#MSCOVID19: Interferon-beta and NABs

Barts-MS rose-tinted-odometer: ★

It is always nice to see evidence supporting a hypothesis you had more than a decade ago see daylight. 

If you are on interferon-beta or have been on interferon-beta in the past this post is important to you. It is clear type 1 interferons, such as interferon-beta and alpha, are important antiviral cytokines and are critical in the body’s fight against coronaviruses. There are two papers in Science that show that people with errors in the interferon pathway or neutralizing anti-interferon antibodies are at high and serious risk of severe COVID-19. The reason for this is that their immune system can’t mount an appropriate antiviral response.  

Why is this important to pwMS? The problem is that people on interferon-beta may generate anti-drug antibodies (ADAs)  to interferon-beta that can inhibit its antiviral activity. The rate of anti-interferon-beta neutralizing antibody (NABs) production depends on the preparation of interferon-beta you are on or have been on in the past. The NAB rates vary from about 2% to 35% and higher. The reason for this is based on whether or not the interferon-beta aggregates in the vial and whether or not there are other impurities in the particular formulation that may make the interferon-beta more immunogenic (more likely to stimulate the immune system to make NABs). 

Please note even if you have been treated with interferon-beta many years ago you may still have NABs. NABs may persist for many years and these will continue to inhibit your own interferon-beta’s activity. 

We reported a single case, our index case (see below), who developed recurrent severe genital herpes that coincided with her developing NABs. The herpes was such a problem that this patient is now on continuous antiviral prophylaxis and has been so for about 8 years. Any attempt to stop the antiviral is followed by rapid recurrent herpetic lesions. 

Based on this I suspect that pwMS who have NABs to interferon-beta may be at increased risk of getting severe COVID-19. I would urge anyone with a cohort of such patients to screen them for NABs and test this hypothesis. 

It is now clear that overall pwMS on interferon-beta are at lower risk of COVID-19 and severe COVID-19 presumably because the antiviral effects of interferon are protecting them against the virus. Therefore being on interferon-beta may be a double-edged sword depending on whether or not you have NABs.

If you don’t know your NAB status ask your HCP for a test. 

Would knowing that someone with MS was NAB-positive change practice? Yes, based on the science you would recommend increased vigilance and possibly self-isolation if the background risk of coronavirus infection is high. 

Fine et al. Do neutralising antibodies against exogenous interferon-beta inhibit endogenous signalling pathways? Mult Scler Relat Disord 2015 Jan;4(1):88-91.

Introduction: Interferon-beta (IFNβ) is currently the most used disease-modifying treatment for relapsing-remitting multiple sclerosis (RRMS), but it can lead to the production of neutralising antibodies (NABs) against IFNβ.

Clinical case: A lady with a past history of genital herpes was diagnosed with RRMS, started IFNβ treatment with a good initial response. Three years later her treatment was interrupted to become pregnant. After delivery she restarted IFNβ; she had more reactivations of genital herpes and experienced intermittent sensory symptoms often coinciding with herpes reactivation. High NABs titres against IFNβ were found. Since the introduction of famciclovir as prophylactic antiviral therapy and a switch from IFNβ to glatiramer acetate, herpes reactivations ceased and she had no further MS relapses.

Conclusion: Exacerbations of genital herpes coinciding with MS relapses suggest a potential link between the development of NABs and inhibition of anti-viral action of endogenous IFNβ. This case highlights that NABs not only decreases exogenous IFNβ treatment efficacy but may also interfere with anti-viral properties of endogenous IFNβ. Investigating patients who are treated with biological medication will allow us to better understand the biology and signalling pathways in humans.

Bastard et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science  24 Sep 2020: eabd4585 DOI: 10.1126/science.abd4585

Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Zhang et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science  24 Sep 2020: eabd4570 DOI: 10.1126/science.abd4570.

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

Parallel Universes

I attended an online meeting yesterday and gave my usual talk on why the MS community needs to change its worldview from MS being a “clinico-radiological” entity to being a “biological disease”. There are many reasons for doing this but an alternative MS worldview will allow us to (1) diagnose MS earlier, (2) start treatment earlier, (3) define prevention strategies targeting very early MS or the at-risk, (4) stop MS being considered two or three diseases, (5) develop combination therapies for smouldering or the real MS and (6) to manage MS more holistically. 

