Tuesday, 5 January 2016

The Special One: Cladribine acting in the CNS




Leukaemia in children - what do these studies have to do with the use of Cladribine (2-chlorodeoxyadenosine) in pwMS?  

Well, they revealed over 20 years ago that Cladribine penetrates into the spinal fluid, and in relevant concentrations (about 1/5 - 1/4 of plasma)

Whilst this property is not unique (among drugs used for pwMS) to Cladribine, it is the only drug where its mechanism of action strongly suggests a direct effect within the central nervous system. 


Penetration into the brain may be important for the mechanism by which Cladribine could potentially work not only in those recently diagnosed with MS, but also in people with advanced MS (EDSS>6): Even though at this stage there is generally less significant blood brain barrier leakage and therefore less overt entry of inflammatory cells from the blood stream into the brain, we know that inflammation plays a role throughout the disease, including its advanced stage.  A drug that can attack T and B lymphocytes, and perhaps plasma cells, in the brain of pwMS directly, even without overt blood brain barrier breakdown, may be effective in preserving important functions such as upper limb strength & coordination, cognition and speech.

Monday, 4 January 2016

Shaken or stirred: How would you like your Cladribine?







25 years ago this team of oncologists from the Karolinska University Hospital in Stockholm showed that Cladribine can not only be given as infusion but also as an injection under the skin, or administered as a drink. When taken orally the dose had to be doubled, but the figure below indicates the stunning similarity between all routes of administration in terms of plasma concentration.



Since Merck Serono took over development of oral Cladribine (Movectro), this route of administration cannot be used without infringing their patent.

However remember, only 6 (six) subcutaneous injections (10mg/vial) are required in a year to achieve a dose equivalent to the one successfully used when oral Cladribine was tested in CLARITY and ORACLE MS.

If Movectro gets a license from the EMA, and the annual course of treatment costs say £25,000, would you be prepared to have six injections* instead of generic Cladribine, for example Litak, costing less than £1,000?

This is a serious question.

*No injection site reactions such as those known from beta-interferons. 

Sunday, 3 January 2016

The early days of Cladribine: pharmacokinetics in people with lympho-proliferative disorders

Liliemark J, Juliusson G. Cancer Res 1991;51:5570-2.

The antitumoral effect of 2-chloro-2'-deoxyadenosine (CdA) in the treatment of lymphoproliferative diseases in general and of hairy cell leukemia in particular has recently been demonstrated. Detailed information on the pharmacokinetics of CdA, however, is lacking. The pharmacokinetics of CdA after 2- and 24-h infusions of 0.14 mg/kg was described in 12 patients with lymphoproliferative diseases using a newly developed high-performance liquid chromatography method. The plasma concentration data from individual patients were fitted to a two-compartment model with α- and β-half-lives of 35 ± 12 (mean ± SD) min and 6.7 ± 2.5h, respectively. The volume of distribution was 9.2 ± 5.4 liters/kg. The steady-state concentration of CdA during the 24-h infusion was 22.5 ± 11.1 nM. The areas under the time versus concentration curves were 552 ±258 and 588 ± 185 nM x h, respectively, for the 24- and 2-h infusions. The inter-individual variability of the determinants of the plasma pharmacokinetics of CdA was small (the coefficients of variation were between 0.22 and 0.58). At 6.3 ± 1.5 h after the start of the 2-h infusion, the concentration of CdA was the same as the steady-state concentration during the 24-h infusion. When the mean plasma concentrations of the 12 patients were fitted to a 3-compartment model, the half-lives of the α-, β-, and τ-phases were 8 min, 1 h 6 min, and 6.3 h, respectively. The long terminal half-life of CdA after 2-h infusion supports the use of intermittent infusions.


In a 70kg individual 0.14mg/kg amounts to approximately 10mg, which is the standard vial size of Cladribine across the Globe.



Over 25 years ago this study suggested Cladribine can be administered as short term (2h) rather than long term (24h) infusions without loss of effect.  A significant contribution towards a better understanding of Cladribine's pharmacokinetics to the point at which we are today, where we know it can be administered effectively and conveniently in short courses (infusions, subcutaneous injections, or tablets) in an outpatient setting.

Saturday, 26 December 2015

Maybe it is not all Doom and Gloom?

Now that our hopes of a UK trial of Cladribine in relapsing MS have been dashed, it is time to move on and get something positive from all this effort.

Currently, Big Pharma is mainly interested in Relapsing MS. Academia, at least in the UK, are focussing their effort on ambulatory people with MS.



Can we do something for the forgotten thousands, those with deteriorating MS (what is "progressive" about worsening MS?), who are wheel chair users most or all of the time? 

We know that 
  • MS is associated with the accumulation of damaging white blood cells (lesions) within the CNS.
  • Lesions in people with relapsing and deteriorating ("progressive") MS are similar.
  • People with deteriorating MS (pwDMS) have inflammatory and smouldering lesions.
  • Modulation of the peripheral immune response blocks relapsing MS and the formation of new lesions.
  • Many pwDMS develop new lesions and have relapses.
  • pwDMS who display disease activity on MRI respond to peripheral immunodulation with current DMT.
  • pwDMS may respond to central neuroprotection.
  • Optimum therapy will likely mean control of immunity plus neuroprotection and repair.

