Tuesday, 28 February 2017

Tabalumab (LY 2127399) Trial in 243 people in 63 Centres. Where you involved? what Happened?

You said 

"I believe patients participating in trials have the right to be informed about the trial results".

I said
"I agree with you...are any of the readers, people who participated in this Eli Lilly MS trial. Were you informed of the results? (NCT00882999)"


However, should we have to be detectives?

   In this case, we have not proof that people were harmed, but the possibility is there and                see   

How long after a trial is finished do you believe is enough time for the results to be submitted for publication in a proper paper? 

When should we start searching for the information, or should we not bother trying to find what is not being said?

Hopefully the Promise is the Publication of the Trial Results including the B cell Phenotyping Data.

Does this relate to Disease Activity?


Modifiable risk factors in MS - help yourself

Modifiable Risk Factors in the Progression of Multiple Sclerosis: A Systematic Review of the Epidemiology and Treatment [Internet].


Hempel S, Fu N, Estrada E, Chen A, Miake-Lye I, Beroes J, Miles J, Shanman R, Shekelle P.


Washington (DC): Department of Veterans Affairs (US); 2015 Dec.
VA Evidence-based Synthesis Program Reports.


Multiple sclerosis (MS) is the most common progressive disease of the central nervous system in young adults and the cause of serious physical disability in adults of working age. Epidemiologic data suggest that rates of MS vary with demographic and environmental factors. The disease presentation is very heterogeneous with diverse clinical manifestations. Progression of MS may vary with modifiable risk factors. This systematic review focused on modifiable risk factors and exposures that are associated with MS progression, and interventions that are directed at modifiable risk factors to delay progression.

I keep a close eye out for research publications looking into improving outcomes in MS, it is not all about disease modifying treatments ;) We keep our blog readers appraised of this on a regular basis and I know many of you embrace the freedom it provides to choose.

Here, Hempel and colleagues identified 8,594 articles but only 94 met their criteria (quality not quantity!).

So what were the modifiable risk factors?
1) VITAMIN D - lower vitamin D levels were associated with higher EDSS (disability) scores.
2) SMOKING - increased risk of faster progression in smokers than non-smokers.

What about risk modification treatments?
1) EXERCISE - although the pooled effect of exercise interventions was not significant from control groups, but when using a sensitivity analysis (a way of determining if specific values of an independent variable, i.e. exercise, impact on a dependent variable, i.e. EDSS) the results favored the exercise arm.
2) VITAMIN D - vitamin D supplementation showed a trend for EDSS improvement.

Overall, the evidence for modifiable based on this meta-analysis is moderate at best, as it is difficult to analyze environmental risk factors. The interactions between environmental risk factors are manifold and direct causal inferences cannot be made. That said, they are out there, easy to do and all with minimal side effects.

"Today you are You, that is truer than true.
There is no one alive who is Youer than You"
- Dr Seuss.

Monday, 27 February 2017

What's Happening with the Clinical Trial Data

As soon as rituximab and then Ocrelizumab was found to inhibit relapsing MS, companies began the hunt for "me-toos" to do the same thing.

Ocreliziumab depletes CD20 B cells and blocks relapses, so it gets rid of memory B cells, but not the earliest of B cells or the antibody forming plasma cells.

Unless you know what CD20-B cell depletion is doing, getting rid of the all B cells may not seem unresponable.

Companies thought that they could get rid of B cells by depleting B cell growth factors

A few companies had the same type of idea to make a buck

Merck made a fusion protein to block BAFF and APRIL B cell growth factors called Atacicept.

Eli Lilly made an antibody that blocked BAFF called LY2127399 or tabalumab

There was another one called Belimumab, which never made it into MS.....Luckily.

Rather than selecting a cashcow, looks they got a different beast
In fact Atacicept made things worse in trials!

1. Atacicept in Subjects With Optic Neuritis (NCT00624468)
2.A Phase 2 Study of Atacicept in Subjects With Relapsing Multiple Sclerosis (ATAMS) (NCT00642902)

It said

Sponsor voluntarily decided to prematurely terminate this trial due to an increase in multiple sclerosis (MS) disease activity observed in atacicept arms of both trials as compared to placebo.

Both trials were eventually published 

Sergott RC, Bennett JL, Rieckmann P, Montalban X, Mikol D, Freudensprung U, Plitz T, van Beek J; ATON Trial Group. ATON: results from a Phase II randomized trial of the B-cell-targeting agent atacicept in patients with optic neuritis. J Neurol Sci. 2015; 351:174-8.