If we think about MS from a biological perspective rather than a clinical (relapses) or MRI (new lesion) perspective then we will not be lulled into a sense of false security that we are on top of this disease or be surprised when patients who are apparently disease-activity free become secondary progressive.

One of the participants and respected colleague asked me what will it take to get the MS community to accept the biological definition of MS and to move away from the clinico-radiological view of the disease. I tried to answer the question but failed horribly. 

On reflecting on my inability to answer this question I realised that I have probably been trying to do this, i.e. redefine MS, for decades and have failed. My research, traditional communication channels (journals, congresses, etc.) and new media platforms (blogging, social media, etc) are clearly not working. 

Maybe the solution is to create a parallel MS universe, i.e. set-up an alternative committee to redefine the disease. This ‘New MS Definition Committee’ would use sound philosophical principles to define MS, avoid the diagnostic tautology that underpins the McDonald criteria, and include definitions that are underpinned by biology. We can then retrospectively validate these criteria on existing data sets, refine the criteria (feedback loop) and then set-up prospective studies to validate the criteria. Yes, validate them, i.e. establish the sensitivity and specificity of the criteria and to then establish how they perform in high, intermediate and low prevalence regions of the world. What clinicians and researchers need to know is the positive and negative predictive value of the criteria in their clinics. You will be surprised by how much incorrect diagnoses or misclassifications affect research outcomes (more on this later).

This parallel MS Universe will have to include a different research and education agenda to challenge the current dogma. And will have to generate a few creative memes (infectious ideas) and policy to speed up adoption. 

I wonder how many of my colleagues would want to join this parallel Universe? Is the status quo tenable? The motivation for doing this is to improve outcomes for people living with MS and to prevent the next generation of people getting MS.

CoI: nil

Is exercise druggable?

Exercise is the most underrated and under-utilised DMT. Why? 

Ever since I ditched football, or soccer as it is called in the Americas, as a skinny 13-year old for long-distance running I knew intuitively that there was something extraordinary about aerobic exercise. Running is not only mindfulness, but it makes you think clearer in general and lifts your mood. Long-distance running is a philosophy and it adds true meaning to life. For those of you who are exercise-junkies, you will know what I am talking about. For those of you who haven’t experienced the uplifting benefits of exercise, I would suggest reading Haruki Murakami’s book ‘What I Talk About When I Talk About Running’. Murakami is an extraordinary writer and brings a wonderful and mystical Japanese philosophical twist to the task at hand.

It is clear that running or exercise, in general, is one of the most underutilised treatments we have for multiple sclerosis and neurodegeneration in general. It is clear that exercise and diet have to be at the base of any brain health pyramid. As always there is biology that underpins the treatment effects of these simple lifestyle interventions. Most of us have assumed exercise works by simply stimulating growth factors and endorphins in the central nervous system. Growth factors are responsible for anti-ageing effects and endorphins for its mood-elevating effects and explain the runner’s high. However, the latest work just published in Science (see below) shows that the health benefits of exercise on ageing may be mediated by a hormone that is released from the liver. 

The circulating factor is glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), which increases after exercise and was shown to correlate with improved cognitive function in aged mice. Importantly blood levels of Gpld1 are increased in active healthy elderly humans. If this work is confirmed it means we may be able to hack exercise’s effects on this pathway and create a drug that you can take that will prevent you from ageing and if you have MS slow down your disease progression. Wouldn’t that be a remarkable innovation?

As always to create a viable market for anti-ageing drugs we need to classify ageing as a disease. This will create the incentive for Big Pharma to invest. If we don’t classify ageing as a disease antiageing medications will be confined to the consumer market, which makes it very difficult to study in diseases such as MS and get them licensed by the regulatory authorities as treatments for multiple sclerosis and other neurodegenerative diseases. If you interested in reading more on this issue please read my Medium post from three years ago where I make the case that ageing is a disease. 

Horowitz et al. Blood Factors Transfer Beneficial Effects of Exercise on Neurogenesis and Cognition to the Aged Brain. Science. 2020 Jul 10;369(6500):167-173. doi: 10.1126/science.aaw2622.

Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.