Current DMT are too expensive and are not considered cost-effective for pwDMS and so DMT is withdrawn.
  • Current trials in pwDMS are focussed (fixated?) on the EDSS as an outcome. This non-linear scale is heavily biased towards lower limb function.
  • Deteriorating MS as measured by EDSS due to smouldering lesions is not responsive to peripheral immuno-modulation by the time it is tested.
  • The longer the distance the nerve signal has to travel the more likely it will hit by MS lesions. One hypothesis therefore goes that the bladder and lower limbs are more likely to be damaged before the upper limbs.
  • pwDMS have evidence of B cell activity within their brains that may cause grey matter lesions. They can produce antibodies that may be damaging in MS. No current drug works in the CNS to tackle this problem.
  • Most importantly: pwDMS who have lost most or all of their lower limb function, will wish to maintain their upper limb function for mobility!

pwDMS who are in wheel chairs (i) have virtually no access to DMT and (ii) are excluded from clinical trials of drugs against deteriorating ("progressive") MS.
They are the forgotten thousands.  People in wheel chairs have active lesions and progress and loose upper limb function.  
  • However, many pwDMS in wheelchairs may indeed respond to DMT.
  • As their neural reserve of lower limb function may be lost pwDMS may not respond in terms of EDSS to peripheral immunomodulation with DMT.
  • However, upper limb function is vital to everyone with MS, including those in wheelchairs and this neural reserve must be saved.
  • Upper limb function may still respond to potent peripheral DMT:
The data from the ASCEND trial provide evidence that upper limb deterioration can be halted in pwDMS, whilst lower limb function continued to deteriorate. Other studies may not show this because the DMT are not good enough to stop active disease.
  • Most companies making peripheral DMT have been burned by failures in progressive MS and may not risk further trials.  
  • People in wheelchairs are ignored as far as DMT goes.

Cladridine inhibits Active Lesion Formation. Gadolinium enhancing lesions drop by over 90%. Fewer lesions means less damage and reduced risk of deterioration

Cladribine inhibits relapses (annual relapse rate decreased to about 0.1 = one every ten years). Fewer relapses means less damage and reduced risk of deterioration.

Cladribine induces NEDA-3 in nearly 50% of people with a 1 year course of treatment.

Cladribine will be of value to slow the accumulation of damage in anyone with active MS... This means it should be of value for everyone with MS.

A cost-effective drug means everyone with active MS could have access to treatment.

Cladribine has the potential to save upper limb function via inhibition of peripheral immunity as it probably is as active as Natalizumab.

Cladribine enters the central nervous system and can kill dividing and non-dividing white blood cells, and it can kill plasma cells and can in some instances get rid of oligoclonal antibody bands. If these are causing grey matter lesions or even deterioration, it will target these mechanisms unlike any other MS drugs including ocrelizumab.

Cladribine is an induction treatment, thus it can act as a platform for layering on neuroprotection and repair agents. 

Are you interested in a study for pwDMS who are wheel chair users?

If so, what should we call the trial?

Friday, 25 December 2015

Cladribine4MS

Cladribine4MS



White Knight Diaries

Many of you have been wondering what we have been prattling on about for the last few years, when I've been posting about the "White Knights". 

The White knights are a group of Neuros who are willing to take on big pharma to try and deliver drugs to you!!

Today I reveal what this has all been about. I have been dropping posts on this for the past few years on the MS Blog as indicator points, so think back when they started. This is to show that things do not just happen overnight and it takes a very,very long time to get things off the ground. Especially when everything is not going to be in your favour. The diaries have been written as we went along. The chances of success are very, very slim.

So you think everything happens overnight and yes things can be done quicker, but we have other things to do as well.

So here we go...

MS Big Pharma drugs are bankrupting the NHS, as it cannot afford them. Therefore existing drugs are being rationed and this has more to do with price rather than risk. Elsewhere, it means escalating insurance premiums and if you have no health insurance, MS drugs are bankrupting you or you are not being treated.

Do you do nothing? 

As a basic scientist you are powerless to do anything! 

Are there any solutions?

Movectro (Oral Cladribine) costing €20,000 was dropped early 2011 by Merck Serono because the EMA and FDA wanted more studies to show safety, but accept that efficacy is proven. 

Rather than do more trials the drug is withdrawn from the markets in Russia and Australia, where it had been licensed.  This is because if they do the trials there will not be enough life in the patents. It is a commercial decision.

They were in a race to be the first oral MS drug, and they lost (to Novartis' Gilenya). They took a gamble that one trial was going to be enough with all the extra data in support. However, a perceived cancer risk in the phase III and the gamble became a folly.

However, it opens a pandoras box because Movectro is an oral pro drug that turns into the active drug when ingested. This means that the parent drug is active!

