Friday, 2 December 2016

#NeuroSpeak & #ClinicSpeak: Alemtuzumab the expert European View

Using alemtuzumab in real-life is far more complicated than you realise. Does this explain the lack of confidence amongst neurologists about using alemtuzumab? #ClinicSpeak #NeuroSpeak #MSBlog

The following recommendations paper from a group of EU experts doesn't address the real issues with using alemtuzumab. Why? May because it was drafted and co-written by a third-party vendor and subsequently proof-read and checked by Sanofi-Genzyme. 

The acknowledgements at the end of the paper state: 'This manuscript was reviewed by Darren P. Baker PhD, and Neli Boyanova MD, of Sanofi Genzyme. Editorial support (assistance in drafting and editing of the manuscript text and tables, as directed by authors, data checking and incorporation of comments from reviewers, and assisting with the submission process) was provided by Steve Banner at Fishawack Communications Ltd., funded by Sanofi Genzyme. This was the only funding provided for the development of this manuscript. This article is based on the outcomes of a European Advisory Board, held in Vienna, Austria, in November 2013, during which a panel of European MS experts provided insights, guidance, and recommendations regarding best practices for alemtuzumab treatment and compliance with ongoing monitoring requirements designed to mitigate potential adverse events. Compliance with Ethical Standards Funding The advisory board was funded by Sanofi Genzyme. All advisors received honoraria payments for their participation. Open access fee was funded by the Medical University of Innsbruck.'

In other words the author's were handcuffed by the SpC and what Sanofi-Genzyme are legally allowed to say. If I was writing this article the kind of issues that I would have discussed would have tried to address the following questions:
  1. Should you consider alemtuzumab in patients with MS who have only had one clinical attack?
  2. How exactly do you transition patients at high-risk of PML from natalizumab to alemtuzumab?
  3. How exactly do you transition patients from fingolimod to alemtuzumab? Would you be guided by the peripheral blood lymphocyte counts? Would these principles apply to other DMTs associated with lymphopaenia?
  4. How do you define an alemtuzumab treatment failure? 
  5. How many courses of alemtuzumab do you give before you consider the pwMS are non-responders?
  6. What treatments can be given post-alemtuzumab? How would you give these treatments?
  7. What do you do if someone has a relapse several months before the next course of alemtuzumab is due? Can you give the next course early?
  8. Can you give the next course of alemtuzumab if someone has persistent lymphopaenia post-alemtuzumab; if no, at what level would you recommend not retreating (grade 1 >800-1000/mm3, grade 2 > 500-800/mm3, grade 3 > 200-500/mm3 or grade 4 < 200/mm3)? 
  9. When do you test for neutralising anti-alemtuzumab antibodies (NABs)? How do you test for NABs?
  10. What do you do if someone does not deplete their peripheral lymphocytes with alemtuzumab? Do you call these individuals non-responders? 
  11. Apart from autoimmune thyroid, anti-GBM and ITP, what about the other autoimmune diseases that you need to be vigilant about post alemtuzumab; i.e. neutropaenia, haemolytic aneamia, bullous skin disease, acquired haemophilia, pernicious anaemia, vasculitis, TTP, etc.?
  12. What about infectious complications post alemtuzumab, i.e. listeriosis, nocardiosis, zoster?
  13. What recommendations regarding Listeria prophylaxis would you give? What works, what doesn't?
  14. What should we be telling pwMS to do regarding preventing Listerial, Nocardial and fungal infections?
  15. Should we be using anti-viral prophylaxis with alemtuzumab?
  16. What about baseline TB, HIV, hepatitis, and HPV (cervical smear) screening? 
  17. When would live vaccines be potentially safe post-alemtuzumab? 
  18. What about travel and exposure to exotic infections?
  19. What is the optimal protocol for reducing infusion related events? Can you avoid steroids?
  20. Is there any way of predicting who will develop secondary autoimmunity? Are there any therapeutic strategies to prevent secondary autoimmunity?
  21. What about CMV reactivation post-alemtuzumab? Is it a problem? Should we screen for it? 
  22. What is the best strategies for engaging pwMS with their own pharmacovigilance? What do you do if someone is non-compliant with their pharmacovigilance? Can you use point-of-care testing for alemtuzumab pharmacovigilance?
  23. What do you do if someone develops PML post-alemtuzumab? Are there any strategies for managing this situation? 
As you can see there are many more questions about using alemtuzumab in real-life than is covered in these recommendations. May be this explains why the uptake of alemtuzumab, outside large centres in the UK, is so much lower than one would expect for such an effective and transformational therapy. Knowing, or addressing the, answers to some of these questions may help make neurologists more confident about using alemtuzumab. Building confidence is a multifaceted process and takes time and transparency.

