Sunday, 31 January 2016


Dehghan S, Hesaraki M, Soleimani M, Mirnajafi-Zadeh J, Fathollahi Y, Javan M. Oct4 transcription factor in conjunction with valproic acid accelerates myelin repair in demyelinated optic chiasm in mice. Neuroscience. 2016 . pii: S0306-4522(16)00047-6.

Multiple sclerosis is a demyelinating disease with severe neurological symptoms due to blockage of signal conduction in affected axons. Spontaneous remyelination via endogenous progenitors is limited and eventually fails. Recent reports showed that forced expression of some transcription factors (factors that control making proteins) within the brain converted cells  to neural progenitors and neuroblasts (cells that make nerves). Here, we report the effect of valproic acid (VPA) along with forced expression of Oct4 transcription factor on lysolecithin (LPC)-(toxin that kills  oligodendrocytes) induced experimental demyelination. Mice were gavaged (fed) with VPA for one week, and then inducible Oct4 expressing lentiviral particles (gene therapy vector) were injected into the lateral ventricle (fluid filled space in the brain). After one-week induction of Oct4, LPC was injected into the optic chiasm (bit where optic nerves leave the brain) . Functional remyelination was assessed by visual-evoked potential (VEP) recording. Myelination level was studied using FluoroMyelin staining and immunohistofluorescent (IHF) against proteolipid protein (PLP). IHF was also performed to detect Oct4 and SSEA1 as pluripotency markers (stem cell markers) and Olig2, Sox10, CNPase and PDGFRα as oligodendrocyte lineage markers. One week after injection of Oct4 expressing vector, pluripotency markers SSEA1 and Oct4 were detected in the rims of the ventricle. LPC injection caused extensive demyelination and significantly delayed the latency (delay) of VEP wave. Animals pre-treated with VPA+Oct4 expressing vector, showed faster recovery in the VEP latency and enhanced myelination. Immunostaining against oligodendrocyte lineage markers showed an increased number of Sox10+ and myelinating cells. Moreover, transdifferentiation of some Oct4-transfected cells (GFP+ cells) to Olig2+ and CNPase+ cells was confirmed by immunostaining. One-week administration of VPA followed by one-week forced expression of Oct4 enhanced myelination by converting transduced cells to myelinating oligodendrocytes. This finding seems promising for enhancing myelin repair within the adult brains.

So more ways to make myelin

Access to Medical Treatments (Innovation) Bill

Access to Medical Treatments (Innovation) Bill Is this the answer.
Bill 8 56/1 Access to Medical Treatments (Innovation) Bill CONTENTS Introductory 
1 Access to innovative medical treatments Database of innovative medical treatments 
2 Database of innovative treatments Responsible innovation 
3 Responsible innovation 
4 Effect on existing law Interpretation 
5 Interpretation etc Final 
6 Extent, 

