Multiple sclerosis: A chronic progressive neurological disease
Multiple sclerosis (MS) is an inflammatory autoimmune disorder affecting the central nervous system (CNS) and the most common cause of neurological disability in young adults. Unidentified environmental factors in the interplay with susceptibility genes trigger events causing inflammatory demyelination, axonal injury, and neurodegeneration. The sequence of these events defines the heterogeneous signs and symptoms of MS with persistent deficits and disability progression. Advances in understanding the underlying pathogenesis paved the way for rational strategies for better treatments.
As an independent biotechnology company, Biogen (Cambridge, MA) has led innovation in treatment and outcomes assessment in MS for >25 years and continues to have an enduring commitment to elevate the science and care of MS (Figure). Biogen has introduced a portfolio of MS disease-modifying therapies (DMTs), while leveraging data to establish innovations in trial methodology and outcomes assessment. This advertorial touches on Biogen’s role in disease management advances in the context of progress in MS.
MS treatment transformation
Approval of the first DMTs
The pivotal clinical trial of Biogen’s intramuscular interferon beta-1a (IFN β-1a; AVONEX®) was being conducted when IFN β-1b (Betaseron®, Bayer, Germany) was approved in 1993 as the first DMT for relapsing-remitting MS. AVONEX was approved for relapsing forms of MS in 1996. Subcutaneous IFN β-1a (Rebif®, Merck, Germany) was approved in Europe in 1998. The three IFN products were tested based on known immunomodulatory and anti-viral effects of type 1 IFN. Glatiramer acetate was approved in the United States in 1997. These four injectable MS DMTs significantly reduced relapse rates by ~30%, ushering in an era of effective disease modification. Seeking lower patient burden, Biogen tested a pegylated IFN β-1a, which retains similar pharmacodynamic activity to IFN β-1a, but its altered pharmacokinetic properties allows less frequent administration.1 Pegylated IFN β-1a (PLEGRIDY®, Biogen) was US Food and Drug Administration (FDA)– and European Medicines Agency (EMA)–approved in 2014.
Establishing new more holistic methods to evaluate MS treatment outcomes
Biogen, along with academic partners, leveraged the AVONEX trial to introduce four clinical trial innovations that subsequently became standard practice, shaping the MS clinical development field.2,3 Firstly, this was the original trial to define disability progression as a specified event (sustained worsening from baseline Expanded Disability Status Scale [EDSS] score). Treatment benefit was determined using survival curves, comparing time-to-disability events for IFN β-1a– versus placebo-treated participants. AVONEX produced 38% reduction in disability progression using this method, which is now standard in the field. Secondly, motivated by the need for a more relevant measure of destructive brain pathology, AVONEX clinical trial investigators pre-specified brain atrophy as an exploratory measure, and applied a new highly precise measure of brain atrophy, the so-called brain parenchymal fraction, to images collected during the trial. Beneficial effects of a DMT on rate of brain atrophy were reported for the first time.4 A follow-up study demonstrated the relevance of atrophy by documenting that the rate of brain atrophy during the AVONEX trial strongly correlated with severe clinical disability 8 years later.5 Atrophy measures are now standard in nearly all MS DMT trials. Thirdly, the AVONEX trial was the first to include the 9-Hole Peg Test, Timed 25-Foot Walk, and the Paced Serial Addition Test, which later were incorporated into the Multiple Sclerosis Functional Composite (MSFC), recommended as a new clinical outcome measure by the National MS Society Task Force on Clinical Outcomes Assessment.6 MSFC has been included in nearly all MS clinical trials since 2000. Lastly, the AVONEX trial was the first study to report a treatment impact of any MS DMT on cognitive function.7
The importance of early intervention was supported by the Biogen-sponsored CHAMPS (Controlled High-risk Avonex MultiPle Sclerosis) study.8 This was the first trial in patients with a first acute demyelinating event (now, clinically isolated syndrome) to show efficacy in delaying time-to-clinically definite MS and was recognized as a significant medical advance as it introduced the concept of early treatment and led to revisions in diagnostic criteria for MS.9
High-efficacy therapies: Balancing risk and benefit
Biogen’s recombinant humanized monoclonal antibody, natalizumab (TYSABRI®), mediates lymphocyte and monocyte cell adhesion and transendothelial migration via the α4β1 integrin pathway. Natalizumab demonstrated twice the efficacy of injectable DMTs; as such, it was the first high-efficacy DMT when introduced to the market in November 2004.10 However, after two cases of progressive multifocal leukoencephalopathy (PML) were confirmed in TYSABRI-treated patients, the drug was voluntarily removed from the market in February 2005, pending complete safety review. After careful assessment of all natalizumab-treated patients failed to identify other cases in MS, TYSABRI was reintroduced to the market in June 2006.
