ECTRIMS 2016: Neurologists appear impressed by cladribine, but will regulators and the market feel the same?
By Inês Guerra, Analyst
21 September 2016
I joined Datamonitor Healthcare as an analyst in early 2015, having completed a Master’s degree in Pharmaceutical Scie...
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With the EMA’s review of the latest MAA for cladribine ongoing, Merck KGaA is using ECTRIMS 2016 as the stage for numerous new presentations on the drug’s efficacy and safety. Neurologists appear to see the benefits of this additional induction therapy; however, regulators and the market could prove more difficult to persuade.
The ongoing 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2016) is bearing witness to the reappearance of Merck KGaA’s cladribine, with an ample number of presentations covering the drug’s safety and efficacy. Most presentations include analyses of data from already-known trials, namely the Phase III CLARITY, CLARITY Extension, and ORACLE-MS studies, as well as the Phase II ONWARD study (ClinicalTrials.gov identifiers: NCT00213135, NCT00641537, NCT00725985, NCT00436826, respectively). In addition, there is an integrated safety analysis from cladribine’s multiple sclerosis (MS) development program, which notably includes data from the ongoing PREMIERE registry and appears supportive of the drug’s risk-benefit profile, especially with regards to the risk of neoplasms (ClinicalTrials.gov identifier: NCT01013350). As cladribine’s potential risk of malignancy was one of the chief reasons behind the European Medicines Agency’s (EMA’s) previous refusal to approve, the positive data presented at ECTRIMS 2016 are certainly promising. Despite this, the lack of direct head-to-head trials involving cladribine versus other MS drugs has hindered its development in the past, and could continue to do so. Finally, Datamonitor Healthcare believes that, even if approved, cladribine would struggle to find a place in MS treatment practices, which have advanced considerably since the drug first underwent regulatory scrutiny.
Cladribine: an oral induction therapy that can penetrate the central nervous system
Cladribine is a small molecule that suppresses the immune system by selectively targeting lymphocytes, which are cells that seem to be major players in MS pathological mechanisms. This purine nucleoside analog is in fact a prodrug; after being phosphorylated into its active form, cladribine incorporates into cellular DNA. This consequently inhibits protein production and DNA synthesis and repair, ultimately resulting in cell apoptosis. Cladribine’s selectivity is an important feature: by selectively targeting lymphocytes, the key cell types required for the innate immune function are maintained (Comi et al., 2013; Merck KGaA, 2016). Cladribine’s ability to cross the blood–brain barrier has also been mentioned at ECTRIMS 2016. Being one of the few disease-modifying therapies (DMTs) that can penetrate the central nervous system, cladribine could potentially achieve more than just modulating patients’ systemic inflammatory response.
Cladribine’s past – and perhaps present – regulatory hurdles
Cladribine’s development history is very complex, having been twice rejected by the EMA’s Committee for Medicinal Products for Human Use (CHMP), and the issues raised by regulators will continue to cast doubt over its continued development. Several factors have contributed to negative opinion on the drug: while the CHMP agreed that efficacy was demonstrated to a certain extent, the lack of an active comparator – like a first-line MS drug – was deemed an issue. More importantly, however, was the concern over the number of malignancies seen in the cladribine-treated group, raising doubts about the drug’s long-term safety. The CHMP considered at the time that there was no explanation for these increased numbers, and that additional studies were required to clarify this concern (EMA, 2010).
New analyses of cladribine’s earlier data display notable efficacy in relapsing MS, but active comparators are still lacking
Numerous ECTRIMS presentations have reinforced cladribine’s effects on a variety of endpoints, some of them using data from a single trial (ECTRIMS posters P497 and P636), others using pooled data from several studies (ECTRIMS posters P642 and P643). Some presentations have touched upon cladribine’s benefits on brain-volume loss (ECTRIMS poster P497), others on its positive effects on magnetic resonance imaging outcomes (ECTRIMS poster P642) or on its reductions in relapse rates and disability progression (ECTRIMS poster P633). One notable presentation focused on cladribine’s effect on the increasingly popular and clinically relevant goal of no evidence of disease activity (NEDA) (ECTRIMS poster P641).
The P641 poster included pooled data from the CLARITY and ONWARD studies, and compared the effect of cladribine (3.5mg/kg and 5.25mg/kg) to placebo in the proportion of patients that reached NEDA. In this presentation, the investigators defined NEDA as having no qualifying relapses, no three-month confirmed Expanded Disability Status Scale (EDSS) progression, no new T1 Gadolinium-enhancing (Gd+) lesions, and no active T2 lesions.
The analysis showed that cladribine patients were four times more likely to achieve NEDA compared with placebo. Furthermore, when the investigators looked at each component of NEDA (patients considered to be relapse-free, three-month confirmed EDSS progression-free, T1 Gd+ lesion-free, and active T2 lesion-free), the proportion of patients achieving NEDA was always higher for cladribine-treated patients. These benefits were seen in the overall pooled population and across a series of subgroups, namely in patients considered to display high levels of disease activity.
The CHMP stance on cladribine’s approval was driven mainly by safety issues, but the drug’s effect on NEDA is positive, particularly as this endpoint has become one of the key therapeutic goals in MS. Datamonitor Healthcare highlights, however, that no new comparative trials were presented: presentations focused on the re-analysis of cladribine’s earlier trials. In a disease market that now benefits from numerous therapeutic options, some of them with very high efficacy, this lack of active comparators could pose a challenge in the ongoing review of cladribine’s latest Marketing Authorization Application (MAA).
