, Nolting A, Hicking C, Galazka A, Sylvester E.Mult Scler Relat Disord. 2019 Apr;29:157-167. doi: 10.1016/j.msard.2018.11.021. Epub 2018 Nov 20.

BACKGROUND:

Treating patients with relapsing multiple sclerosis (MS) with cladribine tablets (two times 4 or 5 days of treatment each year for 2 years) results in long-lasting efficacy, with continued stability in many patients for 4 or more years. Safety and tolerability outcomes from individual clinical studies with cladribine tablets have been reported previously.

OBJECTIVE:

Report safety data from an integrated analysis of clinical trials and follow-up in patients with MS to further characterize the safety profile of cladribine tablets.

METHODS:

Data for patients treated with cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) as monotherapy (n = 923) or placebo (n = 641) in Phase III clinical trials (CLARITY, CLARITY Extension and ORACLE-MS) and followed up in the PREMIERE registry were aggregated (Monotherapy Oral cohort). To better characterize rare events, additional data from earlier studies which involved the use of parenteral cladribine in patients with MS, and the ONWARD study, in which patients were given cladribine tablets in addition to interferon (IFN)-β or placebo plus IFN-β were included in an All Exposed cohort (cladribine, n = 1926; placebo, n = 802). Adjusted adverse events incidences per 100 patient-years (Adj-AE per 100 PY) were calculated for the integrated analyses.

RESULTS:

The incidence rate of treatment-emergent adverse events (TEAEs) in the Monotherapy Oral cohort was 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo. TEAEs that occurred more frequently with cladribine tablets were mainly driven by the TEAEs of lymphopenia (Adj-AE per 100 PY 7.94 vs. 1.06 for placebo) and lymphocyte count decreased (Adj-AE per 100 PY 0.78 vs. 0.10 for placebo) as anticipated due to the mode of action of cladribine. An increase in TEAE incidence rate was also observed in the cladribine tablets 3.5 mg/kg group vs. placebo for herpes zoster (Adj-AE per 100 PY 0.83 vs. 0.20, respectively). There were no cases of systemic, serious disseminated herpes zoster attributed to treatment with cladribine tablets. In general there was no increase in the risk of infections including opportunistic infections with cladribine tablets versus placebo, except for herpes zoster. Periods of severe lymphopenia (< 0.5 × 109 cells/L) were associated with an increased frequency of infections, but the nature of these was not different to that observed in the overall patient group treated with cladribine tablets 3.5 mg/kg. Within the constraints of a limited sample size, malignancy rates in the overall clinical program for cladribine in MS did not show evidence of an increase compared to placebo-treated patients and there was no increase in the incidence of malignancies over time in cladribine-treated patients.

CONCLUSION:

The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients from early to more advanced relapsing MS. There was no increased risk for infections in general except for a higher incidence of herpes zoster. Lymphopenia was amongst the most frequently observed TEAEs that occurred at a higher incidence with cladribine relative to placebo. There was also no increase in malignancy rates for cladribine relative to placebo.

AIMS:

Cladribine tablets have shown significant efficacy for the treatment of relapsing multiple sclerosis, a chronic and debilitating immune-mediated disorder. This study was conducted to examine acute and/or cumulative effects of cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dose over 2 years) on heart rate, AV conduction and cardiac repolarization in patients with relapsing-remitting multiple sclerosis(RRMS).

METHODS:

CLARITY was a 96-week, double-blind, placebo controlled, multicentre trial which evaluated the safety and efficacy of cladribine tablets 3.5 and 5.25 mg/kg body weight in patients with RRMS. A total of 135 patients were included in the ECG substudy, providing a total of 1534 post-dose ECGs. ECG data were collected 15 minutes pre-dose and between 0.5 and 3 hours post-dose at pre-study evaluation, study Day 1 and Weeks 5, 9, 13, 48 and 52.

RESULTS:

For cladribine tablets 3.5 mg/kg, the maximum change in placebo-adjusted post-dose QTcF versus visit-baseline (BL) was -0.42 ms (90% CI: -3.61-4.44) at Week 1 (acute effects), and 3.20 ms (90% CI: -0.08-6.33) for cladribine tablets 5.25 mg/kg. The greatest observed differences in post-dose QTcF versus study BL occurred at Week 48 for both the 3.5 and 5.25 mg/kg doses of cladribine tablets with 5.99 ms (90% CI: 0.53-11.44) and 8.74 ms (90% CI: 3.18-14.31), respectively. No significant changes were observed in T-wave morphology in either treatment group.

CONCLUSIONS:

Cladribine tablets 3.5 mg/kg (approved dose in Europe/other regions) did not confer clinically meaningful effects on heart rate, AV conduction and ventricular repolarization.

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MouseDoctor

3 comments

  • Regarding data ownership:

    I have MS.

    There is an argument that if you gave informed consent in order to take part in a trial and you signed away your rights to your data – what real use is a single data point? – then it isn’t yours anymore.

    What possible use could it be to an individual of it was just delivered to them in R, Stata or the like?

    How many services do we use online where we eaaily give away even more data? In return. You give your data in a trial for the possibility of a return in bettered health.

  • Too bad that this study didn’t address the main question lingering in MS Patients minds: what happens after year four following start of therapy and what advice would they expect to hear from their neurologist at that point?

    Does he recommend a further treatment cycle in case of lymphocyte counts returning to normal? Should both sides start considering alternative therapies? Or does everyone live happily therafter because long term observational studies such as this have shown long term desease remission?

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