 Bill 8 56/1 Access to Medical Treatments (Innovation) Bill 1 A BILL TO Make provision for access to innovative medical treatments; and for connected purposes. E IT ENACTED by the Queen’s most Excellent Majesty, by and with the advice and consent of the Lords Spiritual and Temporal, and Commons, in this present Parliament assembled, and by the authority of the same, as follows:— Introductory 
1 Access to innovative medical treatments The purpose of this Act is to promote access to innovative medical treatments by— 
(a) providing for the establishment of a database of innovative medical treatments, and for access to information contained in the database, and 
(b) encouraging responsible innovation by doctors in relation to the carrying out of medical treatment. Database of innovative medical treatments 
2 Database of innovative treatments 
(1) The Secretary of State may by regulations make provision conferring functions on the Health and Social Care Information Centre (“the HSCIC”) in connection with the establishment, maintenance and operation of a database containing information about— 
(a) innovative medical treatments carried out by doctors in England, and 
(b) the results of such treatments. 
(2) For the purposes of this section, medical treatment for a condition is “innovative” if it involves a departure from the existing range of accepted medical treatments for the condition. 
(3) Regulations under subsection 
(1) may in particular— B 5 10 15 20 2 Access to Medical Treatments (Innovation) Bill (a) confer power on the HSCIC to make provision about— 
(i) the information to be recorded in the database, and 
(ii) procedures relating to the recording of information in the database; 
(b) make provision for and in connection with access to information recorded in the database. 
(4) The provision that may be made by virtue of subsection (3)(b) includes, in particular— 
(a) provision requiring or authorising the HSCIC to disclose information— 
(i) to specified persons or descriptions of person, or 
(ii) for use for specified purposes; 
(b) provision requiring or authorising the HSCIC to impose conditions to be complied with by persons to whom information is disclosed by virtue of paragraph (a) (which may include conditions restricting the use or further disclosure of information). 
(5) Regulations under subsection (1) may be made in relation to innovative medical treatments generally or innovative medical treatments falling within a specified description. 
(6) Before making regulations under subsection (1) the Secretary of State must consult the HSCIC. (7) In this section, “specified” means specified in regulations under subsection (1). 
(8) The power to make regulations under subsection (1) is exercisable by statutory instrument; and an instrument containing such regulations is subject to annulment in pursuance of a resolution of either House of Parliament. Responsible innovation 3 Responsible innovation 
(1) It is not negligent for a doctor to depart from the existing range of accepted medical treatments for a condition if the decision to do so is taken responsibly. 
(2) For the purposes of taking a responsible decision to depart from the existing range of accepted medical treatments for a condition, a doctor must in particular— 
(a) obtain the views of one or more appropriately qualified doctors in relation to the proposed medical treatment, with a view to ascertaining whether the treatment would have the support of a responsible body of medical opinion, 
(b) take full account of the views obtained under paragraph (a) (and do so in a way in which any responsible doctor would be expected to take account of such views), 
(c) obtain any consents required by law to the carrying out of the proposed treatment, 
(d) consider— 
(i) any opinions or requests expressed by or in relation to the patient, 
(ii) the risks and benefits that are, or can reasonably be expected to be, associated with the proposed treatment, the treatments that 5 10 15 20 25 30 35 40 45 Access to Medical Treatments (Innovation) Bill 3 fall within the existing range of accepted medical treatments for the condition, and not carrying out any of those treatments, and 
(iii) any other matter that it is necessary for the doctor to consider in order to reach a clinical judgement, having regard in particular to the requirements of patient safety, and 
(e) take such other steps as are necessary to secure that the decision is made in a way that is accountable and transparent. 
(3) For the purposes of subsection (2)
(a), a doctor is appropriately qualified if the doctor has appropriate expertise and experience in dealing with patients with the condition in question. 
(4) The steps that must be taken by virtue of subsection (2)(e) include the recording in the patient’s notes of details relating to— 
(a) the views obtained under subsection (2)(a), (b) the doctor’s decision to depart from the existing range of accepted medical treatments for the patient’s condition, and (c) the proposed treatment. 
(5) Nothing in this section permits a doctor to carry out treatment for any purpose other than the best interests of the patient. 
4 Effect on existing law 
(1) Nothing in section 3— 
(a) affects any rule of the common law to the effect that a departure from the existing range of accepted medical treatments for a condition is not negligent if supported by a responsible body of medical opinion, or 
(b) is to be read as limiting the circumstances in which any such rule of the common law may be relied on (including, for example, where emergency treatment is required). 
(2) Accordingly— 
(a) any decision by a doctor to depart from the existing range of accepted medical treatments for a condition in accordance with section 3 does not prejudice the doctor’s ability, in relation to the departure, to rely on any rule of the common law referred to in subsection (1)(a); 
(b) a departure from the existing range of accepted medical treatments for a condition is not negligent merely because the decision was taken otherwise than in accordance with section 3. 
(3) Section 3 does not affect liability in respect of the negligent carrying out of medical treatment, notwithstanding that the treatment is carried out pursuant to a decision taken in accordance with that section. Interpretation 
5 Interpretation etc 
(1) In this Act— 
(a) “doctor” means a registered medical practitioner; 
(b) references to treatment of a condition include references to its management (and references to treatment include references to inaction). 5 10 15 20 25 30 35 40 
4 Access to Medical Treatments (Innovation) Bill 
(2) Nothing in this Act applies in relation to treatment carried out for the purposes of medical research. 
(3) Nothing in this Act applies in relation to treatment which is carried out solely for cosmetic purposes. 
Final 6 Extent, commencement and short title 
(1) This Act extends to England and Wales only. 
(2) Sections 1 to 5 come into force on such day or days as the Secretary of State may by regulations made by statutory instrument appoint. 
(3) Regulations under subsection (2) may— 
(a) appoint different days for different purposes; 
(b) make transitional or saving provision. 
(4) This section comes into force on the day on which this Act is passed. 
(5) This Act may be cited as the Access to Medical Treatments (Innovation) Act 
So the debate was made on friday.
You can read the debate  (CLICK)

