Hum Gene Therapy Briefs March 2025

VOYAGER PUSHES BACK IND FILING FOR ALS CANDIDATE, CITING PAYLOAD ISSUE

Voyager Therapeutics has pushed back from mid-2025 its timeline for advancing into clinical trials VY9323, the company’s superoxide dismutase type 1 (SOD1) silencing gene therapy for amyotrophic lateral sclerosis (ALS).

Without specifying when it now anticipated filing an investigational new drug (IND) application for VY9323, Voyager said it decided to assess alternate payloads related to the program after receiving 3-month non-human primate (NHP) data suggesting that an alternate payload would be needed to achieve the desired product profile.

The delay is expected to extend to mid-2027 Voyager’s cash runway, or amount of time that it can continue operating before needing to raise additional funding. That runway does not include any potential milestone payments from existing partnerships.

Voyager added that it plans no changes to the novel capsid component of VY9323. That capsid is the same as the one used by another of the company’s gene therapy programs, VY1706 (tau silencing), which achieved desired activity levels and was well-tolerated in 3-month NHP studies, according to Voyager.

The company expects to file an IND application for VY1706 in 2026. Later this year, Voyager plans to file IND applications for two of its gene therapy candidates—one designed to treat Friedreich’s Ataxia by targeting the Friedreich’s Ataxia gene (FXN), and the other designed to treat Parkinson’s and other diseases by targeting the glucosylceramidase beta 1 (GBA1) gene.

The FXN and GBA1 programs are being developed through collaborations in which Neurocrine Biosciences has agreed to pay Voyager up to $1.3 billion and up to $1.5 billion, respectively. For the FXN program, Voyager could exercise an option for 60/40 cost- and profit-sharing (Neurocrine/Voyager) in the United States, while for the GBA1 program, Voyager maintains an option to elect 50/50 cost- and profit-sharing in the United States following topline data from the first Parkinson’s disease clinical trial.

ENCODED CUTS 29% OF WORKFORCE; FRACTYL AXES 17%, PIVOTS TO PLATFORM

Two gene therapy developers announced workforce reductions in recent weeks. Encoded Therapeutics has implemented a 29% reduction in its headcount, a move that has extended the company’s cash runway through the third quarter of 2026.

Privately held Encoded said that its job cuts primarily impacted technology and early-stage research and development positions but did not say how many jobs were eliminated.

The extended runway, Encoded added, will support its goal of achieving key clinical milestones, including:

Preliminary safety and efficacy for ETX101, an adeno-associated virus type 9 (AAV9)-based gene regulation therapy designed to upregulate expression of the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene in inhibitory neurons and is the first potential one-time therapy to address the underlying genetic cause of Dravet syndrome.

Fractyl Health said it will prioritize advancing its novel Rejuva gene therapy platform into first-in-human studies as part of a companywide strategic reprioritization that will include eliminating 17% of its workforce. Rejuva is a preclinical platform that focuses on developing next-generation AAV-based, locally delivered gene therapies for the treatment of obesity and type 2 diabetes (T2D).

The first clinical candidate developed through Rejuva, RJVA-001, has completed key preclinical in vivo studies and is on track to initiate first-in-human studies in the first half of this year, Fractyl said.

In addition, Fractyl said it will also prioritize clinical development of its Revita outpatient endoscopic procedure designed to durably modify duodenal dysfunction via hydrothermal ablation, with the goal of facilitating weight maintenance following withdrawal from glucagon-like peptide 1 (GLP-1) drugs, citing what it termed significant patient and physician demand in its ongoing REMAIN-1 pivotal study (NCT06484114). The company anticipates releasing a midpoint data analysis in the second quarter and achieving full pivotal study enrollment this summer.

The workforce elimination will amount to 22 employees, according to a regulatory filing that stated: “The Company anticipates the Strategic Reprioritization will be substantially implemented by the second quarter of 2025.” ³

Fractyl estimated that it will incur cash charges of approximately $1.8 million related to severance, employee benefits, and other related personnel reduction costs.

