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

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

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 https://register.gotowebinar.com/register/351330656592328975

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