At an MS Masters Forum in Rome yesterday I was teaching MSologists and MS clinical nurse specialists using a recently created board game, which I like to think of as being MS Monopoly. MS monopoly is based on a game of chance that lets you discuss case scenarios and make treatment choices. Then you roll a dice, which determines the outcome of your choice.
Two things emerge from playing the game. Firstly, how choosing an immune reconstitution (IRT) addresses so many of the treatment aims and longterm issues of safety. The question I ask is why aren’t the IRTs dominating the treatment landscape?
Secondly, it became clear how many times natalizumab was considered as a treatment option and discarded because of its PML risk. From yesterday’s discussions it clear to me that natalizumab is the ‘time-to-think’ DMT, i.e. you start someone on natalizumab for 6-12 months whilst you make the necessary long-term decisions. This may be necessary to wait for lymphopaenia to recover, to complete a vaccination programme (e.g. the three-dose HPV polyvalent vaccine), to wait to get the all-clear on a previously-treated malignancy, to prevent rebound on stopping fingolimod so that the woman with MS can fall pregnant, or to complete a diagnostic work-up. The latter indication underpins our #AttackMS trial design.
Another indication for natalizumab is to prevent CNS adverse events associated with cancer immunotherapy. I recently recommended that a patient with MS who had disseminated bowel cancer and was about to start an immune checkpoint inhibitor go onto natalizumab despite being JCV positive to prevent exacerbation of her MS. The rationale being that the polyclonal activation of her T-cells in the periphery, including her autoimmune cells responsible for her MS, would not traffic to the brain and spinal cord and cause an MS relapse. The downside of this strategy is that if she had occult secondaries in her CNS then natalizumab will prevent her T-cells finding and clearing these cells. As bowel cancer rarely metastasizes to the CNS we thought this was a risk worth taking. Last I heard she was doing well from the MS perspective, but not that well in relation to her bowel cancer.
I am sure natalizumab will prevent the CNS complications associated with CAR-T cell therapies. Could this be a repurposing opportunity for natalizumab?
What makes natalizumab so uniquely special as a DMT are the observations that it has the most rapid onset of action of all the DMTs, it has very high efficacy, its mode of action can be reversed with plasma exchange and natalizumab does not cause systemic immunosuppression. The only downside of natalizumab therapy is the long-term PML and other CNS infection risk and the emerging CNS lymphoma risk. These are all due to reduced CNS immune surveillance. The fact that extended interval dosing (EID) reduces the PML risk by over 80% suggests natalizumab may make a resurgence and all these CNS side effects may be preventable. However, for this to happen we need to be able to prescribe natalizumab more liberally as a first-line treatment for active MS. If anyone from Biogen is reading this blog post can you please ask the powers that be in Biogen to consider asking the EMA to reconsider natalizumab’s label? By not doing this you are denying many pwMS access to natalizumab, albeit for a short period of time as highlighted above.
The good news is that the EMA has accepted the EID data and it is now in natalizumab’s summary of product characteristics.
New text in the EMA’s SmPC: In a pre-specified, retrospective analysis of US anti-JCV antibody-positive natalizumab patients (TOUCH registry), the risk of PML was compared between patients treated with the approved dosing interval and patients treated with extended interval dosing as identified in the last 18 months of exposure (EID, average dosing intervals of approximately 6 weeks). The majority (85%) of patients dosed with EID had received the approved dosing for ≥1 year prior to switching to EID. The interim analysis showed a lower risk of PML in patients treated with EID (hazard ratio = 0.06 95% CI of hazard ratio = 0.01- 0.22). The efficacy of natalizumab, when administered with EID, has not been established, and therefore the benefit/risk balance of EID is unknown (see section 4.4).
For those interested, I have included the latest PML figures from Biogen.
CoI: multiple
Alcohol Awareness Week
This week is alcohol awareness week in the UK and the NHS is encouraging its patients/clients to look in the mirror and ask whether or not they are drinking too much. As part of the holistic management of MS and our marginal gains strategy for managing MS, we are encouraging all pwMS to do the same.
Excessive alcohol consumption is bad for MS in several ways. It disrupts your sleep pattern and may, therefore, make fatigue and other mental health issues worse. It can affect your balance and coordination and increase your risk of falls and fractures. Alcohol lowers your seizure threshold and increases your chances of having seizures. Longterm alcohol consumption is associated with accelerated brain volume loss and hence increases your chances of developing cognitive impairment and is likely to exacerbate MS-related cognitive impairment.