This means that generic subcutaneous or intravenous Cladribine will work! And that Clofarbine (licence held by Genzyme, I believe) will work. Clofarabine is sat on a shelf so as not to compete with Alemtuzumab...  But generic Cladribine is fair game.

The FDA was worried about cancers, but if you look at the data it was unusual that the placebo group had no cancers and the actual number of cancers in the Cladribine studies were half that reported and were no less than found in the Gilenya studies.

Cladribine is twice as effective as Beta Interferon or Glatiramer acetate, Teriflunomide and as effective as BG-12, Gilenya, Tysabri and probably Alemtuzumab, but does not cause the side effects of Alemtuzumab and Tysabri, and being an induction therapy is good for females wanting to get pregnant, as it is quickly out of the system.  

It also gets in the brain where it can kill whites cells in the CNS, unlike any other drug.  Also if we could get a cheap drug, we could give it to people with progressive MS, who need an anti-inflammatory in addition to neuroprotectants and repair agents. 

Cladribine would be a great anti-inflammatory as it could provide a platform for repair and neuroprotection without drug-drug interactions to worry about.

Alemtuzumab is being mooted to cost £50,000-£80,000 and will bankrupt the NHS and will be rationed.

You can drink generic Cladribine, but the oral route is sewn up by Merck's patents.  In trials (CLARITY, ORACLE MS) 3.5mg/kg Movectro were used over the trial duration (96 weeks). Oral Cladribine (Movectro) is 42% bioavailable (amount you take that gets into the blood stream) compared to subcutaneous Cladribine, which is 100% bioavailable, so you will need less drug, about 1.5mg/kg/year.

In the UK the cost of the 10mg vial is £165, we're finding it elsewhere for $32, and being an induction therapy maybe only needing two sets of doses like Alemtuzumab, so maybe £1-2,000 a lifetime!  The NHS would drive a bargain on this and would get the price cut by a half so about £200-£500 a person...

Big Pharma has done repurposing the Big Pharma way and taken a simple cheap drug and spent millions of dollars re-engineering Cladribine to achieve a patent position so it is a pro-drug that turns into Cladribine after swallowing. Why not try repurposing the academic way and take the drug as it's being used in humans (for people with hairy cell leukaemia) and use it for a different purpose than it was originally made.

It is a no brainer to try and develop generic Cladribine, but if you can not deliver the drug to market, there is no point in starting as it will rock the boat. Trials are expensive because of imaging and monitoring costs, but why do we need imaging?  We know the drug works and imaging is not going to add much to a positive clinical response...

19:11:2011 Start with the idea of doing trial, but not at QMUL as ProfG is too conflicted and in bed with Pharma. So he is out of the loop.
Talk with a few Neuros and find I need to get consultant to lead on the Project. 

16:1:2012 starts writing to Neuros outside of QMUL to see if they will be willing to take on the task.  
29:3:2012 First contact from a Neuro who shows signs of interest, 
14:5:2012 Second Attempt 
29:5:2012 Third Attempt as Pharma sue NHS over prescribing cheap drug
26:6:2012 Forth Attempt
18:7:2012 Fifth Attempt
2:8:2012 Sixth Attempt
30:8:2012 Seventh Attempt: " I know I am being a pain in the arse but just a little reminder to think about Cladribine" 

1:9:2012 Neuro accepts the challenge
5:9:2012 Neuro 1 talks to Neuro 2 (who likes the idea) and two neuros are on board!

However, the objective of keeping out of QMUL failed. So two opposing camps ProfG the conflicted on one side and the teutonic knight of the other and a year wasted!

6:9:2012 Another Patent Searches suggest freedom to operate outside oral route.

16:10:2012 MS Society UK and USA NMSS contacted-UK MS Society Upbeat and Very Supportive.

25:10:2012 Meet NMSS in Millenium Hotel London, Lots of problems foreseen and no real enthusiasm. They suggest contacting Rusty Katz at the FDA.

Write to Rusty......No response.

Write to Generic companies making generic cladribine.

13:12:2012 Define a White Knight as a Neuro crusading for generic drugs.

18:12:2012Meet a company producing generic drug
They agree to pay to hold licence (>£100,000/year) but do not have enough resource for supporting trials, but provide important data for development of clinical trial protocol-Game On.

Will they be bought and shut down by the MS pharma, once they get wind of the project and supplier? A $20 billion market versus the cost of buying and closing a small generic company-No brainer.

Surely they will wait to create maximum delaying effect so breathing space for the moment.

29:01:2012 Another patent search suggests freedom to operate.


Meet someone who Advises to the EMA, who advise to speak to MHRA.

13:02:2013. Write to MHRA to request advice and informal no-cost meeting.


6:3:2013  Abstracts from ANN 2013 are published 
Data of three extra Cladribine trials (one follow-up of CLARITY trial) are published indicating the cancer risk of Cladribine is not an issue and that it is a highly effective treatment, as good as any current DMT! 
Confirms the view that there is no real cancer risk compared to that of life and other MS drugs (One of the knights identified others left handed in support).