CoI: none in relation to this post

Live Webinar Tonight 6PM ET! MS and COVID-19: A Webinar Series for Healthcare Providers

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Join the National MS Society and the Consortium of MS Centers for a live webinar featuring Gavin Giovannoni, MBBCh, PhD, Chair of Neurology, Blizard Institute Barts and The London School of Medicine and Dentistry and Aaron Miller, MD , Medical Director, Corinne Goldsmith Dickinson Center for Multiple Sclerosis. This webinar will focus on disease modifying therapies and clinical decision-making in the COVID-19 era and will be moderated by Tim Coetzee, PhD the Chief Advocacy, Services and Research Officer for the National MS Society. Submit questions with your registration or during the webinar.If you haven’t registered yet, click here.

Tuesday, June 30th at 6:00 PM ET
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https://register.gotowebinar.com/register/351330656592328975

COVID-19 & MS update from Australian neurologists

I received this email, which may be of value to you all.

Latest COVID-19 information for people with MS

MS Research Australia

COVID-19 & MS

UPDATE FROM MS NEUROLOGISTS – 08/04/20
Advice for persons with multiple sclerosis and related disorders regarding the COVID-19 pandemic

Dear MS Stakeholder,

We hope you are keeping safe and well since our last communication. In our last COVID-19 update to you on 27/03/20 we shared a statement prepared by an independent group of Australian and New Zealand neurologists. MS Research Australia continues to work closely with these experts and would like to share an update to the advice for people with MS provided at the end of March. The statement is outlined below, with the key updates to the previous information highlighted in red for your convenience.

BACKGROUND

Since December 2019 following cases emerging in and around Wuhan, China most regions of the world have now experienced cases of a novel respiratory illness (COVID-19) caused by a new coronavirus which has been identified as SARS-CoV-2. The mortality of this infection amongst cases displaying symptoms and confirmed to have the virus is in the order of 1-7%. National and International measures to reduce the risk of transmission of the virus have been implemented in most jurisdictions. It is likely that these measures will slow the rate of transmission, but at this point it is unclear if further spread can be prevented and it is unclear how long the present outbreak will last. At present there is no known effective treatment for COVID-19 and there is no vaccine. Older persons and those with pre-existing medical conditions (respiratory disease, heart disease, diabetes, cancer) have a higher risk of complications from COVID-19 infection. Men may also be at a slightly increased risk. At this stage, there is no evidence that being immunosuppressed increases a person’s risk of being infected with COVID-19 or developing complications, but there is a theoretical risk of both.

In Australia, we are still in a containment phase where it is hoped that the measures being implemented will limit the number of people infected and the present risk of being infected with COVID-19 remains low. The latest data indicate that the number of new cases is declining. This suggests that the present transmission prevention efforts may be working. This is result of two main factors. The first is that the population of Australia has largely followed the recommendations of social distancing and personal protection. The second is the outstanding work undertaken by our Public Health team who have successful traced the source of 80-90% of cases and implemented testing, quarantine and self-isolation as necessary. This has been an amazing achievement and goes largely unnoticed. However, we need to remain vigilant as the situation may still change. We will continue to monitor this and change our advice accordingly.

HOW CAN I PROTECT MYSELF FROM GETTING COVID-19?

In order to minimise the risk of being infected by COVID-19, you should follow the standard precautions advised by the Australian Government. This is the best source of advice on how to keep yourself safe and will be updated daily.

WHAT IF I DEVELOP SYMPTOMS OF COVID-19 INFECTION OR HAVE A CONFIRMED DIAGNOSIS OF COVID-19 INFECTION?

If you develop symptoms of COVID-19 infection or have a confirmed diagnosis of COVID-19 infection you should:

  • Follow the standard self-isolation advice.
  • Follow the advice of the diagnosing doctor or health care facility.
  • Seek the advice of your neurologist or ask the diagnosing health care team to discuss with them or the on-call neurologist regarding any changes to your treatment.
  • It is extremely important that you advise your neurologist if you become infected with COVID-19 as we will be collectively monitoring the outcomes for people with MS and various therapies. This will assist in providing appropriate advice to all.

WHO SHOULD I CONTACT IF I HAVE SYMPTOMS OF COVID-19 INFECTION?

If you are concerned that you are developing symptoms of COVID-19 you can:

  1. Phone the Coronavirus Health Information Line 1800 020 080.
  2. Phone the Health Direct Hotline 1800 022 222.
  3. Phone your General Practitioner for an appointment (please phone ahead to make an appointment).
  4. Attend a coronavirus testing centre (these are listed for each state by the relevant health department, again please phone ahead to make an appointment).