Alemtuzumab (Lemtrada™) is a humanized monoclonal antibody approved in more than 50 countries. Within the European Union, alemtuzumab is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features; in the USA, the indication states that alemtuzumab should generally be reserved for the treatment of patients with relapsing forms of multiple sclerosis who have had an inadequate response to two or more disease-modifying therapies (DMTs). In clinical trials, alemtuzumab demonstrated efficacy in treatment-naïve patients with active RRMS and those relapsing on prior DMTs, with a consistent and manageable safety and tolerability profile. The European Union indication provides physicians with significant flexibility regarding treatment decisions, affording the opportunity for individualized treatment. Thus, alemtuzumab may be an appropriate treatment choice across a broad range of patients with RRMS, including, for example, treatment-naïve patients with active disease, patients with highly active disease, or for patients relapsing on prior DMTs. There are several practicalities to consider when using alemtuzumab, including the unique dosing regimen, administered via intravenous infusion on 5 consecutive days at baseline and on 3 consecutive days 12 months later, and as-needed retreatment (3 consecutive days at least 12 months after the last course) in cases of disease recurrence. Additionally, routine monthly monitoring is required for up to 48 months after the last infusion to promptly identify potentially serious autoimmune adverse events. Given these considerations, it is beneficial to gain insight into how alemtuzumab is being used in the real-world clinical setting. Here, we report recommendations from European multiple sclerosis experts regarding best practices for alemtuzumab treatment, including management of adverse events and compliance with ongoing safety monitoring requirements.

CoI: multiple

Advent Calendar 2

Relapses on natalizumab

Risk of relapse after natalizumab withdrawal: Results from the French TYSEDMUS cohort. Papeix C, Vukusic S, Casey R, Debard N, Stankoff B, Mrejen S, Uhry Z, Van Ganse E, Castot A, Clanet M, Lubetzki C, Confavreux C; TYSEDMUS and OFSEP Group.Neurol Neuroimmunol Neuroinflamm. 2016 28;3(6):e297.

To assess disease activity within 12 months after natalizumab (NZ) discontinuation in a large French postmarketing cohort.

METHODS:In France, patients exposed at least once to NZ were included in the TYSEDMUS observational and multicenter cohort, part of the French NZ Risk Management Plan. Clinical disease activity during the year following NZ discontinuation was assessed in this cohort. Time to first relapse after NZ stop was analyzed.

RESULTS:Out of the 4,055 patients with multiple sclerosis (MS) included in TYSEDMUS, 1,253 discontinued NZ and 715 of them had relevant data for our study. The probability of relapse within the year after NZ stop was estimated at 45% (95% confidence interval 0.41-0.49).

CONCLUSIONS: This large and systematic survey of patients with MS after NZ withdrawal allows quantifying the risk of increased disease activity following treatment discontinuation. This study provides large-scale, multicentre, systematic data after NZ cessation in real-life settings.

This study indicates that natalizumab is keeping the cells that are driving relapsing disease in check and once drug is withdrawn disease will return and in many cases this will occur with the year.

Thursday, 1 December 2016

#ThinkHand & #PoliticalSpeak: where to from here for wheelchair users?

Exasperated, but not desperate. We need help getting our #ThinkHand message across. #ThinkHand #PoliticalSpeak #MSBlog

After my experience at the ECF, and from general feedback I am getting from attendees of meetings I have spoken at, it appears as if our #ThinkHand campaign is floundering. We have yet to interest any Pharma company to take arm and hand function, in more advanced MS, seriously. A recent discussion with a one Pharma Exec about targeting pwMS who have an EDSS of 7.0 and 7.5 - wheelchair users but still independent with good upper limb function - drew a blank look. He thought I was too ambitious and any trial in this space was too risky. He thought a discussion with the regulators would be a place to start. 

What do you think? Are we barking-up the wrong tree? Should we really write-off pwMS in wheelchairs as being too far gone to treat? 

A recent comment I received, from someone who shall remain nameless, which really galls me is that 'by the time pwMS are in wheelchairs they tend to be unemployed and hence are not paying tax, therefore we should be trying not to spend excessive amounts of NHS money on them'. This individual is a HCP seeing pwMS. This comment, however, exposes the disincentive for Pharma to invest in  more advanced MS; their business models are underpinned by cost-effectiveness assessments and if the economics don't add up, which won't allow them charge high prices for DMTs, they won't invest. In short the business side of Pharma appears to have also written-off pwMS who use wheelchairs. 

What shall we do about this situation? We are going to push ahead with our plans to do an exploratory trial of an off-label DMT in pwMS in wheelchairs. We had a wonderful and remarkable meeting with a pwMS on Monday who is going to give us a grant/donation to help enable our wheelie trial. We will use the money to update the ABILHAND patient-related outcome measure to become more MS-specific, do some work on neurofilament levels in wheelchair users and host a meeting of possible investigators for the trial. We are also going to need your help in making sure MS stakeholders the world over don't dismiss pwMS who are using wheelchairs and being irredeemable. Any thoughts and suggestions regarding a political lobby are most welcome.

With regard to our three hypotheses that underpin our #ThinkHand campaign, i.e. therapeutic lag, asynchronous progressive MS and the MS length-dependent axonopathy hypotheses, we are convinced they are true and make a strong case for advanced MS being modifiable. Unfortunately, as Arthur Schopenhauer states 'all truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident'. At present our hypotheses are at stage one and are being ridiculed.

Arthur Schopenhauer (22 February 1788 – 21 September 1860)

Advent Calendar 1