Theme 09 - Clinical Trials and Trial Design

Background: The safety and efficacy of sodium phenylbutyrate (PB) and taurursodiol (TURSO, also known as ursodoxicol- taurine) coformulation in ALS were evaluated in a phase 2 US multicenter trial (CENTAUR) encompassing both randomized (NCT03127514) and open-label extension (OLE; NCT03488524) phases. While overall treatment-emergent adverse event (TEAE) incidence was similar in the PB&TURSO versus placebo groups in the randomized phase and between those continuing versus switching to PB&TURSO in the OLE phase, treatment-emergent cardiac adverse events (TECAEs) and centrally read electrocardiographic abnormalities were reported more frequently among those receiving PB&TURSO in both phases. Objective: Describe the findings of independent expert reviews of reported TECAEs and electrocardiographic abnor- malities and of recorded electrocardiographic parameters in CENTAUR. Methods: Occurrence of TEAEs was assessed at each visit during both phases. Standard 12-lead electrocardiograms were performed at baseline in both phases and at a total of 2 visits in the randomized phase and up to 10 visits in the OLE phase, blinded and centrally read. Unblinded independent expert reviews assessed reported TECAEs and electrocar- diographic abnormalities for diagnostic accuracy and treatment emergence based on absence at baseline or lack Background: CD40L/CD40 costimulatory pathway mediates both humoral and adaptive immune responses in the pathophysiology of autoimmunity and transplant rejection. Studies have implicated CD40L (CD154) signaling and adaptive and innate immune cell activation in induction of neuroinflammation in neurodegenerative diseases. Methods: In this multicenter dose escalating phase 2 study 54 participants with a definite or probable diagnosis of ALS by El Escorial Criteria-revised received an anti CD154 antibody, tegoprubart, via intravenous infusion every two weeks for twelve weeks. Enrollment consisted of 9 participants in cohorts 1 and 2 (1 and 2mg/kg) and 18 participants in cohorts 3 and 4 (4 and 8mg/kg). The primary endpoint of the study was safety and tolerability. Secondary endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody responses. Exploratory endpoints evaluated changes in disease progression utilizing the ALS Functional Rating Scale-Revised (ALSFRS-R), assessment of CD154 target engagement specifically looking at change in circulating CD40L and CXCL13, and changes in the levels of pro-inflam-matory biomarkers in circulation, by looking at change from baseline in circulating levels of a panel of inflammatory che-mokines and cytokines. Results: Seventy participants were screened, and fifty-four were enrolled in the study. Forty-nine completed the study (90.7%) receiving all six infusions of tegoprubart and com- pleting their final follow up visit. The most common TEAEs overall ( 10%) were fatigue (25.9%), falls (22.2%), headaches and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. Anti-drug antibody (ADA) titers were low and circulating levels of tego- prubart were as predicted for all cohorts. Tegopurbart demonstrated dose dependent target engagement as evidenced by a reduction in circulating levels of CD40L and CXCL13. While the study was not designed to detect clinical efficacy, target engagement was associated with a trend suggesting slowing in loss of function by change from baseline in ALSFRS-R. Tegoprubart also reduced multiple pro-inflamma- tory biomarkers in circulation in a dose dependent fashion, including TNF a , En-raged, IL-16, IL-18, CXCL9 and CXCL10 among others. The target engagement and inflammatory bio- markers showed increasing levels of reduction from the 1mg/ kg dose cohort to the 2mg/kg dose cohort and then pla- teaued at the 4mg/kg cohort. The changes were seen after the first dose and persisted throughout the treatment period. Conclusions: Tegoprubart was safe and well tolerated in adults with ALS demonstrating dose dependent functional activity to engage target and reduce pro-inflammatory che-mokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS. Background: Platform trial approaches allow for simultan-eous evaluation of multiple investigational products by lever- aging a shared clinical trial infrastructure to reduce time and resources necessary to launch new investigations. Initiation of a platform trial requires tremendous clinical trial expertise, resources, and infrastructure to be successful. Objective: To share our operational experience from launch- ing the first Background: WVE-004 is an investigational stereopure antisense oligonucleotide that was designed to selectively lower transcripts derived from a hexanucleotide-repeat expansion mutation (G4C2) within the C9orf72 gene, which is the most common genetic cause of ALS and FTD. The repeat expan- sion reduces C9orf72 