1) The Secretary of State shall require the National Institute for Health Research to develop and introduce a mechanism for—
(a) gathering and recording existing evidence on off-patent, repurposed drugs, including clinical trial evidence, and
(b) passing this information to relevant bodies.
(2) The Secretary of State shall determine the relevant bodies under subsection (1) and may revise that determination from time to time.
New clause 3—Appraisal in new indications
(1) Where there is an off-patent, repurposed drug with strong evidence of its effectiveness in a new indication, the Secretary of State shall direct theNational Institute for Health and Care Excellence (NICE) to conduct an appraisal in relation to the drug in its new indication.
(2) An appraisal under subsection (2) should include a cost-effectiveness analysis.
New clause 4—National commissioning policy for off-patent new drugs
Where there is an off-patent, repurposed drug with strong evidence of its effectiveness in a new indication, the Secretary of State shall require NHS England to produce and disseminate a national commissioning policy.
New clause 5—Accessibility of the licensing process
(1) The Secretary of State shall require the Medicines and Healthcare products Regulatory Agency to consult key stakeholders about steps to be taken to make the licensing process more accessible to organisations or individuals other than pharmaceutical companies.
(2) For the purposes of subsection (1), key stakeholders shall include, but not be limited to—
(a) patient organisations,
(b) medical research charities,
(c) relevant academics, and
(d) the British Generic Manufacturers Association.
New clause 6—British National Formulary: inclusion of off-patent drugs
The Secretary of State shall require NICE and the British National Formulary (BNF) to review their processes for registering off-label uses of repurposed drugs where there is strong evidence of their effectiveness.
Amendment 10, in clause 1, page 1, line 3, after “treatments” insert “(including treatments consisting in the off-label use of medicines or the use of unlicensed medicines)”
Amendment 13, in clause 5, page 3, line 44, at end insert—
“(1A) For the purposes of section 2(2), the kinds of medical treatment that may be innovative medical treatments include (amongst other things)—
(a) the off-label use of an authorised medicinal product, and
(b) the use of a medicinal product in respect of which no marketing authorisation is in force.
(1B) In subsection (1A)(a), the reference to the off-label use of an authorised medicinal product is a reference to the use of the product—
(a) for a purpose other than one for which its use is specified,
(b) in relation to a person who is not within a description of persons for whom its use is specified, or
(c) in any other way in which its use is not specified.
(1C) In this section—
(a) ‘authorised medicinal product’ means a medicinal product in respect of which a marketing authorisation is in force;
(b) ‘marketing authorisation’ and ‘medicinal product’ have the same meanings as in the Human Medicines Regulations 2012 (S.I. 2012/1916);
(c) ‘specified’, in relation to a medicinal product, means specified in its marketing authorisation.”

Saturday, 30 January 2016

ClinicSpeak: switching from an injectable to an oral DMT

The power of data; moving mountains and liberating people with MS. #ClinicSpeak #MSBlog #MSResearch

"Better the devil you know that the devil you don't. I have been telling my patients who are stable on an injectable that as they are responding to a particular class of DMT do they really want to take a chance and switch  to an oral a new class of DMT when we have no idea if they will respond to or not?"

"I have been saying that if you are currently a responder (NEDA-3) to IFNbeta or glatiramer acetate we have no idea if you will respond to DMF (dimethyl fumarate, Tecfidera) or teriflunomide (Aubagio). As these drugs have different modes of action I have no idea if response to one drug predicts response to another drug. The good news is that it appears I was wrong. The study below using real-life data from MSBase shows that pwMS stable on IFNbeta or GA have no increased relapse rate when they switch to an oral. Good news? Yes, very good news. I know a large number of patients who are simply tired of injecting themselves who will now want to make the switch. It shows you the power of data. Data can move mountains."

"Congratulations to the MSBase team for another wonderful publication. You are really making a difference to the way we practice clinical neurology. I am sure a lot of pwMS will be thankful for your efforts; particularly this study. Prof G can't sit on the fence anymore."

Epub: Spelman et al. Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis. Eur J Neurol. 2016 Jan 19. doi: 10.1111/ene.12929.

BACKGROUND AND PURPOSE: Early relapse outcomes in long-term stable patients switching from interferon β/glatiramer acetate (IFNβ/GA) to oral therapy are unknown.

OBJECTIVE: The objective of this study was to compare early relapse and progression in multiple sclerosis (MS) patients switching to oral therapy following a period of stable disease on IFNβ/GA, relative to a propensity-matched comparator of patients remaining on IFNβ/GA.

METHODS: The MSBase cohort study is a global, longitudinal registry for MS. Time to first 6-month relapse in previously stable MS patients switching from platform injectables ('switchers') to oral agents were compared with propensity-matched patients remaining on IFNβ/GA ('stayers') using a Cox marginal model.