Alcohol is not good for bone health and is a known cause of osteopaenia. Alcohol is metabolised by the liver and can result in liver toxicity. Alcohol interacts with many drugs affecting their activity and metabolism and may interact with MS-related medication resulting in unpredictable side effects.
Alcohol is very calorific and may contribute to weight gain. In general, excessive alcohol consumption is bad for you.
Why don’t you log onto Drink Coach, or download the App, and take the alcohol test to see if you have a drinking problem?
CoI: multiple
Affordable DMTs
My post on the ‘Damp Squib’ has upset several close colleagues. I need to explain my reasons for doing it; the main one being is that I am very frustrated that change happens so slowly, whereas shit happens so quickly.
The catalyst for our Barts-MS off-label initiative was my sabbatical 5 years ago and kicked-off with a blog post I did on the 3rd October 2014. I am ashamed that it is now 5 years since our first activities in this space and nothing has really changed for people with MS living in resource-poor environments. I can count the number of centres on one hand (excluding rituximab users, which is really a high-cost DMT) that are using off-label DMTs and they are all in high-income countries. As a proponent of ‘Time is Brain’ in MS, and that includes the brains of pwMS living in resource-poor countries, I have to ask myself how many brains have been shredded whilst we procrastinate. We want this campaign to become urgent.
A good analogy would be the anti-retroviral access campaign that was run to get people with HIV living in low- and middle-income countries onto treatment. Why can’t we do something similar for people with MS?
When I criticise my colleagues I want to make it clear that there is likely to be an unconscious bias against off-label prescribing of generics and biosimilars despite a robust evidence base. This is the invisible elephant in the room. Whenever I have attempted to shift this issue to the top of the agenda it gets watered down and put at the bottom of the list of solutions for treating people with MS in low- and middle-income countries. In addition, the term off-label tends to be avoided and replaced by euphemisms, for example, repurposed.
I suggest we avoid off-label and use a neutral term that will be all-encompassing and acceptable to all parties. I, therefore, suggest referring to these treatments as “affordable DMTs”, which is counterbalanced by the term “high-cost DMTs”. Affordable captures everything we are trying to do without stating the obvious. The term ‘affordable DMT’ solves the issue as it not only refers to off-label DMTs, but includes generic, biosimilar, and bioequivalent DMTs, and unlicensed and compounded DMTs and any other variation that emerges. In addition, what is affordable may vary from one country to the next.
It is clear that a lot of people in the MS community don’t want to rock the boat when what we really need to do is capsize the boat. Many of my colleagues, including me, are so conflicted that we tend to toe the Pharma-line because we have been indoctrinated by the system, i.e. the only solution to treat and manage MS is with high-cost innovative DMTs. This is clearly not the case and we need to collect and summarise the evidence to make the MS community realise that there are other ways to manage this disease.
So I want to rebrand this the GRAD Initiative (Grass-Roots Affordable DMT Initiative), which may be more acceptable to the wider community and potentially neutralise our cognitive biases. The plan that I am currently formulating is based on a simple grass-roots movement, starting small and local:
- Identifying local MS champions and creating an international network of these champions.
- Creating and disseminating an essential affordable DMT list with detailed protocols on how to use each agent.
- Modified diagnostic criteria for use in resource-poor environments; these will need to country-specific.
- Protocols for derisking and monitoring DMTs in these environments.
- Creating a platform to allow neurologists and other HCPs from these countries to share their experience.
- Putting in place the suitable infrastructure to collect real-world data to assess the effectiveness of using affordable DMTs in these environments.
We are hoping to try to do something small and local in Africa, India and Pakistan. We plan to visit all these countries/regions in 2020.
Please don’t be shy we need champions and wider engagement from the MS community to make this happen. Please get involved and register your interest.
CoI: multiple
Azathioprine revisited
Has azathioprine been given a fair chance as a treatment for MS?
I have noticed over the years that most neurologists, including myself, don’t always use azathioprine correctly. In general, we under-dose azathioprine. Why?
As an example, one of my patients with myasthenia gravis, an autoimmune disease of the nerve-muscle junction, came in this week with a relapse. He weighs 107kg and was on 200mg of azathioprine per day, which is less than 2mg/kg. He had a normal lymphocyte count. Therein lies the problem; his dose of azathioprine was too low, which is one of the reasons his myasthenia had broken through.
