OffLabel: fludarabine

Fludarabine in the treatment of active multiple sclerosis. #OffLabel #MSResearch #MSBlog

In response to following comment in relation to my Future talk at the MS Trust just over a week ago.

'Can I ask why you bother to continue to go on and on about Clabridine? Is it a pride thing because you were involved in development/trials and the drug got vetoed you feel a dent in your collective pride? Is the drug better than Alemtuzumab / Tysabri / Rituximab / Ocrelizumab? If not? Honestly what is the point?'

"In my opinion, the evidence-base for cladribine in MS is very good. I am now confident that the EMA will look on the cladribine data package with new eyes and Merck will get their marketing authorisation. Why? When Merck originally applied for a marketing authorisation they only had data from one pivotal phase 3 trial (CLARITY Study). In addition, the regulatory environment was difficult because of the PML scare with natalizumab. As a result the EMA said no. When Merck eventually go back to the EMA there will be so much new data. The data package will not only include the CLARITY study, but the CLARITY Extension study, the CIS or ORACLE study (second pivotal phase 3 trial), the interferon-beta add-on study (ONWARD study) and the cladribine safety register (PREMIER register). In other words the number of cladribine exposure years has increased massively, which allow the regulators to make a much more informed decision regarding oral cladribine's benefits and risks. More importantly, however, the regulatory environment has changed since alemtuzumab (Lemtrada) got its marketing authorisation. As you are aware alemtuzumab got a very liberal first-line license that allows us to use it in active relapsing MS, defined clinically or on MRI. If alemtuzumab got a license, why shouldn't oral cladribine? Cladribine will provide a very good alternative to alemtuzumab as an induction therapy to treat MS. If cladribine gets a license will it affect our off-label prescribing? Possibly. This is why I am recommending we look beyond cladribine to other purine analogues in the same class; i.e. me-too drugs."

"The study below provides excellent proof of concept data that fludarabine is effective in MS. Fludarabine has essentially replaced cladribine in most of the oncology space. Its big advantage is that there is already a licensed oral tablet of fludarabine, which has a similar effect to cladribine in relation to lymphocyte depletion, etc. Way back in 2009 I tried to get my NHS colleagues to add an oral fludarabine arm to a proposed NIHR-funded natalizumab vs. alemtuzumab head-to-head study. Unfortunately, the latter study was never funded and we never took fludarabine forward. I am aware that Bayer-Schering did due diligence on a fludarabine development programme for MS and eventually decided against it. Their reason was that neurologists, who are very conservative, are unlikely to prescribe a repurposed oncology drug to treat MS. I think they applied the same thinking to the development of alemtuzumab. Thankfully, Genzyme took over the baton and ran with it and the rest is history. They say in business if you blink you may miss out. I wonder what you would say about blinking twice? If Bayer-Schering had run with both alemtuzumab and fludarabine they would have owned the induction MS therapy space, years ago, and many thousands of MSers would be less disabled today. Hindsight is perfect vision."

Why did Bayer-Schering blink twice?

"Based on the fact that fludarabine works in exactly the same way as cladribine, there are both oral and intravenous formulations of the drug, and there is some data to support its use in active MS, I see no reason why we shouldn't add it to our essential off-label list of drugs to be used in resource poor settings. The analogy here would be similar to adding Leflunomide to the list. Based on its pharmacology, I would argue  that clofarabine, another purine analogue, should also be explored in MS and possibly added to the list."

Greenberg et al. Fludarabine Adjunct Therapy in Interferon-[beta]-Treated Relapsing-Remitting Multiple Sclerosis Patients Experiencing Break Through Disease: P02.119. Neurology 2004; 62(7) Supplement S5, p A154.

OBJECTIVE: To determine safety, tolerability and efficacy of fludarabine (FAMP) rescue in relapsing-remitting multiple sclerosis (RRMS) patients experiencing breakthrough disease while on interferon beta (IFN[beta]) therapy.

BACKGROUND: IFN[beta] is effective in RRMS, however some patients may experience a resurgence in the frequency of clinical relapses and there is no widely accepted treatment for patients with break through disease. FAMP, a purine analogue, is cytolytic against dividing and non-dividing mononuclear cells, is proapoptotic, and is effective against indolent lymphoproliferative disorders and has demonstrated off-label efficacy in treating aggressive autoimmune uveitis, neurosarcoidosis, and SLE (combined n=18, author's experience). Based on this preliminary data and favorable tolerability, FAMP may be effective as adjunct therapy in IFN[beta]-treated MS patients.

DESIGN/METHODS: This is a randomized, open-label, 2-arm, phase II clinical trial. Patients (n=30) who experienced =2 exacerbations annually, with or without disability progression, while on IFN[beta] therapy for >1 year were eligible. All patients received IFN[beta]-1a 30 mcg IM QW throughout study. Multivariate brain MRI analyses of BPF, T2 BOD, T1 lesion load, and contrast enhancing lesions (CEL) were performed at baseline and end of study. Patients were stratified at baseline according to number of CELs (neuroimager blinded to treatment). Standard induction: IV-methlyprednisolone (MP) 1 gm QD ± 3 days. Randomization: 3 consecutive monthly cycles of FAMP (25 mg/m2 IV QD ± 5 days) or 3 monthly infusions of IV MP (1 gm QD ± 1 day). Patients were followed for 12 months. Safety and tolerability were assessed by physical and neurologic exams, adverse events, and laboratory assessments. Efficacy was evaluated by exacerbation frequency, modified FS, EDSS, MSFC, MRI, and MP interventions.

RESULTS: Thus far, 20 patients were enrolled and 8 patients completed study. Mean (median) CELs were 1.8 (2) and 1.7 (2), for FAMP and MP groups, respectively. Patients randomized to the FAMP arm (n=10) tolerated treatment well. Most common AEs consisted of transient neutropenia or lymphopenia (n=10), transient fatigue (n=4), urinary tract infection (n=1), mild nausea (n=1), and cough (n=1). Interim analyses suggest trends toward improved efficacy of FAMP vs MP adjunct therapy as measured by clinical parameters, exacerbation frequency, MRI, and need for MP intervention.

CONCLUSIONS: FAMP was well tolerated in a cohort of RRMS patients receiving ongoing IFN[beta] therapy who experience clinical relapse. Preliminary interim analyses suggest FAMP temporary adjunct therapy may provide fast onset, sustained immunosuppression useful in controlling break through disease, while maintaining patients on immunomodulatory monotherapy.

CoI: multiple

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