RESULTS: Three-hundred and ninety-six switchers were successfully matched to 396 stayers on a 1:1 basis. There was no difference in the proportion of patients recording at least one relapse in the first 1-6 months by treatment arm (7.3% switchers, 6.6% stayers; P = 0.675). The mean annualized relapse rate (P = 0.493) and the rate of first 6-month relapse by treatment arm (hazard ratio 1.22, 95% confidence interval 0.70, 2.11) were also comparable. There was no difference in the rate of disability progression by treatment arm (hazard ratio 1.43, 95% confidence interval 0.63, 3.26).

CONCLUSION: This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy. There was no evidence of disease reactivation within the first 6 months of switching to oral therapy.

CoI: multiple

Oxygen to the rescue

Desai RA, Davies AL, Tachrount M, Kasti M, Laulund F, Golay X, Smith KJ.Cause and prevention of demyelination in a model multiple sclerosis lesion.Anals Neurol. 2016 Jan 27. doi: 10.1002/ana.24607. [Epub ahead of print]

BACKGROUND: Demyelination is a cardinal feature of multiple sclerosis, but it remains unclear why new lesions form, and whether they can be prevented. Neuropathological evidence suggests that demyelination can occur in the relative absence of lymphocytes, and with distinctive characteristics suggestive of a tissue energy deficit.

OBJECTIVE: To examine an experimental model of the early multiple sclerosis lesion and identify pathogenic mechanisms and opportunities for therapy.

METHODS: Demyelinating lesions were induced in the rat spinal dorsal column by microinjection of lipopolysaccharide, and examined immunohistochemically at different stages of development. The efficacy of treatment with inspired oxygen for two days following lesion induction was evaluated.

RESULTS: Demyelinating lesions were not centred on the injection site, but rather formed one week later at the white-grey matter border, preferentially including the ventral dorsal column watershed. Lesion formation was preceded by a transient early period of hypoxia and increased production of superoxide and nitric oxide. Oligodendrocyte numbers decreased at the site shortly afterwards, prior to demyelination. Lesions formed at a site of inherent susceptibility to hypoxia, as revealed by exposure of naïve animals to a hypoxic environment. Notably, raising the inspired oxygen (80%, normobaric) during the hypoxic period significantly reduced, or prevented, the demyelination.

INTERPRETATION: Demyelination characteristic of at least some early multiple sclerosis lesions can arise at a vascular watershed following activation of innate immune mechanisms that provoke hypoxia, superoxide and nitric oxide formation, all of which can compromise cellular energy sufficiency. Demyelination can be reduced or eliminated by increasing inspired oxygen to alleviate the transient hypoxia.

In this study they inject a bacterial product that activates the local glia and they produce toxic molecules such as nitric oxide (one molecule of nitrogen and one of oxygen) and superoxide which is a type of damaging oxygen. This causes hypoxia (lack of oxygen) in the tissues and then damage occurs. Then they make the animals breathe oxygen and damage does not occur.

This is not hyperbaric oxygen (pressurised oxygen) but just your typical oxygen. The translatable aspect would be simple give people with relapse oxygen and see how people recover without oxygen. A simple study.

Prof G addendum: We are in discussion with Prof Ken Smith to see if we can help him test this treatment in MSers with acute optic neuritis. If you had optic neuritis would you volunteer for an oxygen therapy trial?

Friday, 29 January 2016

Maybe the Government Does Listen And Take Note

The Repurposing bill ran into problems because the Government did not believe it was necessary. They feel it was not for the government to hold the licence but at the same time being the purchaser and more important they did not believe it was necessary as the Government were insistent that Doctors have the right to prescribe off-label.

We have seen documents by George Freeman that clearly support this view and we are aiming to show a redacted version of this on the blog.

However The Guardian have been on the case (Click)

The government backs wider access to experimental drugs. Some people may talk about last week's disaster but this was phase I testing and we are not talking about this but this is repurposing of currently available drugs.

The government has thrown its weight behind a private member’s bill to encourage GPs and hospital doctors to try experimental medicines.

The life sciences minister George Freeman is supporting the bill on medical innovation, which was put forward by Chris Heaton-Harris and is being debated in the House of Commons on Friday.

The bill, which has some cross-party support, would allow doctors to search a database for drugs that are in trials or are licensed for a different use.

Civil servants at the Department of Health have been involved in the drafting, at Freeman’s request, and he has secured the support of some opposition MPs.

“I’m delighted that after extensive cross-party working, I will be announcing government support for a package of amendments to this bill in order to help accelerate access to new drugs for NHS patients,” Freeman said.ect committee.

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Supporters of the bill believe it has a good chance of becoming law although it may encounter further opposition in the Lords.

