Background

The next generations of MS therapies aim at enhancing remyelination, protecting neurons/axons and altering the slowly progressive course of MS from its inception. To evaluate their efficacy, it is essential to develop novel, patient-centric outcome assessments that can quantify patient’s function with high frequency in their everyday life.

Objectives

To develop a digital solution that enables patients to quantitatively self-assess their function at high frequency in free-living environment in complement to in-clinic supervised administration and derive outcome measures that are able to detect the subtle changes during MS evolution.

Methods

Konectom^TM smartphone application was designed and developed with patient-focused user experience insights to assess cognition, upper extremity function, ambulation/mobility and MS-related quality of life. To optimize accuracy and adherence of self-assessments, tutorials, vocal instructions and completion reward features were built into the app. Konectom^TM was developed under IEC 62304 / ISO 13485 standards. Konectom^TM digital outcome assessments (DOAs) will derive digital features processed from iPhone X accelerometer, gyroscope, touch, force touch, and GPS sensor information. Konectom^TM formal usability study was completed in September 2019, in Chicago and in Paris (N=14 participants). Konectom^TM is being evaluated in two Phase 2 studies in patients with relapsing MS (NCT04079088, N=300, 72 weeks of treatment period; undisclosed RMS Ph2 study).

Results

Konectom^TM DOAs include 9 active test modules (mood/physical state 5-point Likert scale, multiple sclerosis impact scale 29-item questionnaire version 2 [MSIS-29v2], cognitive processing speed test, pinching test, drawing test, grip force test, static balance test, U-turn test and 6-min walk test) and a passive continuous monitoring of mobility behaviour. In the user experience testing, Konectom^TM received a system usability scale (SUS, range 0-100, mean [SD]) score of 87.7 [8.7] which is much above the benchmark average of smartphone applications with a likelihood to recommend (LTR, range 0-10, mean [SD]) of 8.1 [2.0]. Results were consistent between French and US participants.

Conclusions

Konectom^TM provides a patient-centric modular digital platform for ecological monitoring of neurological disability in MS clinical trials and real-world use with potential to be extended to other neurological disorders affecting cognitive and motor functions

Background

Bruton’s tyrosine kinase (BTK) is a key signalling node downstream of the B‑cell receptor (BCR) in B cells and Fc receptors (FcRs) in myeloid cells. Selective BTK inhibition may be beneficial for the treatment of MS by preventing B-cell and myeloid cell activation without immune cell depletion. BIIB091 is an orally active, selective, reversible (noncovalent), small molecule inhibitor of BTK in Phase 1 clinical development for the treatment of MS.

Objectives

Assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of BIIB091 in healthy adult participants.

Methods

This was a Phase I, randomized, double-blind, placebo-controlled, single ascending dose (SAD) and a multiple ascending dose (MAD) study in healthy adult participants (NCT03943056). Admitted participants were randomly assigned to BIIB091 or placebo (6:2). Participants received study drug orally at single dose levels of 50, 150, 300, 600, or 1200 mg in the fasted state during the SAD part. Participants completing 300 mg fasted dosing continued into a second period and received single dose 300 mg with a high fat meal. A separate group of participants enrolled in the MAD part and received doses of 50, 150, or 300 mg twice daily (BID) for 13 days, and a single dose on the morning of day 14. Safety (adverse events [AEs], vital signs, electrocardiograms [ECGs] and laboratory abnormalities), tolerability, and PK measures were assessed. The trial was ongoing as of February 2020. Preliminary results summarized here are based on a blinded data cut-off as of 20 Dec 2019, and include completed SAD cohorts, and 2 of 3 planned MAD cohorts.

Results

56 participants enrolled in the study (n=40 in SAD, n=16 MAD) and contributed to this analysis as of the data cut-off date. No deaths, serious AEs, severe AEs, cardiac related AEs, or AEs leading to study discontinuation were observed. All AEs were mild in severity. No clinically relevant changes in vital signs were reported as of the data cut-off date. BIIB091 PK was approximately dose linear, with median time to maximum plasma concentration ranging from approximately 0.8 to 1.4 hours after fasted dosing in SAD cohorts, with modest accumulation after multiple dosing. Food reduced C_max variability and increased AUC.

Conclusions

BIIB091 was well tolerated at single doses up to 1200 mg. No dose limiting clinical AEs were identified in the MAD as of the data cut-off. Complete study results will be described in the poster. Preliminary safety and PK profile supports continued development of BIIB091 for the treatment of MS.

Supported by: Biogen

Background

Microglia are a unique type of brain-resident immune cell that secretes essential neurotrophic factors, promotes myelinogenesis, provides immune defense, clears debris and phagocytoses apoptotic cells. While this wide array of functional properties is suggestive of microglia heterogeneity, few microglia subsets have been described in the healthy brain thus far.

Objectives

To identify novel microglia subsets present in the steady-state brain and to characterize their unique functional roles.

Methods

Microglia isolated from mice and non-human primates were characterized by flow cytometry, electron microscopy and proteomics.

Results

In microglia isolated from mice and non-human primates and then analyzed by flow cytometry, we serendipitously observed that cellular autofluorescence (AF) presented as a bimodally-distributed signal which identified two subsets of microglia: AF-positive (AF⁺) and AF-negative (AF^–). While these subsets were present across the brain and maintained at a roughly 2:1 ratio (AF⁺:AF^–) throughout most of adulthood, microglia AF increased linearly and exclusively within the AF⁺ subset, while the AF^– subset continued to remain free of AF. Electron microscopy of FACS-isolated AF⁺ microglia revealed large and frequent lysosomal storage bodies, which contained lipids and electron dense material that increased in size and complexity withaging. Proteomic analysis of AF subsets revealed an overrepresentation of endolysosomal, autophagic, catabolic, and mTOR-related proteins in AF⁺ microglia, pointing to a unique dependence of the AF⁺ subset on lysosomal function. Accordingly, genetic disruption of lysosomal or autophagic pathways increased and decreased, respectively, the accumulation of AF in the AF⁺ subset while the AF^– subset remained unaffected. Lastly, both aging and lysosomal disruption differentially impacted AF subsets, as demonstrated by the increased cellular ROS content and apoptotic rates in AF⁺ microglia, which also correlated with diminished cell numbers of AF⁺ microglia at advanced ages.

Conclusions

AF⁺ and AF^– subsets represent discrete populations of microglia, present in healthy brain and marked by distinct subcellular content likely reflective of unique functional roles, and in particular distinct CNS clearance functions in steady-state and aging. The increased accumulation of AF material, restricted to AF⁺ microglia, uniquely impacts their physiology as indicated by elevated cellular ROS and their decreased survival in aging, factors possibly contributing to age-related cognitive decline.