Back in 2009, the launch of the first oral therapy for relapsing-remitting multiple sclerosis was much anticipated. Cladribine, initially studied in MS as a parenteral drug in 1994 (Sipe et al. Lancet 1994;244:9-13), had been reformulated as an oral therapy and had completed phase III testing. The new drug, Movectro, earned a fast-track review by the FDA in 2006, and received early approval for use in Russia and Australia.

But then the European Medicines Agency (EMA) and the Food and Drug Administration raised concerns. The EMA’s key issue was a higher number of cancer cases in the cladribine arms compared to placebo in its phase III CLARITY trial. The FDA said it wanted additional analyses or new studies before proceeding with the new drug application (NDA).

Obtaining additional information would take years, so the manufacturer, Merck Serono, withdrew its applications in 2011. But the company took the unusual steps of continuing its phase II (ONWARD) and III (CLARITY, ORACLE-MS) studies, and maintaining the long-term safety registry (PREMIERE) it had set up in November 2009.

The decision to continue collecting information has led to a better understanding of drug safety, new filings with health regulators that uniquely include long-term data, and a new name (Mavenclad). In June 2017, Mavenclad received a positive nod from the Committee for Medicinal Products for Human Use (CHMP), and forwarded its recommendation for approval to the EMA. A decision is expected in September. Cladribine tablets is currently in review with Health Canada, and is expected to become available for the treatment of RRMS in the next few months.

Addressing safety concerns

The chief safety concern of regulators in 2009 was the risk of malignancies in the CLARITY trial (Giovannoni et al. N Engl J Med 2010;362:416-426; free pdf at www.nejm.org/doi/pdf/10.1056/NEJMoa0902533). The study randomized 1326 patients to one of two doses of oral cladribine (3.5 or 5.25 mg/kg cumulative dose over two years) or placebo. There were 10 neoplasms in the cladribine groups (incidence 1.1%) versus 0 in the placebo group. The neoplasms reported were five cases of benign uterine leiomyoma, three cases of cancer (melanoma, pancreatic carcinoma, ovarian carcinoma), one precancerous neoplasm (stage 0 cervical in situ carcinoma), and one case of myelodysplastic syndrome (believed to be bone marrow changes resulting from tuberculosis rather than MDS). One case of choriocarcinoma was subsequently diagnosed nine months after study completion.

What was anomalous was the absence of neoplasms reported in the placebo arm of the study. As a comparison, in the ORACLE-MS trial of clinically isolated syndrome, the incidence of neoplasms was 0.98% with oral cladribine (four cases) versus 2.91% in the placebo group (six cases) (Leist et al. Lancet Neurol 2014;13:257-267). Indeed, the ORACLE-MS results were remarkably similar to the neoplasm rates reported in the FREEDOMS trial of fingolimod (fingolimod 0.9%; placebo 2.4%) (Kappos et al. N Engl J Med 2010;362:387-401).

This issue was examined further in a meta-analysis of 11 phase III studies of DMTs (Pakpoor et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158; free pdf at www.ncbi.nlm.nih.gov/pmc/articles/PMC4592538/pdf/NEURIMMINFL2015005454.pdf). The overall cancer rate in placebo-controlled trials was 0.6% for the DMT arms, which was not significantly different from the 0.34% cancer rate reported with cladribine in CLARITY and 0.49% with cladribine in ORACLE-MS. What differed was the cancer rate in the placebo arms: 1.1% overall for DMT studies compared to 0% in the CLARITY trial. The authors of the analysis concluded that the data cannot confirm that an excess malignancy risk exists with cladribine; a more definitive assessment can only come from long-term follow-up.

Additional safety information from the PREMIERE registry was presented at this year’s annual meeting of the American Academy of Neurology (Cook et al. AAN 2017; abstract P5.394). To date, the registry has collected data for 923 patients who have received oral cladribine 3.5 mg/kg (3433 patient-years). The incidence of neoplasms was 1.14 per 100 patient-years with cladribine 3.5 mg/kg compared to 1.01/100 PY for placebo. There were no hematologic malignancies, and no safety signal for a specific type of solid tumour.

These findings suggest that cladribine tablets has an acceptable safety profile, which regulators are currently evaluating.