Ananda Ghosh

Ananda Ghosh questioned Amylyx's strategy for educating primary care physicians (PCPs) on PBH diagnosis and asked how Key Opinion Leaders (KOLs) are defining clinical significance for a potential therapy.

Answer

Co-CEO & Co-Founder Josh Cohen clarified that the launch will be endocrinologist-focused, as they are the primary treaters. He stated that KOLs consider the prevention of even a single severe hypoglycemic event to be clinically meaningful, given the potentially life-altering consequences of such events.

Ananda Ghosh from H.C. Wainwright & Co. asked about the Phase I LUMINA trial for AMX0114 in ALS. Given the preclinical data and the importance of neurofilament light chain (NFL) as a biomarker, she questioned if the trial's inclusion criteria required patients to have elevated NFL levels at baseline.

Answer

Co-CEO Justin Klee confirmed this was a key design consideration but explained that the trial does not have an inclusion criterion for high NFL levels. He reasoned that NFL levels in ALS patients are typically already very high, and for a first-in-human study, the company wanted to avoid over-subsetting the population to ensure they could observe signals across a broader patient group. They will, however, analyze outcomes based on baseline NFL levels.

Ananda Ghosh of H.C. Wainwright & Co. asked for details on the pharmacokinetic (PK) profile of the 90mg dose of avexitide, specifically regarding how quickly it counters hypoglycemic events post-dosing.

Answer

Dr. Camille Bedrosian, Chief Medical Officer, explained that avexitide reaches therapeutic range approximately one hour post-dosing and provides coverage for about 24 hours. She noted that PK/PD modeling and early single-dose studies showed a quick onset of effect, which is consistent with its mechanism of competing with endogenous GLP-1 at the receptor level.

Ananda Ghosh of H.C. Wainwright & Co. asked about the potential for pleiotropic effects with the INHBE target and how Wave's AATD program differentiates from siRNA approaches like fasisiran.

Answer

Chief Scientific Officer Dr. Erik Ingelsson explained that the INHBE ligand-receptor pair is highly specific, so they expect only positive downstream metabolic effects, not primary pleiotropy. President and CEO Dr. Paul Bolno added that for AATD, an siRNA approach is suboptimal as it simply silences the protein, creating a need for IV replacement therapy to protect the lungs. He contrasted this with Wave's RNA editing approach, which aims to restore functional protein, thereby addressing both the liver (aggregate) and lung (protective) aspects of the disease with a single therapeutic.

Ananda Ghosh asked a macro-level question about how Acumen is thinking about positioning sabirnetug in the market by the time ALTITUDE-AD data is released, considering future developments like approved plasma biomarkers and new data from competitors.

Answer

Dr. Eric Siemers, Chief Medical Officer, responded that Acumen envisions sabirnetug's data readout in late 2026 will be well-timed to position it as a highly differentiated, next-generation treatment. He noted the landscape will be more mature, with better diagnostic tools and growing adoption of anti-A-beta therapies, creating an opportunity for a product with a potentially improved risk-benefit profile.

Inquired about the FDA's potential openness to surrogate biomarkers for the progranulin program, the temporal relationship between biomarkers and clinical benefit, plans for a TAU-based subgroup analysis for TREM2, and the titration schedule for AL002.

Answer

The company is encouraged by FDA's flexibility but aims for full approval, with biomarkers as a backup. They will analyze the temporal dynamics of biomarkers versus clinical outcomes in the progranulin program. A pre-specified TAU-based subgroup analysis is planned for TREM2. The AL002 titration was every 4 weeks in the main study and is being slowed in the LTE to explore ARIA mitigation.

Ananda Ghosh of H.C. Wainwright & Co. asked about the FDA's potential openness to surrogate biomarkers for the progranulin program, plans for subgroup analyses based on TAU levels in the TREM2 trial, and the speed of the dose titration schedule for AL002.

Answer

Dr. Gary Romano, CMO, expressed encouragement about regulatory flexibility but reiterated the goal is full approval for latozinemab. He confirmed that a pre-specified TAU-based subgroup analysis is planned for AL002. He also detailed that the main study's titration was every four weeks, and a slower schedule is being explored in the long-term extension to potentially mitigate ARIA.

Asked for the company's perspective on what recent SRP-5051 data means for their EDO51 program, and for their take on the regulatory view of a primary endpoint for DM1 and the correlation between splicing correction and the vHoT assay.

Answer

Regarding SRP-5051, the executive stated that a cross-trial comparison showed their EDO51 achieved sixfold higher exon skipping with better tolerability, supporting their confidence in producing >9% dystrophin. On the DM1 endpoint, they noted that conversations with regulators are ongoing but believe splicing correction is a key mechanism that correlates with myotonia correction in animal models. The FREEDOM-DM1 study will help assess the impact on intermediate endpoints like vHoT, which, along with other functional measures, will inform the design of future pivotal trials.