So is the problem APRIL, BAFF or both?

The answer comes with the result of what happened with tabalumab that blocks only BAFF.

A Study of Patients With Relapsing Remitting Multiple Sclerosis NCT00642902

The company has reported on Clinical tiral. gov that the trial was completed.  

What happened.?

We don't know because the results have not been reported.

Blocking BAFF gets rid of  mature B cells and can even get rid of plasma cells and reduce antibodies, but they appear to have the potential to increase the memory B cell pool, which recently we suggested could be the problem in MS.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017. pii: S2352-3964(17)30045-2.

Therefore both tabalumab and atacicept could make MS worse.

Response to therapy may help elucidate whether the idea has any legs, it may help us understand treatement and may help us personalise this treatment. 

For Merck it may help us to understand how Cladribine actually works

For Lilly it may help with responsible reporting and help determine if BAFF inhibition is what makes MS worse

You prompted us to ask more about access to the data, notably Lilly

The company website (Click) says "..companies must act to earn the trust of the public they serve"

However, as we have no access to data or the result, which one could predict worsened MS,  many years after the trial was completed, how is that going to lead us towards trust?

They say "We have an online portal to facilitate requests from legitimate researchers for clinical trial data there

So when requested it is "out of scope"

"Whether favourable or unfavourable, Lilly posts the results of all Lilly-sponsored Phase II, Phase III and Phase IV clinical trials of Lilly marketed products conducted anywhere in the world that were initiated on or after October 15, 2002"

When asked specifically, it was said that "this standard only applies to marketed compounds".

So as Talabummab was not a marketed we are not getting access to the data, 

"Lilly discloses results of Lilly-sponsored clinical trials for compounds whose development terminates on or after October 1, 2009". 

In response to this question about disclosure the response was "We expect to submit the results of this study to Clinicaltrials.gov in the third quarter of this year following the official termination of the molecule’s development marked by the inactivation of the IND this year". 

This will no doubt say the trial failed, but will it say it worsened disease? 

However, on clinical trials.gov it is unlikely to talk about the immunostaining and disease activity, which is the data that will help us understand what occurs in MS.

If there was an increase in B memory cells? How long did this occur, does it relate to disease activity?

I guess, we will never know.

Companies do preclinical testing to ensure their drugs are relatively safe, so that they can make an IND filing.

IND means an Investigational New Drug (IND) program is the means by which a pharmaceutical company obtains permission to ship an experimental drug to clinical investigators before a marketing application for the drug has been approved. The IND application is reviewed for safety to assure that research subjects will not be subjected to unreasonable risk. If the application is cleared, the candidate drug usually enters a Phase 1 clinical trial and beyond until they apply for a New Drug Application (NDA) which allows companies to market a product.

  • Is the drug safe and effective (efficacy) in its proposed use(s) when used as directed, and do the benefits of the drug outweigh the risks?
  • Is the drug’s proposed labeling (package insert) appropriate, and what should it contain?
  • Are the methods used in manufacturing the drug (good manufacturing practice [GMP]) and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity?

It seems development of Talabumab is not going to occur, so why hide results from people?

We will have to wait so see if EL actually does anything

Even with providing access data, the publication process who mean that nothing would get published before Q3 (third quarter) 2017.

Is this just another case of Bad Pharma?

#PolticalSpeak & #OffLabel: rituximab and the future of MS treatment

COMBAT-MS = COMparison Between All Treatments for MS #OffLabel #PoliticalSpeak

Ever since coming back from my sabbatical and witnessing the unmet need in resource poor countries for disease-modifying therapies for MS I have been promoting an Essential Off-Label DMT list for the treatment of MS. It has also become clear to me that this is not only a problem in resource-poor countries, but high-income countries as well.

The term flipping the pyramid refers to treating MS with the most active treatments first-line. In most countries the more effective treatments are only available 2nd or 3rd line mainly due to the costs of the treatments. In some countries, particularly in Sweden and the USA, they have overcome this problem by prescribing cheaper off-label options; rituximab and HSCT being the main off-label high-efficacy options available. To be frank rituximab (anti-CD20) is not really a cheap off-label option, but it is significantly cheaper than the licensed high-efficacy MS DMTs.