Central to the bill now is a database, which any doctor could browse to find not only the standard treatments for their patient, but what drug trials are taking place that the patient might be eligible to join. It will also contain details of the off-label use of drugs – where a medicine has been prescribed by doctors for something for which it is not licensed. Many medicines for children are used off-label because drug companies are reluctant to enter children into trials.

Freeman envisages that the National Institute for Health and Care Excellence (Nice) would be asked to evaluate the evidence for drugs that are used in this way, outside the terms of their licence.

The database will also have details of drugs earmarked for accelerated access to the NHS, under a scheme devised by Freeman that is now the subject of a review chaired by Sir Hugh Taylor. The review, which is due to report in April, is looking at ways to speed up the introduction of innovative drugs that show promise into the NHS.

Amongst those who have been consulted on the bill are the Labour MP Nick Thomas-Symonds, who himself brought forward a private member’s bill to enable off-patent drugs to be licensed for new uses last November; the SNP health spokeswoman in Westminster, Dr Philippa Whitford; and the Liberal Democrat Norman Lamb, who was a health minister in the coalition government.

Freeman said: “Very often on private members’ business on Fridays, backbench MPs bring forward well-intended legislation which government is forced to oppose because it is unworkable.

“In the case of Nick Thomas-Symonds’s off-label bill and Chris Heaton-Harris’s bill on medical innovation, I felt their objectives were so supportable that I have been happy to put officials in the department to work to help come up with amendments to produce a bill that the government could support and I’m delighted that this is an example of cross-party working for the good of all patients.”

We are on this case already, looks like we have found a new white knight or is it a blue knight:-)

ResearchSpeak: daclizumab and black hole formation

Do you want to prevent end-organ damage or loss of brain tissue? #ResearchSpeak #MSBlog #MSResearch

"Preventing end-organ damage is the what we should all be aiming for as a treatment target in MS. The end-organ is the brain and spinal cord. We know that MS, or the shredder, damages the end-organ acutely in MS lesions by transecting axons and killing nerves (relapse). Those axons and nerves that survive the shredder acutely are damaged and soldier on to die off gradually over time (progression). Therefore it makes sense to switch off lesion formation as best we can as soon as possible in the disease; by doing this we prevent further axonal transections (relapses) and priming of nerves to die off in the future (progression). This is the philosophy that underpins the early effective treatment paradigm. To me this is common sense, but not all people in the field agree with me."

"It was only this week that I read a proposal that still suggested we should only start DMTs in people with MS presenting with a clinically isolated syndrome if they had 9 or more lesions on MRI. In other words if you have only 2 lesions on MRI let's wait for  the shredder to leave another 7 or more lesions before we try and turn it off. Never mind the risk the individual that lesion 5 may be the one that leaves him or her paraplegic and doubly incontinent. One of the differences between someone who has 2 lesions vs. 15 lesions, at baseline, when they present with their first attack is time. The person with 15 lesions has probably had asymptomatic MS for sometime and may have already acquired a lot of damage. In comparison the person who presents with 2 lesions has probably had MS for a much shorter period of time, has less damage and may have the most to benefit from early treatment. The person with 2 lesions is lucky that he/she has presented early. The person with 15 lesions is unlucky in that the shredder has been quietly shredding the brain without causing overt symptoms. As this person has less reserve it is not surprising that they don't do as well longterm when compared to people with fewer lesions at baseline. Prognosis is determined by reserve capacity, which gives you the ability to recover and maintain function. I simply can't see the rationale in waiting for damage to occur to the end-organ before starting a treatment. This particularly pertinent as new more effective treatments come on line."

"The good news is that as we move into the upper echelons of effectiveness the treatments have greater impact on preventing or delaying end-organ damage. One marker of end-organ damage is the so called black hole on T1-weighted MRI. We know from pathology studies that black holes are correlated with loss of nerve fibres. It is therefore reassuring to see that daclizumab is effective at reducing the accrual of black holes (damage) on MRI. Interestingly, in a meta-analysis of baseline variables that predict outcome in pwMS treated with placebo that was presented at ECTRIMS last year, T1 black holes was the third best predictor of outcome behind the PASAT (cognition) and the SF-36 physical component (quality of life). In short if I had MS I would want to be on a drug that had been shown to prevent end-organ damage. This is why our treatment target will have to evolve beyond NEDA-3 to incorporate markers of end-organ damage in MS, for example the normalisation of brain volume loss and spinal fluid neurofilament levels. Maybe you disagree?"

"I know many of you dislike the term shredder; it is not my term but it captures in a word what is happening to the brain and spinal cord in people with active MS. If you don't believe me just come and sit-in with me when I do my MS clinic on a Thursday afternoon."