April 2013. Get Clinical trials expert, MS statistician and Cladribine expert on board for MHRA meeting and organise financing for their stay in Hotels in London.

12-14:4:2013 Do Survey on Repurposing Drugs
Do MSers support repurposing and taking on pharma  

13:4:2013 Results of Survey 97% of Respondents think we should take on pharma.

17:4:2013 Pre-MHRA Meeting Discussion & Dinner.

Really upbeat-We plan on asking them (MHRA) to do a registry as it is such a no-brainer.

Member of team booked into rubbishy hotel in Victoria, London smelling of Pooh.  There are no Big Pharma luxuries for us.

18:4:2013 Meet the MRHA for formal discussion. will they see the light and get it?
You have to put a series of questions to the MHRA, some weeks earlier and they do a formal deliberation. You give a short presentation and get answers to questions.

Oh no. It is the same chair as before when we went for a disastrous & embarrassing meeting, and a women with a large frown line that you knew she was going to be mean.

Efficacy of original data is questioned....the new data is ignored, 
a Registry is out of the question! Need a trial for efficacy, in fact may be need two if we don't have access to data from other trials!
Need a trial showing a dose-response, Need a trial against active comparator (will single blinding be enough?)  

Need imaging on subset, Need safety data, Need disability data so trial will need to be 3 years not 2 years-Even current drugs didn't need this!

Asked questions (not needing to blind and two trials) to get then in the minutes. MHRA will only give comment if the minutes are wrong

19:4:2103. Massively disappointing meeting. This will cost millions! This is what Pharma have to do when they start from scratch.

Every hurdle that could be raised was raised. The global approach is clearly a hurdle too far, as we do not have the resource to talk and deal with multi-national regulators.  We need about £3,500 for the MHRA and £33,000 to talk to the EMA.
We have to focus on the UK in the first instance and hope for trickle effect across other countries.

If anybody thinks that the MHRA is going to make it easy for a neuro to develop an MS drug then they are so wrong! 

Are they going to bite their pharma paymasters, as the MHRA is 100% funded by Pharma?

10:5:2013: Plan discussed to a larger group of Neuros and MSers at MS Society Meeting in London and the name CLARIMS is born.

(CLadribine versus Alemtuzumab in RelapsIng Multiple Sclerosis.)
Why Alemtuzumab? Because it may get a first line license and has a similar course of treatment, and risk averse people willing to try Alemtuzumab may be willing to try Cladribine. This allows us to get a blinded trial. BG-12 is a fall back as we could make a dummy pill.

11:6:2013 Meet Clinical Trials Unit and senior scientists. Who could help develop the trial protocol and could help with the financing. It is amazing how some very senior people are clueless about drug development!
12:6:2013 Going round in Circles. Following yesterdays meeting and some new info from senior Government Officials, it is clear that the senior people supporting repurposing have not thought the whole process through. Mixed messages and NICE suggested.

They say we need to get support from Neuros and MSers to get Cladribine onto the agenda.

Canvass a few Neuros, who all appear risk averse and would not want to prescribe without proper authority, therefore we feel we must do a proper licensing study.

Second trial
As data for new drugs have to go into public domain, we attempt to get previous trial data of Cladribine under Freedom of Information request to European and Australian Regulators

European regulators are not providing any data because of ongoing court case with Pharma:-( 

30:09:2013. Meeting of the knights with Senior Science Advisor who is upbeat about taking on Pharma.
Director of NIHR says that NHS can't support doing pharma work, but what is re-purposing all about? Again not thought through. But makes it clear that for the study to go ahead we have to get both MSers and Neuros on board to develop this.


14:11:2013. Get news that EMA will support our Freedom of Information request to get access to previous cladribine trial data. They ask what do we want? We say everything.
Ace in the hole, now we have access to one phase III trial data and tick the MHRA wish list. This means that we do not have to do two phase III trials for registration! 


We have thousands of pages of information...who is going to sort through this?

Alemtuzumab is rejected by the FDA because of "poor trial design" notably the lack of blinding. So despite the suggestion that it may not be critical for the MHRA to approve Cladribine, it means we have to think about blinding, so good job we were planning on this.

Going against the Interferons or Glatiramer acetate as injectables is now out of the question, as it will add too much cost to blind against this as we can't manufacture placebos for a blinded trial. We have to go head to head with first line active treatment and plan for approval of Alemtuzumab, with fall back against an active oral.

We are not going to do what Pharma continues to do-placebo controlled trials, we will do an non-inferiority trial against an active comparator so we are aiming to show the drug is no worse than an approved drug.

Maybe this could change the face of DMT studies as it should be unethical to do placebo control in this day an age. One pharma trial has 800 people on placebo....Unbelieveable. 

17:02:2014 Teleconference start to gear up for application to NIHR (National Institute of Health Research). The design is fully hatched and powered. Find another source of Cladribine, which is less easy to buy and close down. It is time to act. So a few hundred pounds to treat MS.

14:03:2014. Teutonic knight reported on the idea of CLARIMS to UK Neurologists, there are a few pharma people present. 