gene expression; transcription of the repeat leads to aberrant RNA foci and ultimately dipeptide repeat (DPR) proteins such as poly glycine-proline (poly(GP)). In preclinical mouse studies, WVE-004 produced substantial and durable reductions in repeat-containing C9orf72 tran- scripts and pathogenic poly(GP) without reducing C9orf72 protein expression (1). Results: FOCUS-C9 (NCT04931862) is a global, multicenter, placebo-controlled Phase 1b/2a trial with an adaptive design allowing for rapid assessment of the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of single-and multiple-ascending intrathecal doses of WVE-004 in people with C9-ALS or C9-FTD. Initial results (up to day 85) showed significant reductions in CSF poly(GP) with single doses (10mg, n ¼ 2; 30mg, n ¼ 4; 60mg, n ¼ 3) with poly(GP) concentrations not apparently reaching steady-state maximal reduction by day 85. Adverse events (AEs) were balanced across treatment groups, including placebo ( n ¼ 3), and were mostly mild to moderate in intensity. Four patients, including one on placebo, experienced severe and/or serious AEs; one was reported to be related to study drug. These data suggest that single ascending doses of WVE-004 were generally safe, and reductions in CSF poly(GP) provide confirmation of tar- get engagement with a single dose. Based on these initial data, FOCUS-C9 was adapted to evaluate additional and expanded low, single-dose cohorts. Discussion: Treatment is ongoing, with additional data from single and multiple dose cohorts expected in 2022. New data emerging from the study will also be presented. FOCUS-C9 is the first clinical trial to address both ALS and FTD caused by the C9orf72 genetic variant in the same study. Further, FOCUS-C9 ’ s adaptive design has enabled data-driven modifi-cations to the study to support more rapid optimization of dose level and frequency for WVE-004. Introduction objective: Improved functional outcome measures in amyotrophic lateral sclerosis would aid amyo- trophic lateral sclerosis trial design and help hasten drug discovery. We evaluate the longitudinal performance of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) compared to the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised for Self-Entry (ALSFRS-RSE) as patient reported outcomes of functional status in people with ALS. Methods: People with ALS completed the ROADS and the ALSFRS-RSE questionnaires at baseline, 3-, 6-, and 12-months using the web-based platform, Research Electronic Data Capture as a part of a prospective, longitudinal, remote, online survey study of fatigue in ALS from 9/2020 to 12/ 2021. The scales were compared cross-sectionally (at baseline) and longitudinally. Correlation coefficients, coefficient of variation, and descriptive statistics were assessed. Vital status was recorded at follow-up contact at approximately 12-months. Results: 182 adults with ALS consented to the study. This volunteer sample was comprised of predominantly White, non-Hispanic, non-smoking participants. Consented partici- pant survey completion was approximately 90% at baseline and greater than 40% at 12-months.The ALSFRS-RSE and the ROADS had high, significant agreement at 3- and 6 months by Cohen ’ s kappa > 71% ( p < 0.001); the number of functional increases or plateaus on each scale were not signifi- cantly different; and the coefficient of variation of functional decline was similar at the 6-month mark, though higher for the ROADS at 3-months and lower at 12-months. Background: Amyotrophic lateral sclerosis (ALS) therapeutic development has relied largely on staff-administered func- tional rating scales to determine treatment efficacy. Mobile applications (apps) and wearable devices offer multiple opportunities for biometric data collection. Hypothesis: Wearable and smartphone devices can collect patient-reported outcomes and passively collect sensor data that will provide quantitative measurement of ALS disease progression. Methods: Participants were remotely consented, enrolled and followed for 6 months. ALSFRS-R was administered at baseline, 3 and 6 months via phone call. The study app (Beiwe) was installed on the participants ’ personal smart-phones at baseline and delivered ALSFRS-R for Self-Entry (ALSFRS-RSE) and the Rasch Overall ALS Disability Scale (ROADS) surveys every 2 – 4 weeks. Participants also continu-ously wore either a wrist-worn activity monitor (ActiGraph Insight Watch) or an ankle-worn activity monitor (Modus StepWatch). Vendor-provided daily measures (VDMs) were obtained from each device. Investigator-derived daily meas- ures (IDMs) were calculated from ActiGraph ’ s minute-level activity counts data. Participants contributing at least two ALSFRS-RSE and ROADS surveys were included in this analysis. Days with at least 8hours of estimated activity monitor wear time were defined