SHOULD I COME TO MY OUTPATIENT CLINIC, INFUSION, BLOOD TEST OR MRI APPOINTMENT?

If you have visited a high-risk area, have symptoms of COVID-19 infection or have had close contact with someone who has been diagnosed with COVID-19 please do not attend your outpatient, infusion, blood test or MRI appointment. Please contact your specialist clinic, MRI department, infusion centre or MS Nurse to advise of your need to cancel the appointment and make alternative arrangements. Most neurology clinics have now moved to telephone or telehealth consultations.

It is important to remember that MRI scans and blood test form an important part of the monitoring of your disease activity and potential side effects of medication. In some instances, there may be adverse consequences of delaying or cancelling these investigations. Please contact your neurologist before making any changes to your planned investigations. MRI departments in hospitals and private radiology practices have implemented measures to limit the risk of infection. Some private pathology services offer a home collection service. Please contact your pathology service for details. This may require the approval of your neurologist.

SHOULD I TRAVEL OVERSEAS?

Current travel advice is available on the Australian Smart Traveller website, but essentially all travel has now been banned.

SHOULD I HAVE THE FLU AND PNEUMONIA VACCINATIONS?

It is recommended that all persons with MS and related disorders have the flu vaccination when it becomes available in April. The Pneumococcal vaccination is also recommended.

WHAT IF I AM A HEALTHCARE WORKER?

At present we have no evidence of an increased risk of COVID-19 infection or its complications in people with MS or related conditions, even in those on treatment. However, as indicated below there are potential, theoretical risks with some medications and it would be sensible for healthcare workers on any of these therapies to avoid work environments that would bring them into direct contact with people either known to be or likely to be infected with COVID-19. If you require any documentation to this effect, please contact your neurologist who will be happy to assist.

WHAT SHOULD I DO ABOUT MY MEDICATION?

If you are on a regular medication for MS or a related condition, then it is recommended that you should continue to take this medication because of the very real risk of relapse when medication is ceased.

With regards to specific therapies:

  1. Self-injected therapies (glatiramer acetate [Copaxone], beta-interferon [Avonex, Betaferon, Plegridy, Rebif]):
    – These medications are not immunosuppressive.
    – You should continue these medications and follow the standard advice regarding prevention of COVID-19 infection.
  2. Intermittent immunotherapies (plasma exchange, intravenous gammaglobulin [IVIg]):
    – These therapies have a minimal impact on immune function.
    – You should continue these therapies and follow the standard advice regarding prevention of COVID-19 infection.
  3. Regular potentially immunosuppressive MS therapies (natalizumab [Tysabri], fingolimod [Gilenya], siponimod [Mayzent], dimethyl fumarate [Tecfidera], teriflunomide [Aubagio]):
    – These therapies are mildly immunosuppressive, there is currently no evidence that they increase the risk of COVID-19 infection.
    – Because of the very real risk of relapse on discontinuing these therapies compared to the currently low risk of COVID-19 infection the present advice is that these medications should be continued.
    – Your neurologist may wish to monitor your immune cell counts more frequently.
    – You should follow the standard advice regarding prevention of COVID-19 infection.
  4. Immunosuppressive therapies (prednisolone, methotrexate [MTX], azathioprine [Imuran], mycophenolate mofetil [Cellcept], cyclophosphamide [Cytoxan]):
    – The level of immunosuppression with these medications is variable and depends upon the dosage and combination of treatments.
    – Because of the very real risk of relapse on discontinuing these therapies compared to the currently low risk of COVID-19 infection the present advice is that these medications should be continued.
    – Your neurologist may wish to monitor your immune cell counts more frequently.
    – You should follow the standard advice regarding prevention of COVID-19 infection.
  5. Pulsed immunosuppressive therapies (rituximab [Rituxan], ocrelizumab [Ocrevus], alemtuzumab [Lemtrada], cladribine [Mavenclad]):
    – These therapies are immunosuppressive to varying degrees and for variable periods of time.
    – Because of the pulsed nature of these therapies there are options to delay courses of treatment.
    – Decisions on whether or not to delay a course of these therapies should be discussed with your neurologist.
    – You should follow the standard advice regarding prevention of COVID-19 infection, in some situations, on the advice of your neurologist, it may be appropriate to take additional precautions.