Biogen developed the John Cunningham virus (JCV) antibody assay as part of a comprehensive program designed to better understand and mitigate PML risk with natalizumab.11 Risk of PML was found to be concentrated in patients positive for JCV antibodies; thus, the JCV antibody assay achieved widespread use as the first blood-based biomarker test useful to stratify risk in MS. Biogen also identified prior immunosuppressant treatment and natalizumab treatment for >24 months as risk factors for natalizumab-associated PML.12 A JCV index was introduced,13 providing more precise risk prediction. Most recently, it was found that the risk of PML was significantly reduced with less frequent natalizumab dosing.14 Studies are now underway to determine the efficacy of extended-interval dosing. Thus, in addition to introducing the first high-efficacy DMT, Biogen also developed insights and tools for risk stratification, greatly improving patient selection to optimize the risk-benefit ratio.
Oral DMTs: An alternative to injectable therapies
In 2010, fingolimod (Gilenya®, Novartis, Switzerland) was the first oral MS DMT approved by the FDA, with teriflunomide (Aubagio®, Genzyme, France) following in 2012 and cladribine (Mavenclad®, Merck, Germany) in 2017 approved by the EMA. Biogen’s dimethyl fumarate (DMF; TECFIDERA®) was FDA approved in 2013. DMF is a methyl ester of fumaric acid that is rapidly converted to monomethyl fumarate thought to exert neuroprotective action and anti-inflammatory effects. DMF offered an oral option with favorable risk-benefit and has since become the most widely prescribed MS oral therapy.
A focus on individual patient outcome
Establishing treatment goals for individuals with MS became an obvious need as multiple DMTs were introduced. In 2010, TYSABRI clinical trial data were used to define a new outcome: freedom from disease activity,15 defined as absence of EDSS progression, relapse, or new/newly enlarging MS lesions. This was renamed no evidence of disease activity (NEDA), which has become the most common treat-to-target individualized outcome for patients. The NEDA approach continues to evolve, as MS experts have recognized the need to include measures of disease progression such as brain atrophy, and to develop ways to precisely measure outcomes in clinical practice.
The future
Biogen’s commitment to MS management extends beyond understanding the pathogenic role of CNS-targeted autoimmunity and traditional DMT research to fostering innovative treatment initiatives, introducing quantitative measures of outcomes that matter to patients into neurological practice, with the ultimate goal of personalized medicine.
Treatment of disease: Advancing the science of experimental therapeutics
While great strides have been made with the currently approved stable of MS therapies, complete disease control in many patients remains elusive due to residual impairment. Remyelination and axonal repair is an appealing target, with a goal of clinical improvement. Leucine-rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1), which was discovered by Biogen,16 suppresses oligodendrocyte differentiation, axonal regeneration, and neuronal survival. An antibody that blocks LINGO-1, opicinumab, has shown promise and is being tested in proof-of-concept trials by Biogen. If successful, opicinumab could usher in a completely new era, with the aim of neurological repair and functional recovery.
Transitioning MS care to quantitative medicine
Despite advances made in MS, patient assessments in medical practice remain qualitative and nonstandardized. Biogen has recognized the importance of high-quality, standardized, quantitative, multidimensional real-world data to better understand MS, predict and measure outcomes for individual patients, and develop precision and personalized medicine. Along with academic partners in the United States and Europe, Biogen has sponsored a technology-enabled solution, Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS). MS PATHS has four goals: 1) To create a data-generation engine that yields quantitative standardized clinical, imaging, and laboratory results for every participant, available in real time for clinical assessments and decision-making; 2) To more fully engage patients in their care, collecting patient reported outcomes at each visit; 3) To aggregate de-identified data for systematic learning to accelerate the development of personalized medicine; and 4) To create a highly efficient laboratory to develop and validate technologies needed more broadly in MS. Patients use the Multiple Sclerosis Performance Test, an iPad-based medical device, to provide comprehensive clinical assessments at each visit, while de-identified data is made available for systematic learning and research.
As part of the MS PATHS project, Biogen is working with Siemens Healthineers and site neuroradiologists to develop point-of-care magnetic resonance imaging–based metrics to inform clinical decisions while also accelerating research. The MS PATHS network also will be used to validate a new biomarker for MS, serum neurofilament light. This marker holds promise for stratifying disease severity to determine DMT sequencing, and to monitor the effectiveness of treatment in medical practice.
An early result of MS PATHS is the development, validation, and dissemination of CogEval®, a downloadable software designed for in-office patient self-assessment of cognitive processing speed using a test validated against the Symbol Digit Modalities Test. It is hoped that this will increase recognition of the prevalence and importance of cognitive impairment in MS.
Along with its academic collaborators, Biogen believes that high-quality, standardized, quantitative data available at the point of care can simultaneously elevate the care of individuals with MS, while significantly accelerating research progress to eventually secure better outcomes for every patient.
This advertorial was sponsored by Biogen (Cambridge, MA, USA). Writing and editorial support for the preparation of this advertorial was provided by Excel Scientific Solutions (Southport, CT, USA): funding was provided by Biogen. Richard A. Rudick, Michael R. Edwards, Bernd C. Kieseier, and Alfred Sandrock are employees of and hold stock/stock options in Biogen.