Azathioprine is a drug that is broken down by an enzyme called TPMT (thiopurine methyltransferase). There are genetic variants in TPMT which means you can be a slow, intermediate or rapid metaboliser of the drug. Before we start someone on azathioprine we test the activity of TPMT in their red blood cells and then adjust the target dose according to the enzyme activity. In general, we avoid using azathioprine in slow metabolizers as they can develop a low white cell count on very low doses. Intermediate metabolizers need a dose of 2-3mg/kg and rapid metabolizers a dose of 4-5mg/kg. This is a general guide and in practice, I titrate the dose upwards until I cause a mild lymphopaenia of between 0.8 and 1.2, whilst maintaining a normal neutrophil count.
As all the MS trials of azathioprine were done in the pre-TPMT enzyme activity monitoring era I looked up the azathioprine MS trials to see what doses were used. I was horrified to find out that except for one study all the other studies used a sub-therapeutic dose of azathioprine. In the Ellison 1989 trial, azathioprine was started at a daily dose of 2.2 mg/kg body weight, with the dose being increased by 25 mg each month until the white blood cell count was maintained between 3,000 to 4,000 or adverse effects were encountered. In this study, the daily dose was even increased above 4.4 mg/kg when appropriate. All the other studies used fixed-dose protocols with daily doses of azathioprine between 2mg/kg and 3mg/kg (2 mg/kg, Milanese 1993; 2.5 mg/kg, British & Dutch 1988, Ghezzi 1989; 3 mg/kg, Goodkin 1991).
What this is telling me that azathioprine has never really been trialled properly in MS and the fact that subtherapeutic doses seem to work is MS is quite remarkable (see Cochrane review below). This supports many old school neurologists anecdotal evidence that pwMS do better on azathioprine compared to patients, not on treatment. Maybe the WHO committee, who decide on the WHO Essential Medicines List, was right in telling us to reconsider our decision not to revisit azathioprine as a potential DMT for resource-poor countries.
One could argue in an era of treat-2-target and adaptive azathioprine dosing that we should relook at azathioprine as a cost-effective treatment for MS in resource-poor environments. We could start azathioprine at a low dose and titrate it slowly upwards to target a “therapeutic-dose” based on lymphocyte counts. We could then rebaseline and the monitor patients on a 6 or 12 monthly basis and only escalate therapy in patients who had breakthrough activity. I would not be surprised if azathioprine, under these circumstances, worked as well as our other platform therapies.
What do you think?
Barts-MS Essential Off-Label DMT List
- Azathioprine*
- Cladribine
- Cyclophosphamide*
- Fludarabine*
- Leflunomide
- Methotrexate*
- Mitoxantrone
- Rituximab*
- Generic dimethyl fumarate (Skilarence)
- Compounded dimethyl fumarate
- HSCT
*on the 19th WHO Model List of Essential Medicines (April 2015)
If you are interested in helping address the issue of lack of access to MS DMTs in resource-poor countries and environments please sign-up to our Grass Roots Off-Label DMT Initiative (GROLDI)
Casetta et al. Azathioprine for multiple sclerosis. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003982.
BACKGROUND: Azathioprine is the most widely used immunosuppressive treatment in multiple sclerosis (MS). It is an alternative to interferon beta for treating MS also because it is less expensive. Concerns about its safety, mainly a possible increased risk of malignancy, has limited its use. This systematic review aimed to determine the trade off between the benefits and risks of azathioprine in multiple sclerosis.
OBJECTIVES: To compare azathioprine versus placebo. To determine the effect of azathioprine on major clinical outcomes, i.e., disability progression and relapses in patients with multiple sclerosis.
SEARCH STRATEGY: The Multiple Sclerosis Group’s Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL- Issue 4, 2006), Cochrane Database of Systematic Reviews (CDSR – Issue 4, 2006), Database of Abstracts of Reviews of Effectiveness (DARE – searched 28.12.06) MEDLINE (PubMed) (1966 to December 2006), EMBASE (1980 to December 2006). Journals and reference lists were hand searched for relevant articles both to benefit and adverse effects. Regulatory agencies were additional sources of information for adverse effects.
