Mehdi Goudarzi

Mahdi Goudarzi followed up on osteogenesis imperfecta, asking about the potential impact on drug adoption if the Cosmic study (younger, narrower population, superiority vs. bisphosphonates) were to miss its primary endpoint while the Orbit study achieved success.

Answer

Howard Horn, Chief Financial Officer, stated that the bisphosphonate benefit is modest (around 20%), so he was not overly concerned. He explained that even if Cosmic missed superiority, the safety and bone density data from that population would still be supportive for including the age group in the label. He did not anticipate a major impact on overall drug adoption, believing the broader picture across age groups would drive uptake.

Mehdi Goudarzi asked about the scenarios and impact on drug adoption if the Cosmic study, a superiority study in a younger, narrower population, misses its primary endpoint, even if the Orbit study is positive.

Answer

Howard Horn, Chief Financial Officer, acknowledged Cosmic's head-to-head design against bisphosphonates but expressed low concern given the modest 20% benefit of bisphosphonates. He stated that even if Cosmic missed, the safety and bone density data would likely support a label for that age group. He believed that the overall picture across age groups would drive adoption, minimizing the impact of a single study miss.

Mehdi Goudarzi from Truist Securities asked for an explanation of the non-target site factors that contribute to the different dosing regimens between Ultragenyx's GTX-102 and a competitor's drug, both of which use LNA chemistry.

Answer

Emil Kakkis, Founder, President & CEO, explained that the LNA chemistry was selected for its superior potency, which allows for a lower and more advantageous dosing range of 5-14mg. He believes this lower chemical concentration reduces off-target effects, creating a better therapeutic window and contributing to the strong results that led to its Breakthrough Therapy Designation.

Mehdi Goudarzi, on for Joon Lee, asked for details on the Angelman syndrome Aurora study, including its diverse patient population and the optimal endpoint, questioning if it would be the Bayley-4 cognition score.

Answer

CEO Emil Kakkis clarified that the main Phase 3 study is Aspire, which focuses on a specific patient group. The Aurora study is a supportive, open-label trial designed to extend labeling to other populations, including different age groups and genetic types. Its goal is to demonstrate comparable safety and efficacy to the main trial, helping to cover various segments of the Angelman population.

On behalf of Joon Lee at Truist Securities, Mehdi Goudarzi inquired about how study blindness is maintained for LONVOZIE given its potentially binary response, and whether redosing is an option for patients with breakthrough attacks.

Answer

EVP & CMO David Lebwohl assured that the trial uses standard blinding procedures where neither the patient nor the physician knows the infusion content, and a placebo effect can also occur. CEO John Leonard added that the study's primary endpoint is discrete clinical events (attacks), which are objective and not subjective, reinforcing the study's integrity.

Mehdi Goudarzi, on for Joon Lee, asked for the rationale behind Voyager's confidence that the neurotoxicity observed in the SOD1 ALS program was payload-related and not caused by the TRACER capsid, which is also being used for the tau silencing program.

Answer

CEO Dr. Al Sandrock provided two key reasons: first, the toxicity occurred with a three-month delay, consistent with payload expression rather than an immediate capsid effect. Second, the same capsid was used with four other payloads in non-human primates at similar doses without any of the adverse events, strongly indicating the issue was specific to the SOD1 payload.

Mehdi Goudarzi of Truist asked for a big-picture view on the future of CNS-targeted AAVs over the next 12-18 months and how Voyager intends to maintain its leadership position amid industry advances.

Answer

CEO Dr. Al Sandrock acknowledged the competitive field but stressed that future leadership will require a portfolio of capsids tailored to specific diseases. He outlined Voyager's focus on innovating beyond basic brain delivery to include multi-tissue targeting, specific cell-type tropism, enhanced detargeting of liver and DRG, and improved manufacturability and immunogenicity profiles, all of which are part of Voyager's capsid selection process.

Mehdi Goudarzi, on behalf of Joon Lee, inquired about Voyager's plans to leverage its knowledge of the ALPL receptor for delivering other therapeutic modalities, such as antisense oligonucleotides and LNPs, to the central nervous system.

Answer

Executive Alfred Sandrock and Executive Todd Carter explained that Voyager is actively creating ligands against the ALPL receptor to conjugate with various macromolecules, including protein therapeutics and oligonucleotides, to test their ability to cross the blood-brain barrier via transcytosis. They confirmed that some ligands have already been identified and they look forward to sharing data in the future.

Mehdi Goudarzi, on for Joon Lee, requested more color on the plans for the early pipeline asset ARGX-109, an anti-IL-6 antibody, given its long history and recent return to the company.

Answer

CEO Tim Van Hauwermeiren characterized ARGX-109 as a best-in-class IL-6 blocker with high potency and a long half-life. He stated that argenx has a 'unique and novel angle' on IL-6 biology for new autoimmune indications, which are not yet disclosed. Phase I data is expected in the second half of the year.

Mehdi Goudarzi, on for Joon Lee, asked for more detail on the in vivo editing approach versus the previously discussed LSR technology and inquired about the number of diseases amenable to the indel upregulation method.

Answer

Chief Scientific Officer Linda Burkly clarified that LSR is a future technology for large gene replacement, while the current focus is on functional upregulation via indels. Both she and CEO Gilmore O'Neill explained that because many genetic diseases involve loss-of-function mutations and the genome has vast non-coding regulatory regions, there are 'many, many opportunities' for this approach.