Signatories

Simon Broadley
Bill Carroll
Natasha Gerbis
Deborah Mason
Mike Boggild
Heidi Beadnall
Anneke van der Walt
Jeannette Lechner-Scott
Jane Frith
Suzanne Hodgkinson
Stephen Reddel
Richard Macdonell

Michael Barnett
Mark Marriott
Pamela McCombe
Trevor Kilpatrick
Bruce Taylor
Allan Kermode
Ernie Willoughby
Simon Hawke
Mahtab Ghadiri
Tomas Kalincik
Steve Vucic
Ian Sutton

Todd Hardy
Ann French
Mastura Monif
Helmut Butzkueven
John Parratt
Olga Skabina
Caron Chapman
Patrick Aouad
Zara Ioannides
Katherine Buzzard
Nicholas Crump

FOR THE LATEST UPDATES VISIT THE COVID-19 INFORMATION FOR PEOPLE WITH MS HUB ON OUR PARTNER ORGANISATION MS AUSTRALIA’S WEBSITE

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MS Research Australia
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#MSCOVID19: face-2-face telemedicine comes of age

I note some of you via the Q&A session are having problems seeing your MS team or getting hold of them via email or telephone. The reason for this may be because they are off ill or self-isolating or they have been redeployed. I am aware that most MS Centres have moved to remote telemedicine clinics, mainly using a phone.

I discovered that the platform that NHSX (formerly NHS Digital) has been pushing AccuRx Fleming for video consultations. It is particularly common for GPs to use this platform. I set it up for myself in literally 5 minutes yesterday and will be doing as many of my remote clinics via the platform, which runs in a web browser or if you want you can use the App.

The following YouTube video shows you how quick and easy it is to get going.

You may want to nudge your NHS team to use this platform if you prefer a face-2-face consultation. The platform is fully NHS compliant and is the one that is used by most NHS GPs.

CoI: I work for the NHS

A #MSCOVID19 reality check

Are you aware of how the COVID-19 pandemic is going to play out?

People are being lulled into a sense of security that over the next 2-3 months the pandemic and mini-epidemics in each country and region will be over and things will start to return to normal. This is not correct. 

The current strategy is to flatten the curve and extend the tail of the epidemic. What this means is that the COVID-19 epidemic will last many more months and is likely to extend into next year. The purpose of flattening the curve is simply to manage limited NHS resources, i.e. ventilators, CPAP (continuous positive airway pressure) machines, ITU and hospital beds, supplies of PPE (personal protective equipment) and staff. At present, it is estimated that 25% of NHS staff are off ill and/or self-isolating because another family member is ill.

By flattening the curve it will keep the stream of patients with severe COVID-19 infection to a manageable level. Instead of them arriving at NHS hospital in a 3 month window they will now arrive over a 6 to 9 month window. 

If the lockdown is very extensive and prolonged as it has been in China you can stop the spread of infection in the community, but there will still be flares of infection and hence further lockdowns will be required. These flares will be triggered by asymptomatic viral shedders or people returning to China from outside its borders who are infected.  I am almost certain that China is not telling us their whole story. We are not hearing about the COVID-19 flares, which according to basic epidemiological principles has to be happening. 

I think it is highly unlikely that the UK will take the Chinese approach to our epidemic. This means that COVID-19 will move from being an epidemic, i.e. an increasing number of cases, to becoming endemic. The latter means the number of new cases becomes stable and at a level, the NHS can cope with. Eventually, herd immunity will occur that will slow down the spread of infection to very low levels. For herd immunity to occur it is estimated that at least 80% of the population, and possibly more, will have to get infected with SARS-CoV-2 so that it will ring-fence people who are susceptible to infection and stop the person-to-person spread, which has driven the epidemic. 

How quickly herd immunity occurs depends on how soon the government relaxes or stops the lockdown and start letting people socialise and to start spreading the virus again. If the government removes the lockdown at the end of June as some commentators have suggested then I would estimate it would take about 18 months for the British population to acquire herd immunity. 