SELECTION CRITERIA: All parallel group randomised controlled trials (RCTs) comparing azathioprine treatment of a least one year duration with placebo for patients with multiple sclerosis. Cohorts, case controls, case series and case reports were also used to assess adverse effects.
DATA COLLECTION AND ANALYSIS: Potentially relevant references were evaluated and all data extracted by two independent authors.
MAIN RESULTS: The five trials that met our criteria included 698 randomised patients: data from 499 (71.5%) were available for analysis of relapse frequency in patients at one year’s, from 488 (70%) at two years’ and from 415 (59.5%) at three years’ follow-up. Azathioprine reduced the number of patients who had relapses during the first year of treatment (relative risk reduction [RRR] =20%; 95% CI = 5% to 33%), at two years’ (RRR =23%; 95% CI = 12% to 33%) and three years’ (RRR =18%; 95% CI = 7% to 27%) follow-up. These results were consistent in sensitivity analysis. There was no heterogeneity among the studies. Data from only three small trials with a total of 87 patients were available to calculate the number of patients who progressed during the first two to three years. There was a statistically significant benefit (RRR = 42%; 95% CI = 7% to 64%) of azathioprine therapy at three years’ follow-up; this result was robust after sensitivity analyses and there was no heterogeneity among the trials. Gastrointestinal disturbances, bone marrow suppression and hepatic toxicity were greater in the azathioprine group rather than in the placebo group; they were anticipated, and, by monitoring and dosage adjustment, were easily managed. Withdrawals due to adverse effects were few, occurring mostly during the first year of azathioprine treatment and mainly due to gastrointestinal intolerance (5%). Data from the trials and from cohort and case controls studies available in the literature did not show an increase in risk of malignancy from azathioprine. A possible long-term risk of cancer from azathioprine may be related to a treatment duration above ten years and cumulative doses above 600 g.
AUTHORS’ CONCLUSIONS: Azathioprine is an appropriate maintenance treatment for patients with multiple sclerosis who frequently relapse and require steroids. Cumulative doses of 600 g should not be exceeded in relation to a possible increased risk of malignancy. Considering the trade off between the benefits and harms, azathioprine is a fair alternative to interferon beta for treating multiple sclerosis. A logical next step for future trials would seem the direct comparison of azathioprine and interferon beta. In fact the direct comparison between these two widely used treatments in multiple sclerosis has not been made.
CoI: multiple
GROLDI hits a wall
To help with our #OffLabel campaign to help HCPs treat pwMS in resource-poor environments I asked Gisela Kobelt, a health economist, who I have worked with for many years for help. What she said to me made me realise that the hurdles we face are much higher than I expected.
These are her relevant comments:
“The economic case for any treatment in resource-poor countries is difficult, simply because not treating is cheaper than treating, and as no one seems to take care of disabled people in these countries they are left in the charge of their families. Therefore, the usual health economic arguments do not apply. As the economic arguments have been wasted in Europe and the USA, how could we expect them to work in these countries?”
“You need something bigger, in fact, something at the strategy level where the main message is that any health care system, even in poor countries, has been designed to help people with the means available. You need to make humanitarian arguments more than economic ones. Politicians that actually have a heart and a brain (rare birds these days!!) can promote the right arguments. Maybe an economic component would be that currently, even the things that are being done are pretty useless, hence resources are being wasted, and some could be switched to interventions that have some utility.”
The bottom line is that we need to shift the emphasis away from the economic arguments to the humanitarian ones. So if you have any stories to highlight the plight of people with MS living in resource-poor countries to share with us please come forward; you can use the Barts-MS blog as a soap-box. We need to make politicians in these countries and the WHO sit-up and listen.
- Azathioprine*
- Cladribine
- Cyclophosphamide*
- Fludarabine*
- Leflunomide
- Methotrexate*
- Mitoxantrone
- Rituximab*
- Generic dimethyl fumarate (Skilarence)
- Compounded dimethyl fumarate
- HSCT
*on the 19th WHO Model List of Essential Medicines (April 2015)
If you are interested in helping address the issue of lack of access to MS DMTs in resource-poor countries and environments please sign-up to our Grass Roots Off-Label DMT Initiative (GROLDI).
CoI: multiple
Food Coma @MSTrust conference
After my food coma blog post and survey in January, I was asked by the MS Trust to talk about food coma at their annual conference in Hinckley. It is always great to speak at this meeting. The audience is always very enthusiastic and I have had a lot of questions after my presentation. I used my talk to discuss some of the science and issues around excess sugar consumption.
