Biogen – Prof G's MS Blog Archive

Anti-CD20 Derisk Study

Barts-MS rose-tinted-odometer: ★★★★★

Did you watch the anti-CD20 debate on the triMS-online platform yesterday? The question that was asked was ‘Can we use anti-CD20 therapies as immune reconstitution therapies rather than maintenance therapies?’. I am not sure the debaters answered the question.

When I asked Anders Svenningsson, who is probably the world’s biggest adopter of anti-CD20 therapy as a treatment for MS, whether or not someone with MS could stay on anti-CD20 for life, he hesitated before saying ‘YES and NO’. His reason? SAFETY. He described things they were doing to try and reduce the risk of hypogammaglobulinaemia and infections in their patients on longterm anti-CD20 therapy. I am not sure it will work. Interestingly, he suggested stopping anti-CD20 therapy when pwMS get to 55-60 years of age when the risks of treatment outweigh the benefits. In other words, Anders Svenningsson is saying we can’t leave pwMS on anti-CD20 lifelong.

I have been making this exact point on this blog for several years and that is why I have proposed the ADIOS and iTeri studies as ways to derisk long-term anti-CD20 therapies. However, I have been thinking are there any other DMTs we could use after anti-CD20 that would potentially work to derisk the hypogammaglobulinaemia and tackle the cause of MS. I suspect yes. Fumarates, as monotherapy, or in combination with a neuroprotective therapy, also makes sense. The difficulty is what will be the primary outcome of such a trial and how would you do power calculations?

Maybe we could use a non-inferiority design and make safety the primary outcome. Would regulators buy that in addition to non-inferiority as a secondary outcome?

There are not many companies who have the resources, motivation and know-how to do such a study. Roche-Genentech and Novartis would not as this would eat into their franchise. In my opinion, the only company with big enough bollocks and know-how to take this on would be Biogen. Would they be interested?

This is potentially an opportunity for them to come up with a new combination pill of one of their fumarate formulations with an add-on neuroprotective. DMF will maintain MS in remission post-anti-CD20 and the neuroprotective will tackle smouldering MS, which is something anti-CD20 therapies don’t do. A fumarate-neuroprotection combination may actually not only show improved safety but superiority on end-organ damage markers (brain volume loss etc.).

The hypothesis is that if B-cells and in particular memory B-cells are driving MS then starting DMF for example before memory B-cell reconstitution occurs may actually make MS more responsive to fumarates. Add in a combination, to generate new intellectual property (Biogen need this as their fumarate patents are being challenged) and you have a new DMT.

If successful this new combination pill will probably become the most prescribed DMT in MS. Why? To quote Anders Svenningsson you can’t really remain on anti-CD20 lifelong so if you have to derisk an anti-CD20 at some stage. So why not do it before you develop hypogammaglobulinaemia? As more than 50% of MS patients will be treated with anti-CD20 therapy in the near future this combination therapy could potentially capture more than 50% of the market.

If you are on an anti-CD20 therapy (ocrelizumab, rituximab or ofatumumab) would you volunteer to participate in the DERISK study below?

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

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

Compounding Pharmacies

“It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epoch of belief, it was the epoch of incredulity, it was the season of Light, it was the season of Darkness, it was the spring of hope, it was the winter of despair, we had everything before us, we had nothing before us, we were all going direct to Heaven, we were all going direct the other way – in short, the period was so far like the present period, that some of its noisiest authorities insisted on its being received, for good or for evil, in the superlative degree of comparison only.”

A Tale of Two Cities (1859) is a historical novel by Charles Dickens.

Although global inequality seems to be receding since its peak in 2016 we still live in a world of ‘the haves’ and ‘the have nots’. A stark reminder of this is for people living with MS and having to experience global inequality in access to effective MS therapies.

My memory of a relatively wealthy young woman with MS in Banglore, India, who I met back in 2014 when on sabbatical, reminds me that we have so much still to do. This woman was having to raise money from her extended family, and her social network, to purchase her weekly Avonex injection one syringe at a time. If she couldn’t raise the necessary money she would simply miss that week’s injection. Her neurologist informed me that since developing MS her family was facing financial ruin. The question I asked myself later was ‘Why wasn’t her neurologist treating her with an alternative DMT that she could afford?”. Therein lies the problem, i.e. how do we get the neurology community and wider MS community to accept that there are cheaper, effective, alternatives for managing MS in resource-poor environments.

Please note that I prefer using the term resource-poor environments and try to avoid using the term resource-poor country. This is deliberate because even in rich countries there are pockets of disenfranchised people without access to healthcare, for example, refugees, immigrants and the medically uninsured. Britain may soon be included. In the event of a no-deal Brexit, a large number of foreign EU nationals with MS living in this country may have their free-access to the NHS withdrawn. At present, there is no clarity on how the EU and the UK will deal with healthcare coverage in the event of a no-deal Brexit.