One strategy that is likely to be employed is for high-risk people to be screened for immunity to SARS-CoV-2 by testing for the presence of antibodies in their blood and only letting them out of self-isolation if they are immune. This strategy is in anticipation that there will be an effective vaccine for SARS-CoV-2. I personally think this is a high-risk strategy. Vaccines for respiratory infections are notoriously difficult to make. Immunity from a vaccine may not be lifelong and the virus will mutate and drift, which will make the vaccine less effective. Importantly, the logistics of getting a vaccine tested and deployed globally makes it highly unlikely that we will see a vaccine deployed at a population level before 18 months. Just maybe a vaccine may be ready for very high-risk patients towards the end of 2021.

What does this mean for people with MS and the general population? It means that you really need to prepare yourself to be infected with SARS-CoV-2 and to possibly get COVID-19. I predict at 80% of us, yes 4 out of 5 of us, will be infected with SARS-CoV-2. The good news is that it looks like at a population level the proportion of people who get asymptomatic infections may be higher than previous estimates. The CDC (Centre for Disease Control) estimates asymptomatic infection rates as being 25% and higher. This means that when we get the real denominator of people infected with SARS-CoV-2 we will find that the proportion who get severe COVID-19 will be much less than 5% and the mortality or death rate from the infection will be much lower than the 2-5% that is currently being quoted. 

Another possibility that I think is more likely than a vaccine is the emergence of effective antivirals and immunotherapies for treating COVID-19 and severe COVID-19. There are a lot of ongoing trials with repurposed drugs. I predict that when one or more of these trials are positive the registration of the drug, and adoption of the drug, into clinical practice will be very rapid. This means COVID-19 will be treatable and the proportion of people needing ITU and ventilation will drop and the mortality rate will improve. I predict that such a drug discovery is only months away. 

You also have to realise that the ‘suits’ (yes, they tend to be men in grey suits) or the ‘Whitehall economists are frantically working away at their various economic models and will be weighing up the economic costs of the COVID-19 epidemic versus the health of the population. At some point in the near future, they will decide that GB Inc. has to to get back to work and the consequences of doing that will be the loss of lives due to severe COVID-19. The decision will be based on four competing factors (1) is the NHS now in a position to cope vs. (2) the mental health of the population (will they continue to adhere) vs. (3) the cost of a continued lockdown to the British economy vs. (4) the number of lives that will be lost. This is the harsh reality of being in charge of a country.

So, in conclusion, please don’t be lulled into a sense of false security; the COVID-19 pandemic is far from over, you are likely at some point to get COVID-19, don’t hold your breath expecting a vaccine to save you, but be optimistic and expect an anti-viral and/or anti-inflammatory to change the prognosis of COVID-19 soon. Please don’t believe China’s figures and take our politicians comments for what they are; political spin to manage expectations (unrealistic expectations). 

CoI: I am about to leave the trenches to start fighting the war and I am very anxious.

Adamas Announces Top-Line Results from INROADS Phase 3 Trial of ADS-5102 for Multiple Sclerosis Patients with Walking Impairment

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Adamas Announces Top-Line Results from INROADS Phase 3 Trial of ADS-5102 for Multiple Sclerosis Patients with Walking Impairment

– INROADS study achieved its primary endpoint (proportion of responders with at least a 20% improvement from baseline to Week 12) –

– Dose-response observed for both efficacy and safety –

– Safety data consistent with known safety profile of amantadine –

EMERYVILLE, Calif., Dec. 17, 2019 (GLOBE NEWSWIRE) — Adamas Pharmaceuticals, Inc. (Nasdaq: ADMS), a company dedicated to developing and delivering medicines that make a clinically meaningful difference to people affected by neurological diseases, today announced that INROADS, a 3-arm, randomized, double-blind, placebo-controlled study in 594 multiple sclerosis (MS) patients with walking impairment met its primary endpoint.

Results from the study showed that patients taking 274 mg ADS-5102 had a statistically significant improvement in response rate of 21.1% compared to 11.3% taking placebo (p=0.01). Response was defined as at least a 20% improvement in walking speed from baseline to 12 weeks post-treatment, as measured by the Timed 25 Foot Walk. Additionally, the response rate for patients taking a lower dose of 137 mg ADS-5102 was 17.6% (p=0.08). ADS-5102 did not demonstrate a significant effect on the secondary walking measures at either dose.

“We are pleased that ADS-5102 shows a potential benefit for MS patients with walking impairment, for whom there is a significant unmet medical need and limited treatment options,“ said Neil F. McFarlane, Chief Executive Officer of Adamas Pharmaceuticals, Inc. “However, as we did not see the scale of clinical benefit we had hoped for in this study we will fully assess the potential for ADS-5102 in MS patients before determining the extent of our continued investment in this program.”