ProfG (not a knight) blows our cover further and announces the study on the MS Blog. We are now clearly exposed to Big Pharma meddling. 
01:04:2014. The week of activity.  Teutonic Knight sends circular to UK Neuros to drum up support for grant application and to find sites for the trial. If there is no positive response the approach is doomed? 

Teutonic Knight gets Clinical Trials Unit on board and we get the news that Alemtuzumab will be approved by NICE as a first line. So the trial we planned is now a goer and we do not have to worry about fall back.
We have the ammunition for the trial 

27:04:2014 Teutonic Knight presents the plan at MS life 2014
we are out in the open

At the AAN meeting, white knights get that naughty school boy look from some pharma people.

03:06:2014Final meeting of Neuros and others before NIHR preliminary grant application. Some still don't get it.... They think it is just an experiment and that's it. The aim has got to be licensing or the project needs to get canned. 

CLARIMS is killed off and the name CLEAR:MS (the phoenix) is born.

12:06:2014 The grant application is scuppered for the time being, on the eleventh hour...too much of a rush...but not helped by the turn coats (Brutus) at the last minute who created maximum damage....again.
Furthermore not aided by the CTU (Clinical Trials Unit not Counter Terrorist Unit) throwing in a few last minute bombs. Highly frustrating as these bombs could have all been defused had they been raised earlier.
No wonder Jack Bauer turned to torture...too many lazy Chiefs and not enough Indians, such that too few people were doing the hard work and the rest were riding on their coat tails.

26:07:2014Knights get on their bikes again and gear up to go again. Maybe onto the tele as TV station get interested in documenting the story as a public interest piece.


Change in tack...To answer the dose response question of MHRA we had planned an embedded phase II trial design based on imaging such that people in that arm could be switched to the dose we knew worked and off the dose that we suspected may not work before clinical attacks occurred. 

Why did we think this? This was based on studies in leukaemia, because it may not deplete immune cells enough. This low dose arm added to the cost a lot and caused problems with the trial design, which was one of the reasons for pulling it. 

However, in the age of Alemtuzumab where the immune depletion and risks far outweigh anything that Cladribine will offer we are jumping through hurdles to address an issue, which is now not an issue.

Perhaps wrongly we decided to be bullish and not give in on this one. Everyone on the trial will get a drug in a dose that we think will work equally well. This sat a lot better with our MSers on the working panel, who were against the low dose concept.

Now we are being bullish. Do we do a two or three year trial. 

Current standards are two years and the three trials as suggested by the MHRA have not materialised, so 2 years it is, this will be quicker and cheaper.

15:07:2014Meeting to affirm new simpler trial design, meeting of the admin groups who will sort out costing, bits of meeting filmed and two non pharma led studies being discussed on same day.

26:08:2014 TV company wants to air faster than is sensible for the knights, so this idea is dropped and our MSer cameraperson changes the pitch to leave the knights out of it for the time being

26:10:2014 Meeting of knights with completed grant application form, time to submit, we now have over 30 centres across the UK on board who willing to take part.

We do a survey of the MS register to gather support for a trial



29:10:2014 Preliminary grant submitted. Filmed the button being pushed it is all electronic. The grant is too expensive at £4.8 million and expect to get cut back. Let the battle begin.

We initially could not enter the savings to NHS in the form of the grant...These estimated savings are a minimum of £32 million and probably an estimated saving over £50,000,000 including the cost of the study.




 

Who are the 14? Sorry, lips are sealed but definitely not Brutus...


Why so much saving....the drug costs alone are 50 times cheaper, you don't have to give drug in hospital, don't have to deal with the problems of infusion, you will not have to monitor every month for 4 years after last Alemtuzumb dose and will not have to deal and treat the the problems of the secondary autoimmunities that will occur in 50% of people treated.

7:11: 2014. Meeting of UK knights with Australian knights.  They loved Movectro. However, they are not under the same post code lottery pressure as UK pwMS. UK knight gets patting on the back, but no more.

Meeting with Chinese neuro of interest as their MSer population (20k-30k) face big hurdles to access DMT due to price. UK knights consider linking up with Oriental knights. NMO as further therapeutic target discussed.

18:11:2014 Merck person mentions company is to go back to EMA for re-licensing of Movectro. Is this their response to hearing what the Knights are up to? 

If they get Movectro licensed, it will probably derail the crusade and make it difficult to encourage Neuros  to use generic Cladribine. Surely they would not have bothered doing this except to damage our chances.  If it was not financially sensible in 2011 it will be less financially sensible in 2015?

It could, of course, make an easy trial oral versus subcutaneous Cladribine. This trial would make CLEAR:MS much cheaper.




UK knights also seeking help from House of Lords members again.  
18:11:2014.  Italian Neuros show that cheap DMT azathioprine works as well as beta interferons.
So more knights on a new campaign and even more clues of what this is all about in the comments posted on 19:11:2014, in fact the beans are spilled then if you put two and two together,


15:12:2014: Meet potential Big benefactor who might ease some of the pain associated with getting the trial off the ground, through providing additional support outside of the trial. However, it is in the air.