Radue et al. Daclizumab high-yield process reduced the evolution of new gadolinium-enhancing lesions to T1 black holes in patients with relapsing-remitting multiple sclerosis. Eur J Neurol. 2016 Feb;23(2):412-5. doi: 10.1111/ene.12922.

BACKGROUND AND PURPOSE: In the SELECT study, treatment with daclizumab high-yield process (DAC HYP) versus placebo reduced the frequency of gadolinium-enhancing (Gd(+) ) lesions in patients with relapsing-remitting multiple sclerosis (RRMS). The objective of this post hoc analysis of SELECT was to evaluate the effect of DAC HYP on the evolution of new Gd(+) lesions to T1 hypointense lesions (T1 black holes).

METHODS: SELECT was a randomized double-blind study of subcutaneous DAC HYP 150 or 300 mg or placebo every 4 weeks. Magnetic resonance imaging (MRI) scans were performed at baseline and weeks 24, 36 and 52 in all patients and monthly between weeks 4 and 20 in a subset of patients. MRI scans were evaluated for new Gd(+) lesions that evolved to T1 black holes at week 52. Data for the DAC HYP groups were pooled for analysis.

RESULTS: Daclizumab high-yield process reduced the number of new Gd(+) lesions present at week 24 (P = 0.005) or between weeks 4 and 20 (P = 0.014) that evolved into T1 black holes at week 52 versus placebo. DAC HYP treatment also reduced the percentage of patients with Gd(+) lesions evolving to T1 black holes versus placebo.

CONCLUSIONS: Treatment with DAC HYP reduced the evolution of Gd(+) lesions to T1 black holes versus placebo, suggesting that inflammatory lesions that evolved during DAC HYP treatment are less destructive than those evolving during placebo treatment.

CoI: multiple, I am a co-author on this paper and was member of the DECIDE steering committee

Is fludarabine the next hope to knock cladribine off its perch

Greenberg SJ et al.Fludarabine add-on therapy in interferon-beta-treated patients with multiple sclerosis experiencing breakthrough disease. Therapeutic Advances in Neurological Disorders January 21, 20161756285615626049

Background: Patients with relapsing–remitting multiple sclerosis (RRMS) may experience breakthrough disease despite effective interferon beta (IFNβ) therapy. Fludarabine (FLU) is a chemotherapeutic agent used in lymphoproliferative disorders that may be synergistic when combined with immunomodulatory therapy to control active multiple sclerosis (MS).

Objective: The objective of this study was to explore the safety and tolerability of FLUversus monthly methylprednisolone (MP) in IFNβ-treated RRMS patients with breakthrough disease. Clinical and MRI effects of IFNβ-1a plus FLU were evaluated.
Methods: Eighteen patients with breakthrough disease [⩾2 relapses over the prior year and ⩾1.0-point increase in Expanded Disability Status Scale (EDSS) score sustained for ⩾3 months] after >1 year of IFNβ therapy were enrolled in this prospective, open-label, randomized, proof-of-concept, pilot study. Patients received intravenous (IV) MP 1 g daily for 3 days and then were randomized to receive 3 monthly IV infusions of FLU 25 mg/m2 daily for 5 consecutive days (n = 10) or MP 1 g (n = 8). All patients maintained their intramuscular IFNβ-1a treatment throughout the study. Analyses explored safety signals and directional trends; this preliminary study was not powered to detect clinically meaningful differences.

Results: Both combination treatments were safe and well tolerated, with all adverse events mild. Patients treated with IFNβ-1a plus FLU had similar relapse rates, EDSS scores, and MS Functional Composite scores, but significantly less acute corticosteroid use for on-study relapses and better responses on some MRI outcomes, versus patients treated with IFNβ-1a plus MP.

Conclusions: Further study of FLU for breakthrough disease in patients with RRMS is warranted.

Fludarabine is a chemotherapy drug used in the treatment of cancers of blood cells such as leukemias and lymphomas). 

Fludarabine is a purine analog, and can be given both orally and intravenously. Fludarabine inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase. It is active against both dividing and resting cells. Being phosphorylated, fludarabine is ionized at physiologic pH and is effectually trapped in blood. This provides some level of specificity for blood cells, both cancerous and healthy.
Fludarabine causes anemia, thrombocytopenia and neutropaenia, requiring regular blood count monitoring.

Fludarabine is like Cladribine is also a purine analog, Chemically, it mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, which interferes with the cell's ability to process DNA. It is easily destroyed by normal cells except for blood cells, with the result that it produces relatively few side effects and results in very little non-target cell loss.

In this study they look at the effect of combining fludarabine with beta interferon and compare this with a combination of interferon beta and steroids (methylprednisolone) in people with breakthrough disease.