I suspect that my food coma observation and our audit will lead to a reassessment and a change in the dietary advice we give pwMS. As I have said before there is no MS diet and I would sum up my dietary advice as follows.
Eat real food, avoid processed and particularly ultra-processed foods. Eat local and seasonal produce. As eat socially; a lot of eating is about rituals around social interactions. Finally, eat mindfully; be aware of the impact your diet is having on others.
You can download my presentation from my SlideShare site.
CoI: nothing to declare for this lecture
The Phoenix
Like a phoenix rising from the ashes for the third or fourth time, alemtuzumab is given yet another life. I am sure many neurologists and people living with MS will be grateful, but I don’t agree with its positioning.
EMA’s safety committee or PRAC has handcuffed alemtuzumab and is restricting it for adults with relapsing-remitting multiple sclerosis that is highly active despite adequate treatment with at least one DMT or if the disease is worsening rapidly with at least two disabling relapses in a year and brain-imaging showing activity. The new indication is not too dissimilar to that of natalizumab. Just when we are pushing for natalizumab to get a first-line license to address our #AttackMS concept, alemtuzumab gets yoked to natalizumab.
In my opinion, the contraindication handcuff that alemtuzumab must no longer be used in patients who have auto-immune disorders other than MS is not necessarily correct. I am not aware that having another comorbid autoimmune disease puts you at increased risk of developing another autoimmune disease after being treated with alemtuzumab. I have asked Joanne Jones and Alasdair Coles from Cambridge who have the most experience with alemtuzumab, both clinically and scientifically, and they agree. I think we need to appeal this contraindication as it may deny many pwMS access to one of our most effective DMTs. I suspect that Sanofi-Genzyme will have data from their trial programme to help appeal this contraindication.
Looking at this with from a glass-half-full perspective is the good news that at least we still have alemtuzumab as a treatment option for pwMS with more active disease. However, this will deny many pwMS with active MS from being treated with the most effective DMT first-line.
When will regulators come to the realisation that the decision to take on risks should be taken by the person with the disease guided by their HCP and not the regulators? By moving alemtuzumab to a predominantly 2nd-line position means pwMS will now have to wait several years to access the most effective DMT. I am not sure the new positioning of alemtuzumab in the therapeutic hierarchy will stop the more educated and determined people with MS seeking HSCT abroad or in the private sector.
I am curious to know if my letter to the EMA (below) helped. But having alemtuzumab back on the treatment landscape as predominantly 2nd-line therapy means we will at least be able to offer alemtuzumab as a realistic option before, or alongside, HSCT in London. This also means we can go ahead with our head-2-head comparison of alemtuzumab vs. HSCT to assess HSCT’s relative efficacy and safety against a licensed DMT.
Open letter the EMA sent on the 20th August 2019
European Medicines Agency
Amsterdam
Dear Sir/Madam
Alemtuzumab has transformed the MS treatment landscape. It not only provides superior short term efficacy, but a significant number of patients treated with alemtuzumab note improvement in disability. However, its main advantage over other DMTs is that a large proportion of patients go into longterm remission and normalise the rate of their brain volume loss. In regard to the latter, this is unprecedented in comparison to other licensed MS disease-modifying therapies, with the possible exception of haemopoietic stem cell transplantation (HSCT), which is not licensed and hence not widely available to treat patients with MS in Europe. Alemtuzumab, therefore, is the only realistic alternative to HSCT, which has become a very popular treatment choice amongst people with multiple sclerosis, in particular, ‘digital natives’ who get their information online. As with all DMTs the earlier you use them the more effective they are and the greater the benefit to the individual patient. Alemtuzumab is, therefore, an important treatment option for people with MS; being able to offer alemtuzumab early as a treatment option is an important factor in my clinical practice to dissuade many Britsih patients from travelling abroad for HSCT.