It is clear that world wide there are many people who do not have access to DMT. However, neuros will not prescribe without a licence; so if we get a UK licence it will placate them and help open the flood gates.  

No reply from the Lords, so trying to activate former speech writer for Lady Thatcher to help with contacts into Westminster.

Written to All-Parliamentary group for MS to ask for support of NIHR application...nothing they are a real load of deadbeats.

08:01:2014. A day of filming for the documentary
Take more abuse about the "white knight posts".

17:1:2015 Informally meet senior Civil Servant within the Government Treasury and start to discuss the potential costs of "CLEAR:MS" to the NIHR and the potential gains for UK Plc. and the potential need to move finances from grant budgets. 

30:1:2015. Have to respond to the preliminary feedback from the NIHR. The feeling is that this is touch and go. Is the trial too much money?  They are going to want arms to cut off.

The trial planned currently has 220MSers on Dose 1 of Cladribine, 220MSers on Dose 2 of Cladribine, and 220MSers on Alemtuzumab.

The referees do not believe the potential saving to the NHS.

However 440 people not on alemtuzumab saves about £26,000,000 on drug costs alone and then not having to deal with autoimmunities.


They are worried about the trial design and whether it can be blinded properly (However the EMA and FDA have accepted that Alemtuzumab did not need to be blinded and we have it in writing that blinding is not absolutely necessary). They are questioning the powering of the trial and amount of difference can be between Alemtuzumab and Cladribine, which could add an extra 200 people per arm meaning the study is less likely to be fundable.

They are also questioning if the knights need two arms (of Cladribine). The tone is that they may want to cut one arm but will the MHRA accept this? If they won't, it should be time to halt and regroup or find funding for an arm.


We will know the outcome next week....Live to fight another day to move onto the next stage, loose an arm, or be killed off. 

16:3:2015 Bad news-Project killed off! (Now I know what the FA felt like with the failed FIFA world cup bid, at least we did not waste £18,000,000 in the process)
               
        They are not interested in you simple as that!!!!!!!!!

The NIHR are not interested in saving the NHS money and don't want to rock the Big Pharma apple cart because they do not see this as important. They see no merit in developing a treatment when there are alternatives available, so you will be stuck with what Pharma can serve up to you and the less than ideal offerings currently on show.

Whilst we have to accept that it could be seen as a bad application. Here are the reasons given:

1. Further justification for the choice of Cladribine over other agents would have been required; particularly, given that the manufacturers are not currently pursuing the development or supply of the drug due to the side effect profile. It was felt that, given the number of other agents available, a multi-arm study of all of these may have been beneficial.

Em: Justification of Choice Ease, Safety, Efficacy, Cost, CNS entry 
Maybe do not understand the concept of generic or read Ingrish

Alemtuzumab verse the others. Surely Genzyme should have to pay for this?

2. The Board was concerned that blinding could not be achieved given the differences in regimen and needs for premedication; further reassurance would have strengthened the application.

Although the MRHA had indicated that we did not need to blind
and remember in the Alemtuzumab the pivotal studies did not pretend to blind. But everything was put in place to blind as well as could happen. We could not do more than was planned. There can be a infusion reaction, which you use steroids to stop and mask them.   

However, can you truly mask any trial?     
                 
3. The Board felt that the study design made a number of assumptions of efficacy and safety for Cladribine and therefore would have required further preliminary data showing that Cladribine is at least as effective as Alemtuzumab. Further evidence to support the translation of Cladribine from the previously studied population to this one would have been helpful.

The Board want a  phase II trial of Cladribine versus Alemtuzumab. 

They are not happy that Cladribine was active in three phase III studies. It is indeed a risk that Alemtuzumab is better, but to waste 2 years could be a death wish because once Ocreluzimab comes along are neurologists going to take the risk of prescribing Alemtuzumab, its shelf life may have gone.

The request was for a trial of Cladbrine, two dosing schedules at the request of the MHRA. So they are saying cut off an arm. 
Why not cut off an arm and let us go back to MHRA to see if they accept this for licensing?

Further evidence to support the translation of Cladribine from the previously studied population to this one.

The original trial was in RRMS, this trial is in RRMS are they different..no or are they saying Britisth MSers are not like European, North American, Australina, Russian and British MSers?

4. The Board questioned the recruitment rate; further evidence of the participating centres may have been useful.

Over 30 centres across the UK had agreed to participate. However, if Neuros would not presecribe Alemtuzumab, which some won't, it would make it difficult. This may have been a fair point, which we could survey to find out if it was a problem to find 1 person with MS a month willing to go on a trial. We have the rates of recruitment which we could use as preliminary data.

5. The Board noted that the links between the non-inferiority margins and clinically important differences were not clearly articulated.

We had set a margin of 15% inferiority of Cladribine compared to Alemtuzumab because even if it was not quite as good as Alemtuzumab it would still be better than most other MS drugs.