Despite confirming cladribine’s incidences of lymphopenia, the safety analysis appears to clear doubts on malignancy risk
Cladribine’s clinical efficacy is already well established and accepted, so it was the drug’s comprehensive safety analysis that provided arguably the most valuable information. The integrated safety analysis from cladribine’s MS program (ECTRIMS poster P644) was based on data from the CLARITY, CLARITY Extension, ORACLE-MS, and the PREMIERE registry studies. Overall, the monotherapy cohorts derived from these trials included 641 patients on placebo (corresponding to 2,026 patient-years follow-up), 923 patients on a 3.5mg/kg cumulative dose of cladribine (corresponding to 3,433 patient-years), and 632 patients on a 5.25mg/kg dose (corresponding to 2,317 patient-years). Despite the fact that the two different cladribine doses have been extensively studied, the safety analysis presented at ECTRIMS 2016 only included data on the lower dose (3.5mg/kg).
The presentation showed that the overall number of adverse events (AEs) was higher with cladribine than with placebo, but also that the incidence of AEs leading to death, the occurrence of serious AEs, and discontinuation rates were low in both patient cohorts.
As the selective reduction of lymphocytes that occurs with cladribine can lead to several clinical complications, namely lymphopenia, infections, and malignancies, these AEs were investigated in greater detail. Overall, the incidence of lymphopenia events was approximately eight times higher in cladribine-treated patients. Despite not presenting the relevant data, the investigators claim these events were dose-related, with incidence rates in patients receiving the 5.25mg/kg cladribine dose higher than in those receiving the lower dose of 3.5mg/kg. A more detailed assessment of lymphopenia was made with data from the individual clinical trials, and suggests that patients can recover from these events. In the ORACLE-MS study (ECTRIMS poster P645), for example, all patients originally treated with cladribine 3.5mg/kg with grade 2 lymphopenia returned to grade 0 or 1 by 13 weeks into the follow-up period (after the end of year two).
With regards to infections, the integrated analysis displayed no evidence for an overall increased risk. For infection and infestations, the AE rate for cladribine 3.5mg/kg was 24.93 per 100 patient-years (100PY), and 27.05 per 100PY for placebo. When looking specifically at herpes zoster infections, cladribine was associated with higher incidence rates: 0.83 per 100PY versus 0.20 per 100PY with placebo. Herpes zoster was also reported more frequently in patients experiencing grade 3 or 4 lymphopenia, so both AEs would require close monitoring.
Finally, and perhaps most importantly, the integrated safety analysis revealed no increased risk of neoplasms. There was no clustering of malignancies with a common etiology, nor any increased incidence of hematological malignancies associated with immunosuppression. Adjusted AE incidences per 100PY for neoplasms (benign, malignant, and unspecified) were similar for cladribine 3.5mg/kg (1.14 per 100PY) and for placebo (1.01 per 100PY). This is likely to be the most important finding of cladribine’s safety analysis, and a result that Merck KGaA highlighted in its latest resubmission of the drug’s MAA.
And what if European regulators do decide in cladribine’s favor?
If approved, cladribine could reach the market by October 2017; however, the drug hardly seems positioned to claim a large share of the MS market. The current competitive landscape is very different to the one that existed in 2010 at the time of cladribine’s initial rejection. Numerous drug approvals have occurred in MS in recent years – there are now three oral DMTs available in Gilenya (fingolimod; Novartis/Mitsubishi Tanabe), Tecfidera (dimethyl fumarate; Biogen), and Aubagio (teriflunomide; Sanofi) – diminishing any novelty around cladribine’s oral formulation. The recent approval of Lemtrada (alemtuzumab; Sanofi/Bayer) also means that there is already an effective induction therapy on the market, once again weakening another of cladribine’s key competitive advantages. Finally, Roche’s Ocrevus (ocrelizumab) is poised to further revolutionize the treatment landscape in 2017 as a high-efficacy and well-tolerated B-cell-targeting drug that is effective across a range of MS subtypes.
In conclusion, Datamonitor Healthcare considers that Merck KGaA will come up against the same obstacles from the CHMP as it faced in the past, owing to the lack of comparative trials involving cladribine. Furthermore, even if the company does overcome these obstacles, the large number of DMT competitors, coupled with the current low usage of induction treatment strategies, will limit cladribine’s commercial potential.
Comi G, Hartung HP, Kurukulasuriya NC, Greenberg SJ, Scaramozza M (2013) Cladribine tablets for the treatment of relapsing–remitting multiple sclerosis. Expert Opinion on Pharmacotherapy, 14(1), 123–36 <DOI>10.1517/14656566.2013.754012</DOI>.
EMA (2010) Withdrawal Assessment Report for Movectro. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2011/03/WC500104393.pdf [Accessed 15 September 2016].
Merck KGaA (2016) Merck Presents New Data on the Safety and Durable Efficacy of Cladribine Tablets and Advantages of Early Treatment with Rebif® at the 2016 ECTRIMS Congress. Available from: http://news.merck.de/N/0/D9D6238F386CBC15C125802B0069B483/$File/ECTRIMS_2016_Curtain_Raiser.pdf [Accessed 15 September 2016].
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