Wednesday, 18 November 2015

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

21 comments:

  1. Will you be abandoning your own cladribine initiative in favor of Fludara?

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    1. RE: "Will you be abandoning your own cladribine initiative in favor of Fludara?"

      Unlikely as the fludarabine oral tablet is still under patent and sc. cladribine is backed-up by a lot more data than fludarabine.

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    2. ProfG never had his own cladribine initiative, so you can't abandon some thing you never had:-)

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    3. DrK is the lead on the Barts-MS off-label cladribine programme. We have treated several MSers already. We are not going to be changing things.

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    4. To clarify this ProfG is fully committed to the development redevelopment of movectro and is too conflicted to have developed any off label activities however he believes as does DrK that cladribine in whatever guise is a valuable treatment option.

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  2. Rumour has it Bayer also turned down Antegren (now known as natalizumab, Tysabri), Fumaderm (repurposed as DMF, Tecfidera), clofarabine and several other orals. And look at them now; they seem to disinvesting from the MS space. What a tragedy? The story of the German Pharma industry.

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    1. Re: "Rumour has it Bayer also turned down..."

      Truly amazing; rather than a blink I suspect Bayer has developed blepharospasm.

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    2. Many companies seem to ready to disinvest

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  3. It looks like the tablet form is still on patent with an expiry date in 2024. Is this not an opportunity for you for to partner with Pharma to test it in MS?

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    1. It will take until 2016 to formulate the plan, it will take another year or more to get a trial funded 2017, it will take 4-5 years to do, then another 2 years for NICE so 2024 and we are ready for the generic to come and take our profits. Who is going to Partner that?

      So the injectable form of CLAD is free to use, you can't drink it because the oral route is still patented...although I am told it does not work that way. It could be done

      Does anyone have a spare £4,000,000? :-(.

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    2. Dr MD,

      So £4 M is a lot of money, more than I have, but it is not an insurmountable amount to raise, what does that figure include? I would like to discuss the idea of forming a ‘Not For Profit’ entity, taking a drug through trials, repaying the investors and then once the investors are repaid we would drop the price from normally MS drug levels to cost and also declare all the Firm’s IP to be open source. I know this is overly simplified but what do you think?

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    3. An academic 30-35 centre trial that would satisfy the regulators to licence the drug, however I am not sure there is IP to be had.

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    4. I think there is sufficient room to pay back the money with appropriate interest and then give it away.

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  4. is it better you ask is some ways yes it has a similar level of efficacy but a better safety profile as there is no reported pml and it does not induce autoimmunities and the cancer risk is no higher than the others or life and so in contrast to the others you get your treatment but then you dont get reminded every day week or month that you have ms as it is an induction treatment and there is no current reason to screen for safety issues
    it is the only on to get in the brain so yes there is areason not to cast it aside

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  5. Off the wall question:

    Post zombie apocalypse, in world war Z rules, all the zombies ignore us because of our medical condition. I have access to hospitals etc but there is no more tysabri - what would I take?

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    1. Chances are cladribine will have survived whilst biologicals haven't:-)

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    2. Sounds like the indestructible cockroach that can withstand the nuclear attack

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  6. Can we assume that fludarabine will be associated with the same cancer risk as cladribine?

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    1. Ha Ha this old nugget that sticks like a limpet mine

      Yes the same risk as fingolimod, alemtuzumab, tecfidera etc. oh and life and much lower than mitoxantrone. You sound like the MHRA:-)

      The cancer risk has not been substantiated in any follow on studies but this mud still sticks but please read with an open mind. It may be difficult as this is difficult for many neuros too.

      http://multiple-sclerosis-research.blogspot.com/2015/10/cladribine-and-risk-of-cancer-in-people.html

      Can you say there is no cancer risk... no you can't but the result in the trial was a probably a statistical fluke and the only way to know for sure is to prescribed it and monitor it. A 2 year tiral is too short for this outcome.

      Remember only a couple of weeks ago the paper from the South West of England and Wales showed 10% occurance in their population. Remember about 33% of population get cancer.

      I wonder if you will get on your high horse if this occurs in any other study, because 10% in the Alemtuzumab data is higher than the 1% in the CLARITY study.

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    2. If it was so easy to predict cancer there wouldn't be scientists around the country trying to find out why people get it with no known reason.

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  7. My only concern with Fludarabine is that if you read Wikipedia, the side-effects sound pretty bad, too. It also says that it creates "profound lymphopenia". Doesn't that create a risk for PML?

    Is Fludarabine associated with more adverse side effects than Cladribine?

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