6. It was felt that the mechanistic studies were very expensive and the Board would have required further justification for their inclusion. 

To get funding for the work there had to be a science component to the grant. We requested money to use the monthly blood samples collected to see why autoimmunity develops (as this would occur in 20-50% of people on trial treated with alemtuzumab) and see what happens before MS returns as (50% of people) would need another course of treatment. We had planned to bank the samples for future analysis. We wanted to know if you get rid of inflammation can you see evidence of repair by MRI.

They could have removed them without affecting the ability to do the work...

7. The Board was not convinced about the figures stated for the NHS treatment costs and would have required these to be reworked.

A person volunteering for the trial would be someone wanting Alemtuzmab but would do the trial to avoid side effects. Someone wanting beta interferon would not risk the trial . We estimated costs of drug administration and dealing with autoimmunities and the monthly monitoring was £32,000,000

400 people on Cladribine 400 x £1000 = 400,0000
400 people not on CAMPATH-1H £60,000 per person =
£24,000,000.

Saving = £23,600,000 + plus the cost of dealing with 20-50% autoimmunities and the infusions and monthly monitoring.

400 people on beta interferon £16,000 =  £18,400,000
Saving £18,000,000.

This is a nonsense comment doing the trial at £4,000,000 would easily pay for itself.

8. The high cost of the study was noted and the Board was not convinced that this study could provide value for money. 

Trial = £4,000,000

6,000 people diagnosed with MS a year

6,000 x £1,000 for cladribine = £6,000,000 

6,000 on beta interferon about £48,000,000 a year, 
6,000 on tecfidera £84,000,000 a year. 


So within one year it would pay for itself.

However, if you have a ring-fenced budget then if your trial costs more than about £2-2.5 million it is not going to get funded. So the costs of this study are just too high which we knew and expected to get cut back. A major cost was the CTU and their monitoring...

26:3:2015 Had an investigator meeting about calling it a day. I guess I knew this was going to happen, but now we have evidence.

We went through the meeting to discuss the failed grant application. It is clear that Non-MS science are not interested in developing an alternative to pharma drugs. They are more interested in science than substance. So if there is a sexy trial design with some cruddy old drug the work is sexy and gets support without any real thought about the possibility of actually delivering treatments (OK this may be a bit harsh).

The killer comments are about Alemtuzumab and whether neurologists will prescribe it and whether you will take it and by the time we are ready to start Ocrelizumab will be around and no-one will probably want Alemtuzumab if the Ocrelizumab data is any good. We talked about Tecfidera as a new kid on the block as the alternative. We could blind by making some dummy pills.  Again Tecfidera has side effects that can easily unmask. Cladribine is probably better than Tecfidera. To cut costs we would have to slash one arm of the Cladribine. 

The Wellcome Trust and the Department of Health are still doing repurposing and we have already contacted them. We get a green light to go for it. Which is done, however we get response.

"It does fit the re-purposing theme in a general sense. However, I think the panel are likely to view this as something where the innovative aspect of the re-purposing has already occurred and this is a large trial that one would expect an interested Pharma company to pick up. This would put the proposal outside the overall requirement for innovative solutions". 


So the public position is science is more important than the substance and it is still all about getting pharma to take the baton. So any clinician who thinks they are doing studies for the good of man-kind are deluding themselves, they are working for the man. The Progressive MS Alliance is about to start this whole process there is talk of Simvastatin trial. And then what?

I would put it to them to ask can repurposing occur without pharma and the answer is increasing clear I think, it is no. So let's not kid ourselves otherwise. 

I always knew it but was prepared to give it a go.

10:4:2015. Get quotes from companies that do the data monitoring for trials and there quotes are up to £50,000,000 (apparently that is a discounted rate if we sign up within 30 days) so they are having a laugh with Pharma... Funny thing is they pay it. Get one quote at a few million.

21:4:2015. One of the companies we talked to about data monitoring have been blabbing everything to Pharma (Merck), They probably have known everything anyway . What to you do take it on the chin or take legal action about a confidentiality agreement being broken.

We hear on the grapevine again that the giant is waking and Merck are planning on bringing Movectro out of mothballs, we have known this for months. This says something about the risk as they would not do this if they thought the risk  profile was real. 

So the ultimate way to stop the knights is occurring, as Cladribine comes back on the table. However, on the plus side ProfG and QMUL will get a an impact outcome if the drug comes back for the next REF:-)

1:5:15 Have meeting with Innovate UK about business prospects of Cladribine. Interesting but I suspect too much effort..this is taking up too much of our time.

5:5:15 Have meeting in the Wellcome Trust Cafe, which is where the fly (Forensics Exhibition) comes from for a debrief about the failed application. There is a view that the idea of  developing a DMT is not dead with the NIHR, but we have to bin the science and reduce cost substantially. Personally I don't buy this. You can't get a cheap and good trial. Plus they are going to pull the lack of medical need card.  There is a need for a smaller trials to establish dosing which puts us back to two years ago. There is option discussed of PPMS study maybe we can get something from this project.