The most common adverse events (occurring in greater than 5% of any ADS-5102 treatment group) were: peripheral edema, dry mouth, fall, constipation, UTI, and insomnia. 20.5% of patients discontinued study drug due to adverse events in the 274 mg group, compared to 6.4% in the 137 mg group, and 3.8% in the placebo group. The reported adverse events associated with ADS-5102 in this study were dose-dependent and consistent with the known safety profile of amantadine.

“We would like to extend our sincere thanks to everyone involved in this study including the patients, investigators, and coordinators,” said Rajiv Patni, M.D., Chief Medical Officer of Adamas Pharmaceuticals, Inc. “We will now complete our analyses of these data to fully characterize the efficacy and safety profile of ADS-5102 and the dose response seen in this study. Given these data, we will not initiate the originally planned replicate second Phase 3 placebo-controlled study. We are continuing the open-label extension study and will engage with the FDA to discuss a potential regulatory pathway.”

“Walking impairment negatively impacts many aspects of daily life for a large number of patients, and additional treatment options are needed,” said INROADS Steering Committee Chair, Jeffrey Cohen, M.D., Director of experimental therapeutics at the Mellen Center for Multiple Sclerosis at Cleveland Clinic and a paid consultant for Adamas. “This trial result is encouraging for the MS patient and physician community and we look forward to reviewing the full data set.”

About ADS-5102

Adamas is evaluating ADS-5102 in the INROADS Phase 3 clinical study for multiple sclerosis patients with walking impairment. ADS-5102 was previously approved by the FDA under the trade name GOCOVRI® (amantadine) extended-release capsules for the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy. GOCOVRI is not FDA-approved for the treatment of multiple sclerosis patients with walking impairment.

About INROADS

The INROADS study was a 12-week, three-arm, multi-center, randomized, double-blind, placebo-controlled study with a 4-week placebo-run in designed to evaluate the efficacy and safety of ADS-5102 for the treatment of walking impairment in multiple sclerosis. The study enrolled 594 patients with walking impairment in the US and Canada and randomized 560 patients in a 1:1:1 fashion to receive 274 mg ADS-5102 (N=185), 137 mg ADS-5102 (N=187), or placebo (N=186). The primary endpoint was the proportion of responders (at least 20% improvement in Timed 25-Foot Walk from baseline) at Week 12.
Key secondary endpoints include the mean change in the Timed 25-Foot Walk, the Timed Up and Go, and the 2-Minute Walk at 12-week post-treatment at both the 274 mg and 137 mg dose.

Baseline characteristics were similar across all treatment arms. The mean time since diagnosis of MS was 15.9 years, median EDSS at screening was 6.0, and mean timed 25-foot walk at baseline was between 11.5 to 12.4 seconds. Prior dalfampridine use was reported in 52.5% of patients and prior amantadine use was reported in 12.9% of patients.

About Walking Impairment in Multiple Sclerosis
Multiple sclerosis (MS) is a chronic neurological autoimmune disease that is often disabling with unpredictable symptoms. Among the MS patients in the US, nearly 270,000 have walking impairment, which is present throughout the day. Walking impairment in MS remains an area of high unmet need, as there is only one approved product on the market for this indication.

About Adamas Pharmaceuticals, Inc.

At Adamas, our purpose is clear: deliver innovative medicines that make a clinically meaningful difference for patients, caregivers and society. We are a fully-integrated company with a growing portfolio of therapies that address a range of neurological diseases. For more information, please visit www.adamaspharma.com.

Forward-looking statements

Statements contained in this press release regarding matters that may occur in the future are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including but not limited to, statements contained in this press release regarding Adamas’ development plans for ADS-5102, including its plan to fully assess its program in multiple sclerosis walking impairment and engage with the FDA on a potential regulatory pathway. Such statements are subject to risks and uncertainties, and actual results may differ materially from those expressed or implied by such forward-looking statements. For a description of risks and uncertainties that could cause actual results to differ from those expressed in forward-looking statements, including risks relating to Adamas’ research, clinical, development and commercial activities relating to GOCOVRI and ADS-5102, and the regulatory and competitive environment and Adamas’ business in general, see Adamas’ Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on November 7, 2019, particularly under the caption “Risk Factors.” Investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this release. Adamas undertakes no obligation to update any forward-looking statement in this press release, except as required by law.