In the study they suggest that the action of fludarabine may be synergistic when used with beta interferon. Synergistic is a word used by many but seldom really show. Synergism occurs when the the action of two drugs is better than their additive effect alone. However when you use a non linear scale to assess efficacy it is very difficult to  to show true synergy over a simple additive effect so addition is 2 + 2 = 4 where as synergy is 2 + 2 = 5.

People were first given steroids for a week then went on to fludarabine 5 times in a month for 3 months of steroids once a month for 3 months whilst taking interferon once a week and assessors were not blinded and if neutrophil numbers became low you could have cytokine therapy to increase this and people on steroids could have more steroids if they relapsed. 

The study however only involved only 18 people and it is impossible to draw any real conclusions about efficacy or safety for that matter. There appeared to less However, the study was not based on any real sample size studies  and not surprisingly in the end because the trial was so small them there was no differences to be seen, so more trials need to be done. A few people continued to relapse

If fludarabine was as good cladribine, one may expect that it could be better than beta interferon and you could simply do fludarabine by itself. In the cladribine verses beta interferon trial presented at the AAN 2013, I believe Cladribine was better than interferon beta.

However in this study they use a trickle dose of repeated injections and I wonder if this is the way to take these types of drugs, as it may drip feed side effects/infection risk and maybe best to get larger dose for the drug to do its stuff.

Prof G has questioned about whether people and neurologists are risk adverse and will "wait and see". This clearly shows there is some truth to be had and people are relapsing on treatment.

So the question one can have if people are failing beta interferon is, is it a good idea to carry on trying to treat people with interferons when they are relapsing or should they be switched onto a more effective treatments. 

 Maybe it time to read

This study was funded by Biogen in support of the lead author who is an employee of Abbvie, which makes daclizumab HYP. So is pharma now supporting off label:-)?...I'm only joking, but if you are having relapses time to escalate

Thursday, 28 January 2016

ResearchSpeak: what are the implications of the negative fingolimod PPMS trial

What can we learn from the negative fingolimod in PPMS trial? #MSBlog #MSResearch #ResearchSpeak

"The INFORMS, or fingolimod in PPMS, study results have just been published online. We have discussed this study before in great detail. The fact this study was negative and fingolimod did not have an impact on any of the composite endpoints including upper limb function, nor an impact on brain atrophy, raises real questions about the pathogenesis of PPMS and progressive MS in general. In short this trial suggests we don't have clue about what is driving non-relapsing progressive MS. Or do we? The positive ocrelizumab PPMS trials suggests that may be the problem in non-relapsing progressive MS has something to do with B cells and plasma cells that are responsible for producing antibodies within the intrathecal compartment (within the meninges) of the brain and spinal cord."

"Did we get the therapeutic target wrong with fingolimod? In hindsight yes. Let's hope we learn and move on. I personally think if the DMT hasn't been shown to have an impact on intrathecal B cells and plasma cells it won't work in non-relapsing progressive MS. I hope I am wrong, the siponimod SPMS trial will be the next to report. Siponimod is a follow-on S1P modulator and has the same mode of action to fingolimod. If there are enough active or relapsing SPMS subjects in this trial it should be positive."

"Please note the results of this trial challenge my length-dependent axonopathy hypothesis. I would have expected fingolimod to have an impact on upper limb function."

Lublin et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2016; DOI:

Background: No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis.

Methods: In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25–65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2–10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with, number NCT00731692. The study is now closed.

Findings: 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87–82·51) of patients in the fingolimod group versus 80·3% (73·31–87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80–1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%).

Interpretation: The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis.

CoI: multiple

ClinicSpeak & BrainHealth: solifenacin trial shows positive influence on bladder function

Are you on a centrally acting anticholinergic? If yes, you may want to consider stopping it. #ClinicSpeak #BrainHealth #MSBlog #MSResearch

"The study below shows that the drug solifenacin (Vesicare), a so called anti-cholinergic drug of the antimuscarinic class, is effective in reducing contractions of overactive bladders and increasing bladder volume. This results in reduced urinary frequency, urgency, urge incontinence and nocturia (need to pass urine at night). These findings are not new; we have been using solifenacin for years and a large number of pwMS find it helpful."

"What is not covered in this abstract is the real reason why solifenacin (Vesicare) is so much better than oxybutynin (Ditropan) and older generation anticholinergic drug. Oxybutynin crosses the blood brain barrier and enters the brain and blocks brain cholinergic receptors, which impairs cognition. Studies suggest that centrally  acting anticholinergics, such as oxybutynin,  clips IQ by about 7 IQ points or half a standard deviation. This effect is not trivial given that the majority of people with established MS, and bladder problems, already have cognitive problems. In comparison solifenacin, and the other newer generation anticholinergics, don't cross into the brain to the same extent and therefore have a minimal impact on cognition. Why take a drug that impairs cognition when you can take an alternative that does not?"