BOEHRINGER INGELHEIM, EXPRESSIONEDITS PARTNER ON ENHANCED GENE THERAPIES

Boehringer Ingelheim has launched a partnership with ExpressionEdits to develop enhanced gene therapies for two undisclosed targets using ExpressionEdits’ Genetic Syntax Engine artificial intelligence (AI)-powered platform, through a collaboration and licensing agreement whose value has not been disclosed.

ExpressionEdits’ Genetic Syntax Engine is designed to use optimized introns to enhance gene expression without altering the underlying genetic sequence. Specifically, it creates in-cDNA with optimal sites and introns that increase protein production without altering the underlying genetic sequence.

“Nature doesn’t have perfect introns. It doesn’t care to splice carefully or to express things in a single form. If I trained a model to predict a good intron [using] data that is already in nature, we wouldn’t get good rules. That meant that “we had to make the data ourselves,” explained Kärt Tomberg, PhD, co-founder and CEO of ExpressionEdits. ⁴

By restoring introns, a process the company calls intronization, ExpressionEdits aims to enhance therapeutic gene expression and eliminate the need for high viral loads or repeated dosing due to insufficient expression of the therapeutic protein, often a limiting factor in the effectiveness of gene therapies.

“By combining our technology platform with Boehringer Ingelheim’s expertise in therapeutic development we aim to accelerate the development of high-impact gene therapies. ExpressionEdits is essentially reintroducing punctuation into the genome’s language, creating clearer and more accurate instructions for protein production,” said Paul Bolno, MD, MBA, Chair of the Board, ExpressionEdits. ⁵

Boehringer Ingelheim has agreed to pay ExpressionEdits undisclosed payments during the collaboration, plus potential additional payments tied to achieving preclinical, clinical, and commercial milestones.

RHYGAZE RAISES $86M IN SERIES A FINANCING

RhyGaze today announced that it has secured a Series A financing of $86 million, with the proceeds intended to enable further development of its lead clinical candidate, a novel gene therapy for optogenetic vision restoration in diseases causing blindness.

Activities to be supported by the financing include formal pharmacology and toxicology testing; a non-interventional, observational study to assess potential clinical endpoints in patient groups eligible for the therapy; and a first-in-human clinical trial to test the safety, tolerability, and potential efficacy of the lead candidate.

Based in Basel, Switzerland, and Philadelphia, RhyGaze is a developer of gene therapies for retinal diseases causing blindness. RhyGaze was founded on intellectual property exclusively licensed to the company by the Institute of Molecular and Clinical Ophthalmology Basel (IOB). IOB is led by Director Botond Roska, MD, PhD, a scientific co-founder of RhyGaze.

The name RhyGaze derives from the Basel-German word for the Rhein (Rhy), on the banks of which the IOB is located. Roska said RhyGaze’s lead program exemplified a key goal of IOB: combining its deep understanding of retinal biology and vision with breakthrough technologies to develop novel therapies for vision loss.

RhyGaze’s financing round was led by GV (Google Ventures), alongside Arch Venture Partners, F-Prime Capital, and founding investors BioGeneration Ventures and Novartis Venture Fund, which contributed $11 million to an earlier seed round.

SAREPTA RELEASES TOPLINE RESULTS FROM PHASE III TRIAL OF ELEVIDYS®

Sarepta Therapeutics has released positive topline results from Part 2 of its Phase III EMBARK trial (SRP-9001-301; NCT05096221) showing sustained benefits and disease stabilization in ambulatory patients with Duchenne muscular dystrophy (DMD) following treatment with the company’s ELEVIDYS® (delandistrogene moxeparvovec-rokl), the only FDA-approved gene therapy indicated to treat the disease.

Crossover-treated patients who received a placebo in Part 1, then crossed over at 52 weeks, and were treated with ELEVIDYS in Part 2 improved 2.34 points from baseline compared with matched external controls on the North Star Ambulatory Assessment (NSAA) 52 weeks after treatment, during which time the study remained blinded.