Contact:

Investors:
Peter Vozzo
Managing Director, Westwicke
443-213-0505
peter.vozzo@westwicke.com

Media:
Sarah Mathieson
Vice President of Corporate Communications
510-450-3528
smathieson@adamaspharma.com

My prevention hat

About three years ago I started wearing another hat; a preventive medicine hat.

We started the Preventive Neurology Unit within our medical school focusing on MS, Parkison’s Disease and all-cause dementia. The unit is growing rapidly and gaining momentum. It was with great pride that I was able to attend and speak at first symposium. I have uploaded my slides for anyone who wants to download them for personal use. 

It is clear that we have an obligation to the next generation of pwMS. The study below shows that young people with MS take a massive cognitive hit. The study shows that at a presentation about a quarter of young people with MS have cognitive impairment at baseline and ~15% had a measurable decline over the next 2 years. In a world where our self-worth is largely defined by our cognition, these figures are scary. The observation that MS is a dementing disease is not new and goes back many decades. 

The willingness of the MS community to accept this is worrying; they say calling MS a dementing disease is stigmatising. Yes and no. Yes, if you want to put your head in the sand and no if you want the MS community to do something about it. It is clear that the dementia is preventable; i.e. the less brain damage that you allow to accumulate the less cognitively impaired the pwMS will become. This is the message behind our treat-early treat-effectively campaign and why we need to flip the pyramid. Access to the most effective treatments early on is the only way to really prevent end-organ damage. 

More importantly, is the observation that MS is preventable. We estimate that by tackling childhood and adolescent obesity and smoking may reduce the incidence of my MS by ~25%. Vitamin D supplementation may reduce the incidence by a further 40%. Preventing EBV infection with a vaccine strategy may prevent the majority of people developing MS. May be admitting how bad MS is at a personal and population-level will get funders to put more money and resources into prevention. 

I think we should call a spade a spade and forget the rose-tinted world most people like to live in. We need to take MS prevention seriously; we owe it the next generation of people who are destined to develop MS. Wouldn’t it be nice if they didn’t get MS? 

Wallach et al. Cognitive processing speed in pediatric-onset multiple sclerosis: Baseline characteristics of impairment and prediction of decline. Mult Scler. 2019 Nov 28:1352458519891984.

BACKGROUND: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS.

OBJECTIVE: To screen for cognitive impairment early in the course of POMS and analyze predictive factors.

METHODS: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free.

RESULTS: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing (n = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT.

CONCLUSION: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.

CoI: multiple

Hopebird

The debate about what is active and inactive secondary progressive MS will not be settled by the EMA adopting a positive opinion, recommending the granting of a marketing authorisation for siponimod, which is now ‘licensed’ for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease. Siponimod reduces disability progression in people with active SPMS. The most common side effects are headache, hypertension and increased liver enzyme levels. The full indication is: “treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity (see section 5.1)”

This label will disappoint the many pwSPMS who don’t have active scans and therefore won’t be eligible for DMTs. I have commented on what is and is not active SPMS in the past. I think the siponimod label entrenches the MRIcentric worldview of what is active MS. We know that the majority of people dying with SPMS have ongoing inflammation in their brains and spinal cords at post-mortem. Try telling someone with SPMS who is getting worse that they don’t have active MS because they have no enhancing, or new or enlarging T2, lesions on MRI. And what about using CSF and/or peripheral blood neurofilament levels to assess activity? We clearly need to challenge the EMA’s and FDA’s definitions of what is active SPMS.

At least the licensing of siponimod for treating SPMS is a big positive for the field and indicates that we are beginning to address the unmet need in treating more advanced MS. 

The impact that this will have on our MS services should not be underestimated. We are now going to have to monitor our SPMS patients with annual MRI scans. Do we have the resources for this? What about the extra follow-up clinic slots? This alongside ocrelizumab for active PPMS is going to put a major strain on our MS services. Will our managers give us more resources?

Siponimod may not be an eagle, phoenix or maven, but rather a hopebird which symbolises the importance of “an optimistic approach to what lies ahead” and why it is important to have a “glass half full” attitude. Less than a decade ago we were telling our patients with a progressive course that they were beyond hope, that has now changed. 

CoI: multiple