"Are there any other anticholinergic drugs that affect cognition that you should be aware of? Yes, tricyclic antidepressants, for example amitriptyline, and older generation antihistamines also have central anticholinergic effects and affect cognition. It has recently been shown that long term exposure to anticholinergics is a risk factor for dementia in later life. Therefore one component of our Brain Health initiative is try and get pwMS to avoid or stop centrally acting anticholinergic drugs and other drugs that affect cognition."

"If you are on one of the drugs that has centrally acting anticholinergic effects I suggest you discuss the possibility of stopping the medication, or switching to alternative medication, with your neurologist or family doctor."

Epub: Amarenco et al. Solifenacin is effective and well tolerated in patients with neurogenic detrusor overactivity: Results from the double-blind, randomized, active- and placebo-controlled SONIC urodynamic study. Neurourol Urodyn. 2015 . doi: 10.1002/nau.22945.

AIMS: To investigate the effect on urodynamics of 4 weeks treatment with solifenacin succinate in patients with neurogenic detrusor overactivity (NDO) due to multiple sclerosis (MS) or spinal cord injury (SCI).

METHODS: SONIC was a prospective, multicenter, double-blind, phase 3b/4 study investigating the efficacy and safety of solifenacin 10 mg in patients with NDO due to MS or SCI. Patients (n = 189) were randomized to placebo or active treatment (solifenacin 5 mg, 10 mg or oxybutynin hydrochloride 15 mg) for 4 weeks, after a 2-week, single-blind, placebo run-in period. The primary endpoint was change in maximum cystometric capacity (MCC) from baseline to end of treatment. The primary analysis compared solifenacin 10 mg versus placebo; all other comparisons were considered secondary. Secondary endpoints included changes in urodynamic parameters, patient-reported outcomes, and safety assessments.

RESULTS: In the primary analysis, solifenacin 10 mg significantly improved mean change from baseline MCC versus placebo (P < 0.001) and was associated with improvements in bladder volume at first contraction and at first leak as well as detrusor pressure at first leak. Similar results were obtained for oxybutynin versus placebo. Patient perception of bladder condition significantly improved with solifenacin 10 mg versus placebo (P = 0.041). There was a clear improvement in quality of life (QoL) in the solifenacin arms versus placebo. The overall incidence of adverse events was low.

CONCLUSIONS: In patients with NDO due to MS and SCI, 4 weeks of treatment with solifenacin 10 mg improved urodynamic variables and QoL versus placebo and was well tolerated

CoI: multiple

Wednesday, 27 January 2016

Do you have Emotional Incontinence

Hanna J, Feinstein A, Morrow SA.The association of pathological laughing and crying and cognitive impairment in multiple sclerosis.
J Neurol Sci. 2016 Feb 15;361:200-3.

BACKGROUND:Pathological laughing and crying (PLC) is common in multiple sclerosis (MS), defined as emotional expression that is exaggerated/incongruent with underlying mood. In other neurological disorders, PLC is associated with cognitive impairment (CI). Few studies have examined this relationship in MS.
OBJECTIVE:To determine the association between PLC and CI in an MS population.
METHODS:Retrospective chart review study of 153 MS subjects assessed in an outpatient clinic for CI. Data was collected on the minimal assessment of cognitive function in MS (MACFIMS), the Center for neurological study-lability scale (CNS-LS), a screening measure for PLC symptoms and the hospital anxiety and depression scale (HADS). Analyses of covariance compared performance on the MACFIMS between PLC (CNS-LS score≥17, HADS-D≤7) and non-PLC groups.
RESULTS:MS subjects positive for PLC on the CNS-LS but without depression had lower scores on the controlled oral word association test, a measure of verbal fluency, and the California verbal learning test - 2 immediate recall score, a verbal memory measure.
CONCLUSIONS:This study demonstrates a connection between CI, specifically verbal fluency and verbal learning, and PLC in MS subjects. 

I was an MS Life in Manchester with ProfG when we were doing "Meet the Scientitis" this chap came up to talk to us. He was one of those people who had not looked into their condition and so did not know much about MS. He said that he used to uncontrollably cry alot and ProfG said that he had "emotional incontinence" and that there were treatments that may help with the problem and so if you do have this then speak to your MS care team. This study suggests that there appears to be a link between uncontrollable laughing and crying with cognitive issues and suggests there may be lesions in the pathways controlling these emotions.