In addition to NSAA, crossover-treated patients showed clinically meaningful and statistically significant functional benefit in Time to Rise (TTR; −2.7 s improvement) and 10-meter walk/run function tests (10MWR; −1.07 s improvement) compared with a pre-specified, propensity-weighted external control group (EC), despite having average ages that were 1 year older than those treated in Part 1–7.18 years versus 5.98 years.

Biopsies taken 64 weeks after dosing in patients treated in Part 1 showed consistent and sustained expression of ELEVIDYS micro-dystrophin compared with week-12 biopsies, as measured by western blot—results that, according to Sarepta, provide biological support for observed functional outcomes.

At 2 years, Sarepta added, patients treated in Part 1 of EMBARK showed clinically meaningful and statistically significant functional benefit in NSAA (+2.88 points), TTR (−2.06 s improvement), and 10MWR (−1.36 s improvement) compared with EC.

Least square means (LSM) differences seen between the patients treated in Part 1 and the EC group increased from year 1 to year 2 for all three functional outcomes. Sarepta said those results indicated that the trajectory of disease in patients treated with ELEVIDYS was continuing to diverge from the natural history of DMD.

Skeletal muscle MRI conducted on patients treated in Part 1 found minimal progression in underlying muscle pathology and remains highly consistent with the functional benefits shown.

RENTSCHLER WITHDRAWS FROM CELL AND GENE THERAPY ARENA

Rentschler Biopharma says it is withdrawing from the field of cell and gene therapy, ceasing operations at its Stevenage, U.K. site, and increasing its focus on biologics—namely cell culture-based therapeutic proteins.

Executives of the contract development and manufacturing organization (CDMO) said the decision represented a realignment of its global business operations as part of a long-term strategic shift based on evolving market conditions and client needs, prioritizing sustainable growth, and driving innovation.

“We continuously evaluate new approaches to meet the needs of our clients and their patients. The cell and gene therapy market has experienced slower-than-expected growth with demand across the industry not meeting our expectations. Following a comprehensive strategic review, we are focusing our efforts on areas where we see the greatest demand and potential to create value sustainably. Biologics remain central to our operations while we continue to evaluate other potential modalities,” Rentschler CEO Benedikt von Braunmühl said. ⁸

In recent years, Rentschler has made significant investments to further strengthen its global capabilities and support long-term growth, von Braunmühl said. Last year, Rentschler announced its largest single investment to date at its headquarters in Laupheim, Germany, to enhance production efficiency and upgrade site capabilities.

Earlier in 2024, Rentschler’s new production line in Milford, MA, became fully operational with four new 2,000 L single-use bioreactors, which further advanced the company’s ability to meet growing demand for biopharmaceuticals, and marked the largest investment in its more than 150-year history, von Braunmühl added.

GENETHON, EUKARŸS PARTNER ON AAV GENE THERAPY PRODUCTION

Genethon, a non-profit focused on gene therapies for rare diseases, and Eukarÿs, a developer of technology for boosting biomanufacturing yields, have agreed to adapt Eukarÿs’ C3P3 technology to work with adeno-associated viruses (AAVs), through a strategic partnership agreement that they said could help reduce overall production costs associated with gene therapies.

Eukarÿs’ C3P3 is a commercially available engineered enzyme that boosts the production capacity of mammalian cells by enhancing their mRNA synthesis capabilities. The company estimates that C3P3 enables a 5- to 7-fold increase in production yields in all mammalian cell types. These cells can be used to generate a wide range of biopharmaceuticals including monoclonal antibodies, recombinant proteins, and virus-like particles.

C3P3 currently works with almost any cell type with no adaptations required except for lentiviruses and AAVs.

Genethon is contributing its expertise in AAV design and production. Technologies developed at Genethon were used to develop the first gene therapy for treating spinal muscular atrophy. At present, 13 products from Genethon’s research and development initiatives or collaborations are in clinical trials for diseases of the liver, blood, immune system, muscles, and eyes. Genethon estimates that another seven products could soon enter clinical trials within the next 5 years.