Each month starting today, GEN Edge will publish Gene Therapy Briefs, a roundup of commercial developments in gene therapy and other genome editing technologies. Gene Therapy Briefs has long appeared in the journal Human Gene Therapy, published by GEN publisher Mary Ann Liebert Inc., publishers.

The 27-year-old brother of Cure Rare Disease founder and CEO Rich Horgan has died while participating in a clinical trial sponsored by the nonprofit organization to study a CRISPR gene-editing therapeutic.

Terry Horgan was the sole participant in a Phase I study (NCT05514249) designed to evaluate CRD-TMH-001, which is designed to treat a rare mutation of Duchenne muscular dystrophy (DMD). The goal of the study is to assess the safety and preliminary efficacy of CRD-TMH-001 after intravenous administration for a period of one year with long-term follow-up out to 15 years.

Terry Horgan was the first and sole patient to have been dosed with the treatment in the trial, led by Brenda Wong, MD, at the University of Massachusetts Chan Medical School.

“The loss of Terry is heartbreaking, and he will be remembered as a hero. He was a medical pioneer whose courage and unflinching determination has paved the way for increased focus and attention on funding and developing new therapies for patients with rare and ultra-rare conditions,” Cure Rare Disease said in a statement.

It had not been determined at deadline whether Horgan received the treatment and whether CRISPR, other aspects of the study or the disease itself contributed to his death.

Jack K. Allen, CFA, senior research analyst with Baird, wrote in a research note that the death of Terry Horgan was one of several unwelcome developments to have occurred in genome editing in recent weeks. Allen also cited the clinical hold placed on Verve Therapeutics’ lead therapeutic by the FDA (See brief below), and a regulatory delay announced by Beam Therapeutics (See brief below).

“Given the negative recent updates from this space, we believe that investors could become increasingly cautious about the FDA’s interest in allowing for in vivo CRISPR-based gene editing programs to progress into U.S.-based studies,” Allen wrote.

FDA places clinical hold on Verve base editing therapy  

The U.S. Food and Drug Administration (FDA) has placed on clinical hold Verve Therapeutics’ Investigational New Drug application for its lead pipeline candidate VERVE-101, the first in vivo base editing therapy to reach the clinic as a potential treatment for Heterozygous Familial Hypercholesterolemia (HeFH).

Verve, a developer of gene editing therapies for cardiovascular disease, did not detail what led to the clinical hold, only saying that it expected to receive a formal letter with questions from the FDA within 30 days of the agency’s notification to the company, which occurred November 4.

“Verve plans to provide updates pending engagement with the FDA and intends to work closely with the FDA to resolve the hold as promptly as possible in order to initiate dosing in the U.S.,” the company stated.

VERVE-101 is a single-course gene editing treatment designed to reduce the low-density lipoprotein cholesterol (LDL-C) that drives HeFH. VERVE-101 consists of an adenine base editor messenger RNA that Verve has licensed from Beam Therapeutics, as well as an optimized guide RNA targeting the PCSK9 gene packaged in an engineered lipid nanoparticle. By making a single A-to-G change in the DNA genetic sequence of PCSK9, VERVE-101 aims to inactivate that target gene.

In July, Verve dosed the first patient with VERVE-101 in the Phase Ib heart-1 trial (NCT05398029), designed to assess the safety and tolerability of VERVE-101 with additional analyses for pharmacokinetics and reductions in blood PCSK9 protein and LDL-C.

Verve has completed dosing of VERVE-101 in the first dose cohort of the dose-escalation portion of the heart-1 trial. As of November 4, no treatment-related adverse events had been reported, and all adverse events observed had been Grade 1 in nature, Verve said.

Verve plans to report initial safety and pharmacodynamic data for all dose cohorts of heart-1 in the second half of 2023.

The heart-1 trial is designed to enroll approximately 40 adults and includes a single ascending dose portion, followed by an expansion single-dose cohort where additional participants will receive the selected potentially therapeutic dose. To date, enrollment efforts have been ongoing in New Zealand and the U.K.