The issues around off-label prescribing when licensed therapies are available have been debated and discussed on this blog many times (search term OffLabel). These issues are rehearsed in an Editorial in last week's BMJ (see below). Morales & Guthrie make the point '... off-label prescribing may need more explicit justification, the evidence supporting prescribing is actually more important than the presence or absence of a licence in itself...'. How do we get the necessary evidence to support clinicians and patients make the correct decision? One way is to do randomised controlled trials comparing say rituximab with one of the licensed DMTs. Who will pay for this? Fortunately, PCORI (Patient-Centered Outcomes Research Institute) has funded a pragmatic trial to generate evidence on the relative efficacy and safety of rituximab to other licensed DMTs. PCORI as an organisation was established to evaluate the benefit and harm of already existing methods and treatments used in health care in real world populations and where there is a decisional dilemma. PCORI was part of the 2010 Affordable Care Act (“Obamacare”) and is an independent non-profit trust-fund.

In July 2016 PCORI announced a $8.5 million study comparing the effectiveness of rituximab, a biologic drug, to other commonly used disease-modifying therapies in individuals with the relapsing-remitting form of the disease. The study will be based at Karolinska Institute in Sweden and conducted in collaboration with Kaiser Permanente Southern California. In particular, it will assess the comparative safety outcomes of medications.

I am privileged to have been invited to be a stakeholder on this important study. My role is advisory and to help with keeping the wider MS community engaged and up-to-date on the progress and the aims of the study. The good news is that we had our first meeting on the 9th February and have made good progress. It seems as if we have found an appropriate name for the study COMBAT-MS (COMparison Between All Treatments for MS). The term may be appropriate in that the results of this study may be very disruptive. Could these results be what is required to start and off-label prescribing revolution? I sincerely hope it does in resource poor environments where so many pwMS are being left without any DMTs and MS is simply allowed to run its natural course. In high-income countries the battle between off-label prescribing and licensed therapies will be more nuanced. On the one hand the politicians and the EMA want to support Pharma, and their innovation machines, and on the other cash-strapped healthcare systems will be looking to reduce their drug costs. Who will win? I sincerely hope our patients win; surely they deserve the choice of a flipped pyramid? I would therefore like to thank the COMBAT-MS team for trying to make a difference and generate the real-life evidence we need to assess the efficacy and safety of rituximab in the management of MS. 

The other good news is that rituximab is coming off patent and we can expect several, hopefully cheaper, biosimilars to emerge on the market in the next year or so. Some concerns remain about the future of PCORI under the new Trump administration. However, we all expect funded projects, such as COMBAT-MS, to be completed.

What this study highlights is the need to explore how to optimise the use of off-label rituximab in MS. What dose should be used? Could it be used as a PIRT (pulsed immune reconstitution therapy)? Will a response marker emerge that will allow us to use anti-CD20 therapies more intelligently? How will rituximab do in a head-2-head study against ocrelizumab? Will the fact that anti-drug antibodies are higher with rituximab, than ocrelizumab, make a difference long-term?

Morales & Guthrie. Off-label prescribing of antidepressants. BMJ 2017;356:j849 (Editorial)


..... Strength of evidence matters more than presence or absence of a specific licence

..... In most countries, medicines have a product licence that describes how they should be used. Licensing is intended to ensure that medicines meet acceptable standards of efficacy, safety, and quality for a particular indication in a particular group of patients.

..... “Off-label” use occurs when a drug is prescribed for an unlicensed indication, to an unlicensed patient group (such as children), and/or as an unlicensed dosage or formulation.

.... Clinicians can legally prescribe off-label, and professional licensing agencies recognise that off-label use is necessary if licensed medicines are ineffective, if they are associated with adverse effects, or if the licensed dose or formulation does not meet the patient’s needs.

..... Professional responsibility in these circumstances is fundamentally the same as for on-label prescribing. As the UK medical regulator says, “We expect you to carefully consider any treatment that you prescribe, and we expect you to be able to justify your decisions and actions when prescribing, administering and managing medicines regardless of whether they are licensed or unlicensed.”

.... Although off-label prescribing may need more explicit justification, the evidence supporting prescribing is actually more important than the presence or absence of a licence in itself.

..... These mismatches between licensing, evidence, and guidelines within countries complicate clinical and shared decision making, and variations in licensing and guidelines between countries add further confusion.