As an MSologist with a large number of EU nationals under my care, the prospect of a no-deal Brexit gives me sleepless nights. How will we respond to a scenario of a home office and/or NHS official demanding that we stop prescribing high-cost DMTs to some of our patients? Rebound MS disease activity on withdrawing natalizumab or fingolimod is potentially life-threatening.

It is essential that the MS community seek solutions for treating people with MS in resource-poor environments. This is why we are exploring different solutions including prescribing low-cost off-label DMTs, developing compassionate access schemes, creating low-cost generics and buyers clubs. Another grass-roots solution is to use compounding pharmacies.

In short, compounding refers to the process of creating a pharmaceutical preparation or drug by a licensed pharmacist to meet the needs of a community when a commercially available drug does not meet those needs or is too expensive. When you look at our list of essential off-label DMTs we could add dimethyl fumarate to that list. There will criticism from Pharma that compounded, or home-brew, DMF formulations are inferior. But when it comes down to a choice of either bankrupting your family due to the high-costs of innovative treatments or taking a chance on a compounded formulation of the drug I know which one I would choose.

We have previously covered the topic of a DIY DMF formulation on this blog and you can read how to make your own DMF tablets via this website. I am not advocating that individual pwMS do their own compounding, but this could be done centrally via a licensed compounding pharmacy. The quality of the compounded formulations could then be tested using an international quality control laboratory. The latter could be funded by the global MS community (MSIF) or charities with a vested interest in finding solutions to this problem, for example, the Melinda and Bill Gates Foundation or the Wellcome Trust.

How to make a DIY version of Tecfidera or DMF

Obviously, Pharma will object and produce papers such as the one below claiming their product is superior and that compounded formulations are inferior, but maybe this will nudge them to do something about the hundreds of thousands of untreated people living with MS in resource-poor environments. To be fair to Biogen they were the only Pharma company who responded to my call-to-arms a few years ago about trying to find a solution to treating MS in resource-poor environments and I note that one of their senior executives has already signed up to our Grass Roots Off-Label DMT Initiative (GROLDI). To do this is bold and I suspect brave, but their action shows you that even Pharma executives are prepared to acknowledge that access to DMTs is a global problem.

Please note our Barts-MS Essential Off-label DMT list has just been expanded to include compounded DMF and the generic version of DMF that is used to treat psoriasis.

*on the 19th WHO Model List of Essential Medicines (April 2015)

Compounding pharmacies could be one way of improving access to DMTs in low-income countries. Do you think compounding pharmacies will address the problem of access to DMTs in resource-poor environments? Let us know your thoughts.

If you are interested in helping address the issue of lack of access to MS DMTs in resource-poor countries and environments post please sign-up to our Grass Roots Off-Label DMT Initiative (GROLDI).

Thank you.

Boulas P (Biogen, Cambridge, MA, USA). Compounded Formulations of Dimethyl Fumarate Show Significant Variability in Product Characteristics. Drug Res (Stuttg). 2016 May;66(5):275-8.

BACKGROUND: Pharmacy compounded products are not regulated to the same standards as commercially available, approved products, increasing potential safety and efficacy risks to patients. This report describes an in vitro study examining consistency of content and release profile of compounded dimethyl fumarates.

METHODS: Samples of compounded dimethyl fumarate (cDMF-A, cDMF-B, cFumaderm) from separate Austrian compounding pharmacies were analyzed for drug content, uniformity of dosage, impurity, and in vitro release.

RESULTS: The average dimethyl fumarate (DMF) content ranged from 102.5 to 96.7% of the 120 mg content listed on the product labels. While the DMF capsule-to-capsule content of cDMF-A was somewhat uniform (~20% difference), there was greater variability amongst cDMF-B and cFumaderm capsules (> 30% difference). Impurity testing revealed 2 and 4 unknown components within cDMF-A and cDMF-B, respectively, with levels ranging from 0.05 to 0.81% of total drug content. In in vitro testing of cDMF-A,>10% (12 mg) of DMF was released after 120 min in simulated gastric fluid and 17% (20 mg) released in simulated intestinal fluid after 60 min. While minimal amount of DMF was released from cDMF-B in simulated gastric fluid, 50% (60 mg) of DMF was released after 60 min in simulated intestinal fluid. Similarly for cFumaderm, a fraction (< 20 mg) of the 120 mg target dose was released after several hours in simulated intestinal fluid. The uniformity of release rates across capsules varied significantly.