Novartis shuts Illinois plant, consolidating Zolgensma production in Durham, NC

Novartis said it will consolidate production of Zogensma® (onasemnogene abeparvovec-xioi) in Durham, NC, by shutting down a manufacturing plant in the Chicago suburb of Libertyville, IL, with the sole purpose of producing the gene therapy, and eliminating the facility’s 275 jobs.

“Our most recent network assessment, along with clarified demand expectations and higher yields through process improvements, show that we can meet current and anticipated global demand for Zolgensma and future gene therapies through a single site,” Novartis stated. “Gene therapies and advanced platforms are still expected to play an increasingly important role in the years and decades to come at Novartis.”

In April, the U.S. Food and Drug Administration (FDA) granted commercial licensure approval for the 170,000 square-foot facility, allowing it to manufacture, test and release commercial Zolgensma, as well as produce gene therapy product for current and future clinical trials. The approval enabled Novartis Gene Therapies to create a two-site production network by adding segregated production suites for multi-product manufacturing.

Zolgensma is a one-time gene therapy indicated for some forms of spinal muscular atrophy (SMA). The Libertyville site was approved for Zolgensma production in 2019, a year after Novartis gained ownership of the gene therapy by acquiring its original developer, AveXis, for $8.7 billion. Earlier in 2018, plans for the Durham plant were announced by AveXis, with Novartis opening the site in 2020.

AveXis moved into Libertyville in 2016 when it entered into a 10-year lease for approximately 48,529 square feet of warehouse and office space, with a portion of the warehouse space used for manufacturing.

The Libertyville site is expected to remain operational through the end of 2023, with some activities ceasing earlier while others take time to complete. Novartis said it will offer 90-day notifications to workers along with severance packages, outplacement support, and other benefits.

Novartis disclosed plans in June to eliminate about 8,000 jobs worldwide as part of a cost-cutting effort intended to save the pharma giant at least $1 billion by 2024.

Sarepta raises $1.2B toward launch of DMD gene therapy

Sarepta Therapeutics said it has raised $1.2 billion during the third quarter toward a successful launch of SRP-9001 (delandistrogene moxeparvovec), a gene therapy candidate for Duchenne Muscular Dystrophy (DMD) that the company has developed with Roche—and which is now under review by the U.S. Food and drug Administration (FDA).

The FDA is reviewing the Biologics License Application (BLA) submitted in September by Sarepta, which is seeking accelerated approval of SRP-9001 based on expression of SRP-9001 dystrophin protein, an internally shortened and functional version of dystrophin, as a surrogate endpoint reasonably likely to predict clinical benefit.

“We anticipate a PDUFA [Prescription Drug User Fee Act] date on our BLA in May of 2023 and if successful, a launch by the middle of 2023,” Sarepta CEO Doug Ingram told analysts following the company’s release of third-quarter results. Sarepta finished the third quarter with approximately $2.1 billion in cash, cash equivalents and investments as of September 30, 2022: “Therefore, we are well capitalized to support the launch of SRP-9001, if approved,” Ingram added.

Sarepta’s BLA is based on positive preclinical, biomarker, and clinical functional results generated by SRP-9001 in clinical trials. The BLA includes efficacy and safety data from three clinical studies: The Phase I/II SRP-9001-101 (NCT03375164); the Phase II SRP-9001-102 (NCT03769116), and the Phase III SRP-9001-103 (also called ENDEAVOR; NCT04626674), as well as an integrated analysis across these three clinical studies comparing functional results to a propensity-score-matched external control (EC).

Sarepta has offered support an accelerated approval by conducting a post-marketing confirmatory study, the fully-enrolled EMBARK trial (also called SRP-9001-301; NCT05096221). SRP-9001 has shown positive results at one-, two- and four-years after treatment, in addition to a consistent safety profile, according to the company.

SRP-9001 is a gene transfer therapy that is intended to deliver the treatment to muscle tissue for the targeted production of functional components of dystrophin. Sarepta is responsible for global development and manufacturing for SRP-9001 and plans to commercialize SRP-9001 in the United States upon receiving FDA approval. Roche began partnering with Sarepta in 2019, with the intent of accelerating access to SRP-9001 outside the U.S.

Beam delays IND for SCD program BEAM-102

Beam Therapeutics said it will not submit this year a previously planned Investigational New Drug (IND) application for BEAM-102, its base editing program designed to treat sickle cell disease.