..... For all prescribing, patients (or their parents or carers) should be given enough information to allow them to make an informed decision whether to take a medicine. This should include whether the intended use is off-label, but more importantly prescribers should discuss the strength of the evidence base underlying their recommendation.

..... Off-label prescribing matters because it is usually (but not always) associated with substantial uncertainty about the balance of benefit and harm. Prescribers should therefore be cautious when they prescribe an off-label medicine on the basis of an extrapolation of evidence for a different indication, in a different patient group, or for a substantially different dose or formulation.

..... Equally, however, on-label prescribing also often involves extrapolation, most commonly because the patient needing treatment is very different from the patients included in trials.

CoI: multiple

Sunday, 26 February 2017

#ClinicSpeak: pressure ulcers in MS

If you have a pressure ulcer you need to do something about it. #ClinicSpeak #MSBlog 

Dogs are increasingly being used as diagnosticians in medicine to help sniff out cancers and other metabolic conditions by using their ultra-sensitive sense of smell and their ability to learn and be trained. One condition that doesn't require a dog's nose are pressure ulcers. Patients with pressure ulcers have a characteristic smell; the bacteria and organisms that live in the ulcer produce odorants that is hard for the trained clinician to miss. 

Two week's ago when I collected one of my patients from the waiting room her odour told me that she had developed a pressure sore. My heart sank; the time and effort that goes into treating a pressure ulcer is enormous. Not to mention preventing it from reoccurring in the future. 

When I was training to be a neurologist pressure ulcers were the norm in patients with more advanced MS. Over the last two decades it is now unusual to see pressure ulcers. I say that, but in the last two years they are beginning to be more common. Why? I suspect like any other healthcare problem they are an indicator of austerity Britain; cut health and social care spending and you will see pressure sores becoming a problem again. In MS pressure ulcers are at the vanguard of a failing healthcare system

The paper below finds that pressure ulcers have a major impact on QoL for pwMS and they are strongly linked to problems with mobility. 

We are in the process of developing a C-QUIT (continuous quality improvement tool) with the idea of it being the 'carrot' and 'stick' to help drive adoption of the policies in the 'Brain Health: Time Matters' document. One metric that may get into the final tool is the proportion of pwMS with advanced disease who develop pressure ulcers. Pressure ulcers, or the lack of pressure ulcers, are a very good index of the quality care of care someone who is immobile is receiving. Do you agree? Keeping someone who is wheelchair, or bed, bound healthy and free of pressure sores takes resources and effort, not to mention love and compassion.  

If you are a carer, or a family member, of someone with advanced MS and they have a pressure ulcer or early skin changes suggestive of an early pressure ulcer, don't ignore the problem. Early intervention, or prevention, of pressure ulcers is better than having to wait until they are a problem. 

Please note that pressure ulcers are typically confined to people with advanced MS; if we can prevent, or delay, people getting advanced MS we should reduce this problem substantially. This is another reminder for us to treat MS early and effectively.

PaperpileMcGinnis et al. What is different for people with MS who have pressure ulcers: A reflective study of the impact upon people's quality of life? J Tissue Viability. 2015 Aug;24(3):83-90.

BACKGROUND: Multiple Sclerosis (MS) is a progressive, degenerative disease of the central nervous system. People with advanced disease who have compromised mobility, activity, sensory and/or cognitive abilities are at risk of pressure ulcers. Having a pressure ulcer has a substantial impact on a person's quality of life; a generic pressure ulcer Health Related Quality of Life (HRQL) framework has been used in this study.

AIM: To explore the views and opinions of patients with MS who have a pressure ulcer using a thematic framework and compare these to the general pressure ulcer population.

METHODS: Data for six MS patients was obtained through secondary analysis of transcripts from semi-structured interviews conducted during two studies which were part of a programme of HRQL Research.

FINDINGS: Patients with MS reported that their pressure ulcer affected their lives physically, psychologically and socially. All were confined to bed (as part of their pressure ulcer treatment) and therefore unable to participate in activities. Difficulties with movement and activity were partially attributed to the MS. Patients with MS did not report feeling ill with their pressure ulcer and expressed positive emotions and optimism. Pain or discomfort was a feature of the pressure ulcer for most patients.

CONCLUSIONS: Pressure ulcers have a major impact on QOL for all patients. Problems with mobility and activity associated with the pressure ulcer were confounded by the MS.