At our centre, Barts Health NHS Trust, we have now treated over 250 patients with alemtuzumab with over 40% being treated with alemtuzumab first-line. Patients receiving alemtuzumab first-line tend to have more active disease and less favourable baseline prognostic profile. Despite its side effect profile and the need for monthly monitoring, many patients are willing to take on the risks and the burden of monitoring to be treated with the most effective licensed DMT first-line. All our patients are extensively counselled about the risks and benefits of alemtuzumab treatment and sign an informed consent and a patient contract agreeing to the mandatory monitoring programme. We feel the use of alemtuzumab in the correct environment is relatively safe and the adverse events manageable. Not having alemtuzumab for use in early active disease would mean patients having to wait to fail several other, less effective, licensed DMTs prior to accessing alemtuzumab. I firmly believe in the concept that ‘time is brain and spinal cord’ in MS and delaying access to the most effective treatment would limit our ability to optimise the management of MS in patients with more active disease and in those with a poor prognostic profile. In addition, shifting the use of alemtuzumab to a population of patients with more advanced disease would unfavourably change the benefit-risk profile of alemtuzumab and make it less appealing as a treatment option.
The real-life data of alemtuzumab clearly supports it as being the most effective DMT on the market and its other attributes in relation to its posology make it a very appealing therapy; for example in women wanting to start or extend their families.
In summary, limiting alemtuzumab to a third-line, last resort DMT, will severely limit our treatment options for managing this devastating disease. Alemtuzumab offers many patients with MS a real hope of living as normal a life as possible, however, this option does depend on using alemtuzumab early in the course of the disease. I, therefore, appeal to the MS community and the European Medicine Agency to consider these factors when reviewing the benefits and risks of alemtuzumab as a treatment for MS.
Yours faithfully
GAVIN GIOVANNONI
CoI: multiple
A new kid on the block
FDA APPROVAL OF DIROXIMEL FUMARATE FOR MULTIPLE SCLEROSIS
Time for another me-too or better-tolerated fumarate to treat relapsing-forms MS.
The following is a summary and adapted version of yesterday’s press release.
Biogen and Alkermes announced yesterday that the U.S. Food and Drug Administration (FDA) approved diroximel fumarate, a novel oral fumarate with a distinct chemical structure, for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease.
“The FDA’s approval of diroximel fumarate delivers on Biogen’s commitment to pursue new therapies that may provide meaningful impact for people living with relapsing MS, and we look forward to bringing it to the MS community as an additional treatment option,” said Alfred Sandrock, executive vice president, research and development, and chief medical officer at Biogen.
“Diroximel fumarate is a novel fumarate that offers the well-characterized efficacy of dimethyl fumarate and has been studied for improved patient-reported gastrointestinal tolerability.”
“The approval of diroximel fumarate for relapsing MS marks the culmination of a multi-year development program and is the latest milestone in our mission to develop new treatments for patients living with chronic central nervous system disorders,” said Craig Hopkinson, M.D., chief medical officer and senior vice president of medicines development and medical affairs at Alkermes. “We are grateful to the patients and study investigators who have participated in our diroximel fumarate clinical trials and we look forward to working with our collaboration partners at Biogen to make this new treatment available to patients.”
The FDA approval of diroximel fumarate was based on a New Drug Application (NDA) submitted under the 505(b)(2) filing pathway. It included data from pharmacokinetic bridging studies comparing diroximel fumarate and dimethyl fumarate to establish bioequivalence, and relied, in part, on the FDA’s findings of safety and efficacy for dimethyl fumarate.
The NDA submission also included interim exposure and safety findings from EVOLVE-MS-1, an ongoing, Phase 3, single-arm, open-label, two-year safety study evaluating diroximel fumarate in patients with relapsing-remitting MS. Interim results from EVOLVE-MS-1 at the time of NDA submission included a low overall rate of diroximel fumarate treatment discontinuation due to adverse events (6.3 percent), and a rate of less than one percent of patients who discontinued diroximel fumarate treatment due to gastrointestinal (GI) adverse events. Additional exploratory efficacy endpoints in the ongoing EVOLVE-MS-1 study showed changes in clinical and radiological measures compared to baseline.
“MS is a heterogeneous disease, and real-world patient circumstances can vary, reinforcing the benefits of having therapeutic choices to support the diverse range of treatment considerations,” said Robert Naismith, M.D., professor of neurology, Washington University School of Medicine in St. Louis. “Throughout its clinical development program, diroximel fumarate has demonstrated a desirable therapeutic profile, making it a compelling new option for patients.”
“MS is a lifelong disease that has a significant impact on the people affected and their caregivers. We are encouraged by the progress being made in the treatment of MS, and pleased that another treatment option will soon be available,” said Bruce Bebo, Ph.D., executive vice president, research, National MS Society. “It’s important for people with MS to have treatments that are both efficacious and tolerable to help manage their disease.”