CONCLUSION: These results demonstrate that compounded fumarates are not equivalent to licensed products and may present unknown safety, efficacy, or quality risks.

CoI: multiple

The Natalizumab #AttackMS Trial

We propose the very early use of natalizumab to maximise outcomes in people with very early relapsing MS.

In the European Union, natalizumab is licensed to treat adults with highly active relapsing-remitting multiple sclerosis for the following patient groups:

Patients with highly active disease despite a full and adequate course of treatment with at least one disease-modifying therapy (DMT)

Patients with rapidly evolving severe relapsing-remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.

The reason for this restrictive labelling is historical and relates to the undefined risk of developing PML prior to the implementation of JC virus serological testing to derisk PML. As a consequence of natalizumab’s restricted label, an increasingly small number of patients with MS are being treated with natalizumab.

Natalizumab’s attributes of being a very high efficacy agent, having a rapid onset of action, being relatively safe in the short-term (12 months) and having the ability to reverse its mode of action (washout or using plasma exchange) make it the ideal DMT to treat active MS acutely to prevent further damage.

There is emerging evidence that the earlier you treat MS the better the outcome. We have anecdotal evidence, from individual patients, that even short delays in starting DMTs may have consequences for individual patients with multiple sclerosis. In many parts of the world healthcare systems are not configured for the rapid diagnosis and treatment of multiple sclerosis, which results in many pwMS waiting months, and in some cases years, to be diagnosed and treated. We feel this laissez-faire approach to the management of MS is wrong and is counterintuitive to how we approach other neurological diseases in particular stroke where time matters.

We hypothesise that by treating people who are likely to have MS acutely with natalizumab we will improve outcomes, i.e. these patients will acquire less disability and may even have improved rates of disability improvement, compared to patients managed in a standard way.

We have therefore designed the #AttackMS Natalizumab trial to test these hypotheses and have approached Biogen to fund and/or sponsor this study.

The trial plans to recruit patients with clinically isolated syndromes, with an abnormal MRI (two or more lesions suggestive of demyelination), within 7 days of onset and to randomise them to being treated with natalizumab (300mg ivi 4 weekly) or placebo. Subjects will then be managed according to a protocol that will ensure they are diagnosed and considered for licensed treatments within an 8-week period. The latter has been chosen as it is within the timeframe set out by an international panel of MS experts as being an appropriate period of time for being diagnosed with MS and started on treatment (please note in most healthcare systems it takes longer than this). At 8 weeks, i.e. after their third infusion of natalizumab or placebo, subjects will be unblinded; those on natalizumab will then continue on natalizumab for another 10 infusions and those on placebo will be started on the DMT that their treating neurologist and themselves have chosen. Subjects will then be followed for a further 10 months.

The primary outcome will be an area-under-the-curve (AUC) analysis of serum neurofilament levels, a biomarker of neuroaxonal damage, performed on serial blood samples taken over the period of the study. Secondary outcome measures will include MRI, clinical and patient-related outcome measures (PROMS).

MRI metrics will include (1) new T2 lesions as a marker of focal inflammation, (2) single lesion MTR as a marker of remyelination, (3) T1 hypodensity as a marker of tissue damage. Clinical outcomes will focus on disease improvement using a composite of the EDSS, T25W, 9HPT, SDMT, and low-contrast visual acuity (LCVA). PROMS will include a fatigue scale and important symptom for pwMS that has been shown to be improved by natalizumab.

At the end of the 12 months of the study treating neurologists and participating subjects in the natalizumab arm will be informed about their JCV serostatus and a decision will be made to continue on natalizumab or switch to another DMT. Subjects will then be rolled over into an extension study to be followed for a further 12 to 24 months to collect long-term clinical and MRI outcomes. The latter is important to assess brain atrophy or brain volume loss.

What we are interested in hearing from you the MS community is this trial ethical and do you think the scientific principles underpinning it are sound?

If you work for Biogen and are reading this blog post and are wearing your commercial hat you will see this trial may be the vehicle you need to resuscitate natalizumab as a mainstream DMT and to convince the EMA to reconsider natalizumab role in the management of MS and grant it a first-line license it deserves; particularly for people who are JCV seronegative.

At Barts-MS we are so convinced that the #AttackMS treatment paradigm will improve MS outcomes for individuals with MS that we have started using it already in a few isolated patients with highly active MS. We want to take this paradigm to all our of our patients. Yes, all of our patients, because we want to maximise their outcomes.

From a political perspective, this trial may nudge the MS community to be more proactive about treating MS and cement the message that we have been promoting for several years that ‘Time is Brain’. Why should we value the MS brain any less than the stroke brain?

CoI: multiple