11:5:15 White Goes Grey as we begin talks with Merck about oral Cladribine. If we can help them get it back on the agenda we will.

It seems decision time is looming with the EMA

26:6:2015: A cryptic post appears - Is there a shimmer of light in the darkness? Are we looking down a tunnel with light at the end? Or is it just an illusion, some sweaty dream during a restless night at full moon?  After supposedly throwing the final blow against the knights some influential voices at the NIHR have apparently returned to the battle field to search for survivors and say ??sorry?? we didn't fully understand what you said before hacking off your limbs. Can we sit down and talk over afternoon tea? We err... would consider some prosthetics for you and help you learning to run again, to fight for another day...

30:6:2015. Get a word that we may be able try again with NIHR, if we can show that our study is feasible and we can cut costs.

So this helps us to Re-Arm an recharge our batteries. This post is so ambiguous and readership thinks this is something that it is not. i.e. it is not a mechanical exoskeleton.

20:7:2015 Paper on cancer risk nearly accepted but now we have to find £2,000 for the open access fee. We had got pharma lined up to pay for it but medical student on the paper can't be seen to be associated with pharma or they will loose their job.  Nothing is straight forward with this project.

This paper is the information that Merck need for their EMA submission,  so we give them that and don't sign the confidentiality agreement that they want us to sign.

Meetings take place and we get powering for an MRI trial.

11:9:2015. News leaks that Cladribine is going back to the EMA

01:10:2012. More problems with CTU...We need Jack Baurer to get them sorted. They have been on board for 1.5 years and now we have to go to them and explain the trial. They (including a guy from the NIHR) say they don't think the NIHR will fund the phase II and want a phase III with two arms instead. I despair. 

This is too much, no support anywhere. Head of NIHR says "quick and dirty study with a few people"....This simply will not work as would be too small to be useful.

02:10:2015. Cladribine paper published suggesting the risk of cancer was probably a fluke due to no cancers in the placebo arm.
10:10:2012 DrK posts the Cladribine story. Is there a donor out there?


The case is put there for all to see why this is a worthwhile cause and details of the trial laid bare. 

13:10:2015. UK MS Society want to support the drug repurposing bill. But we are second choice in their eyes, they want to support simvastatin though Cladribine is much closer to the finish post.

This is taking too much time for no reward and we are swimming in treacle. Any chance of going back to the NIHR in the near future is delayed because we are getting pushed back down the pecking order by a trial of DMT supported by the MS Society's Clinical Trials Network, that we would need to co-ordinate any trial.

Our plan to get proper people to do the trial monitoring is scuppered by cold feet by our people in the NIHR, who are now worried about the re-awakening of the Movectro programme

The teutonic knight looses it...

"The NIHR should stop wetting their pants .........Please tell Tom (Tom Walley Director of the NIHR) the NIHR is in danger of turning into a giant smoke screen for a public that believes his organisation could facilitate real change in and for the NHS should they shy away from reasonable, evidence-based and solid science with - yes - potential for significant impact, and only because an unpredictable company expresses "the intent" of doing something (nothing has really happened on the ground!)".

The teutonic knight will not do a placebo controlled trial and therefore you need the NIHR support as who will pay for the drug comparator. The NIHR won't support such a trial. So catch 22.

29:10:2015 Hear that the Department of Health will not support the Repurposing Bill so it is essentially dead irrespective of what happens



30:10:2015
Give up on the idea of NIHR for the time being unless we get your support we will not get this going in the UK, until patent life of DMT dies. Mercks plans wins?

The only way to make this happen is either a change of mind by the MS Societies or a Philantrophic benefactor.

We request that NICE undertake a single technology appraisal to provide guidelines on how to prescribe generic Cladribine...NICE reply they will only do this for licenced drugs and if Pharma ask them to do it....After all pharma under-write much of the cost of NICE...

2:11:2015 Kill off the White Knights on the Barts MS Blog-Sorry



You can take part and push the agenda or you can let it die. 

If you let it die you are part of the collective problem and don't say we can't do anything, because you can. 

We tried and failed. If you are a mega donor maybe we can do something. Contact us.

Has it been worthwhile. Many say it has been a waste of time, we did not raise hopes for you as you did not know what was going on.  

However on the plus side...

1. We have learned a lot more about the drug development process and some of the details that Pharma have to do to get drugs approved.

2. We have identified failings in the system in the UK that will stop academic neurologists developing treatments, yes it could be done in yesteryear but that time has passsed

3.We have kept Cladribine alive and may have contributed in some small way to Merck bringing it back or trying to bring it back.

4. Importantly we have developed our own Cladribine protocol to give people with MS a treatment, where currently there is none. 

People with PPMS and gadolinium enhancing lesions will respond to this type of treatment and until and if Ocrelizumab is approved there is nothing in the UK, as our hospital has stopped funding Rituximab. For people in wheelchairs with brains full of lesions there are no treatments for them either, but there is now...for the time being.

What does the future hold?

Who knows? 

The Second Crusade? Anyone up for it?