BEAM-102 treats sickle cell disease by directly editing the causative sickle hemoglobin (HbS) point mutation to create the naturally occurring normal human hemoglobin variant, human hemoglobin G (HbG)-Makassar.

The company said in August it was on track for the second half of 2022—But in releasing third-quarter results, Beam said it was skipping the IND this year—in order to optimize its Makassar approach, alongside its fetal hemoglobin (HbF) upregulation approach, for future ex vivo and in vivo hematopoietic stem cell (HSC) candidates.

Those candidates will emerge, according to Beam, in its Wave 2 ex vivo HSC development strategy, designed to enable an improved, reduced-toxicity conditioning regimen for patients undergoing HSC transplantation; and Wave 3 development, focused on in vivo delivery of base editors directly to HSCs.

Beam added that it was instead prioritizing the BEACON trial (NCT05456880), designed to assess the company’s lead base editing candidate BEAM-101, being developed to treat sickle cell disease.

BEAM-101 is designed to produce base edits designed to potentially alleviate the effects of sickle cell disease by mimicking genetic variants seen in individuals who have hereditary persistence of fetal hemoglobin.

“We are laser-focused on screening and site activation efforts to enroll our first sickle cell patient by year-end,” Beam CEO John Evans stated.

FDA requests three-year results for BioMarin’s Val Rox

BioMarin Pharmaceutical said the U.S. Food and Drug Administration (FDA) has, as anticipated, requested that the company submit results of an upcoming three-year data analysis from the ongoing Phase III GENEr8-1 Study (NCT03370913) evaluating valoctocogene roxaparvovec (val rox), an adeno-associated virus (AAV)-based gene therapy for adults with severe Hemophilia A.

According to BioMarin, the FDA stated that the data are expected to provide longer-term efficacy and safety information and would thus be useful to people with Hemophilia A and healthcare providers in making better and more informed decisions when considering valoctocogene roxaparvovec as a treatment choice should it be approved.

According to BioMarin, the FDA stated that submission of these results may qualify as a Major Amendment to its Biologics License Application (BLA) for val rox. As a result, BioMarin said, the FDA may extend by three months its target action date of March 31, 2023, set under the Prescription Drug User Fee Act (PDUFA).

The agency had not communicated to BioMarin any change to the current PDUFA target action date at deadline. FDA will evaluate the additional data prior to deciding whether the PDUFA date will be extended.

“We are encouraged by the bleed control results observed in the first cohort of patients who reached three years of observation in the Phase III study as shared in January, and we look forward to reviewing the three-year results from all participants,” Hank Fuchs, MD, BioMarin’s President of Worldwide Research and Development, said in a statement. “We anticipate sharing the three-year results from all 134 participants in our Phase III study in early 2023.”

As part of its review of the BLA, the FDA has also scheduled a Pre-Licensure Inspection (PLI) of BioMarin’s gene therapy manufacturing facility, located in Novato, CA.

Danaher, Duke partner on viral vector manufacturing

Danaher has entered a strategic partnership with Duke University to form the Danaher Beacon for Gene Therapy Innovation—part of a new initiative by the science and technology conglomerate to create new technologies and applications designed to improve human health.

Through the Danaher Beacon for Gene Therapy Innovation, Danaher and Duke will partner to develop genomic medicines, precision diagnostics, next generation biomanufacturing, human systems, and data sciences by investing in product innovation that advances external R&D strategies.

“Collaboration is key to advancing science. Visionary academic leaders are a primary source of innovative solutions for tomorrow’s medicines, which is why Beacons is geared toward academic institutions,” Vanessa Almendro, Danaher’s vice president and head of Innovation, Science and Technology, said in a statement.

The Danaher Beacon for Gene Therapy Innovation will be led by Aravind Asokan, PhD, a synthetic virologist whose appointments at Duke include professor in surgery, director of gene therapy, professor of biomedical engineering, and professor of molecular genetics and microbiology.

The Beacon will specialize in developing product solutions that address yield and quality bottlenecks in the manufacturing of viral vectors.

The partnership began in late October, and is expected to run for multiple years, Danaher and Duke said.

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