Under the terms of the license and collaboration agreement between Biogen and Alkermes, Biogen will pay Alkermes $150 million in connection with the FDA’s approval of diroximel fumarate. Biogen plans to account for this milestone payment as an asset that will be amortized over the expected useful life of the product. Alkermes is also entitled to receive a mid-teens percentage royalty on worldwide net commercial sales of diroximel fumarate, subject, under certain circumstances, to minimum annual payments for the first five years following FDA approval and customary reductions as set forth in the agreement.
Please see full Prescribing Information for diroximel fumarate.
About diroximel fumarate (diroximel fumarate)
Diroximel fumarate is a novel oral fumarate with a distinct chemical structure approved in the U.S. for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease. Once in the body, diroximel fumarate rapidly converts to monomethyl fumarate, the same active metabolite of dimethyl fumarate.
About the diroximel fumarate EVOLVE-MS Clinical Development Program
The key components of the EVOLVE-MS (Endeavoring to Advance Treatment for Patients Living with Multiple Sclerosis) clinical development program of diroximel fumarate include the EVOLVE-MS-1 study, a Phase 3, open-label, two-year safety study in relapsing-remitting multiple sclerosis (MS) patients, along with pharmacokinetic bridging studies comparing diroximel fumarate and dimethyl fumarate to demonstrate bioequivalence. The EVOLVE-MS clinical development program also includes the EVOLVE-MS-2 study, an elective Phase 3, five-week randomized, prospective, double-blind, multi-centre study that assessed the gastrointestinal (GI) tolerability of diroximel fumarate and dimethyl fumarate using self-administered GI questionnaires.
INDICATION and IMPORTANT SAFETY INFORMATION for diroximel fumarate (diroximel fumarate)
What is diroximel fumarate (diroximel fumarate)?
Diroximel fumarate is a prescription medicine used to treat people with relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. It is not known if diroximel fumarate is safe and effective in children.
Important Safety Information
Who should not take diroximel fumarate?
Patients should not use diroximel fumarate if they have had an allergic reaction (such as welts, hives, swelling of the face, lips, mouth or tongue, or difficulty breathing) to diroximel fumarate, dimethyl fumarate, or any of the ingredients in diroximel fumarate or if they are taking dimethyl fumarate.
Before taking and while taking diroximel fumarate, patients should tell their healthcare provider if they: have liver problems; kidney problems; have or have had low white blood cell counts or an infection; are pregnant or plan to become pregnant because it is not known if diroximel fumarate will harm an unborn baby; are breastfeeding or plan to breastfeed because it is not known if diroximel fumarate passes into breast milk; are taking prescription or over-the-counter medicines, vitamins, or herbal supplements.
What should patients avoid while taking diroximel fumarate?
Patients should not drink alcohol at the same time they take a diroximel fumarate dose.
What are the possible side effects of diroximel fumarate?
Diroximel fumarate may cause serious side effects including:
- Allergic reaction (such as welts, hives, swelling of the face, lips, mouth or tongue, or difficulty breathing).
- PML (progressive multifocal leukoencephalopathy), a rare brain infection that usually leads to death or severe disability over a period of weeks or months. Patients should tell their doctor right away if they get any of these symptoms of PML: weakness on one side of the body that gets worse, clumsiness in their arms or legs, vision problems, changes in thinking and memory, confusion, or personality changes.
- Decreases in your white blood cell count, the patient’s healthcare provider should do a blood test to check their white blood cell count before starting treatment with diroximel fumarate and while on therapy. Patients should have bloods tests after 6 months of treatment and every 6 to 12 months after that.
- Liver problems, the patient’s healthcare provider should do blood tests to check liver function before starting treatment with diroximel fumarate and during treatment if needed. Patients should tell their healthcare provider right away if they get any of these symptoms of a liver problem during treatment: severe tiredness, loss of appetite, pain on the right side of the stomach, have dark or brown (tea color) urine, or yellowing of the skin or the white part of the eyes.
The most common side effects of diroximel fumarate include: flushing, redness, itching, or rash; nausea, vomiting, diarrhea, stomach pain, or indigestion. Flushing and stomach problems are the most common reactions, especially at the start of therapy, and may decrease over time. Taking diroximel fumarate with food (avoid high-fat, high-calorie meal or snack) may help reduce flushing. Patients should call their healthcare provider if they have any of these symptoms, are bothered by them, or if they do not go away.
These are not all the possible side effects of diroximel fumarate. Patients should call their healthcare provider for medical advice about side effects. Patients may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov.
CoI: multiple
Catastrophe
Have you heard the term catastrophic health expenditure or CHE before? You should have as many MSers and their families are exposed to catastrophic health expenditure.
CHE occurs when the spending on health exceeds a pre-defined percentage of a person’s or household’s capacity to pay. CHE has a massive impact on MSers’ lives and usually discourages them from using healthcare services and often leads to a reduction in the use of other essential goods and services. In summary, CHE exposes families of MSers to poverty and economic ruin.
In 2014 when I was visiting India on my sabbatical I remember meeting a relatively well-off woman with MS who was having to buy her weekly Avonex (interferon-beta-1a) injection one syringe at a time. She told me that if she couldn’t raise the money from family and friends she would simply miss that week’s injections. Her neurologist told me that she was from quite a wealthy middle-class family and that her MS had devastated their finances. Does this story sound familiar?
If you live in the UK or another country with a socialist healthcare system you are generally protected from CHE by having free access to healthcare and social safety net in the form of unemployment and/or disability benefits. However, if you live in a country with a healthcare system that is based on a fee-for-service private model with substantial out-of-pocket payments it is easy to see how MS can cause CHE.
Iran is a country with substantial out-of-pocket payments for health system financing. The study below shows that about 1 in 25 families with someone with MS encounter catastrophic healthcare costs. Importantly, the brand of DMT, housing, income and health insurance were significantly correlated with catastrophic expenditure. This is one of our motivations for forming a Grass Roots Off-Label DMT Initiative (GROLDI), which promises to lower the costs of treating MS in countries such as Iran by addressing the unacceptable costs of innovator DMTs in countries such as Iran. Iran is not even a good example as the government has at least allowed biosimilars and generics to emerge to try and lower prices of the so-called ‘innovator DMTs’.
Not surprisingly there is a literature of CHE in many low- and middle-income countries, for example, Brazil. Kenya, China, Nepal, Korea and India. But it is also a growing problem in countries such as the USA in the medically uninsured. Over 60% of personal bankruptcies in the USA are triggered by health crises. I sincerely hope you will agree that CHE is another reason why we need to move off-label DMTs up the political agenda and to push-back on Pharma’s influence to prevent off-label prescribing.
I am prepared to bet that if we studied the economic impact of MS worldwide we would find that MS is a common cause of CHE. Is anyone prepared to take on this challenge? How common is CHE in your country and how often is it triggered by someone in the family being diagnosed with MS?
Juyani et al. Multiple Sclerosis and Catastrophic Health Expenditure in Iran. Glob J Health Sci. 2016 Sep 1;8(9):53778.
BACKGROUND: There are many disabling medical conditions which can result in catastrophic health expenditure. Multiple Sclerosis is one of the most costly medical conditions through the world which encounter families to the catastrophic health expenditures. This study aims to investigate on what extent Multiple sclerosis patients face catastrophic costs.
METHOD: This study was carried out in Ahvaz, Iran (2014). The study population included households that at least one of their members suffers from MS. To analyze data, Logit regression model was employed by using the default software STATA12.
RESULTS: 3.37% of families were encountered with catastrophic costs. Important variables including brand of drug, housing, income and health insurance were significantly correlated with catastrophic expenditure.
CONCLUSIONS: This study suggests that although a small proportion of MS patients met the catastrophic health expenditure, mechanisms that pool risk and cost (e.g. health insurance) are required to protect them and improve financial and access equity in health care.
CoI: multiple
Our prize winners
You may recall Barts-MS held a competition before ECTRIMS to see if any of you could guess the results of OPTIMUM and ASCLEPIOS trials, i.e. “Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM)” and “Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis (ASCLEPIOS I & II)”.
We now have our winners.
Heather Davies (UK) won the prize for the best average predictions of OPTIMUM results & Michael Heindel (Germany) for the ASCLEPIOS trials. Well done.
Here you can see Heather’s daughter constructing and then showing off her Barts-MS Lego creation.
Michael chose a Barts-MS T-shirt as a prize, but when we heard he had young sons we sent him a lego set as well. It looks like his sons enjoyed the challenge.
