ASGCT24: Early Trial Results from Freeline, Rocket, Creyon and More

Baltimore Skyline_Taylor Tieden

Pictured: Baltimore skyline with color treatment/Taylor Tieden for BioSpace

The American Society of Gene & Cell Therapy’s 27th annual meeting kicks off Tuesday in Baltimore, with a record 2,000 abstracts to be presented. ASGCT President Jeffrey Chamberlain told BioSpace this year’s conference will be “the largest yet,” with an increasing number of approvals in the space.

Stay tuned to BioSpace as we keep you updated on all of the biggest data and news from the conference.

Updated: May 10, 11:10 a.m. EST

The FDA recently approved two new gene therapies for sickle cell disease (SCD): Vertex Pharmaceuticals’ CRISPR-based Casgevy and bluebird bio’s gene therapy Lyfgenia. As the race between the two companies heats up, Tessera reported at ASGCT on Friday that its Gene Writers, delivered to the bone marrow of humanized mice via lipid nanoparticle, successfully editing the hemoglobin genes of about a quarter of the targeted cells—enough to potentially treat SCD if it works in humans. Mice given a second dose had an average rewriting efficiency of 44%. 

“The minimum threshold for sickle cell we think is about 20% normal hemoglobin,” Tessera CEO Michael Severino told Endpoints News. “We are there with a single dose and well above it with two doses. And we will continue trying to push up as high as possible.”

Current gene therapies for SCD cost millions of dollars and require extracting cells from patients and treating them outside the body. Patients must undergo chemotherapy to make space in the bone marrow for the treated cells to be reintroduced. Many observers think that in vivo gene therapy could be performed more cheaply and easily but developing these therapies poses safety and delivery challenges.

Long-term data from pivotal Phase I/II studies of Rocket Pharmaceuticals’ Kresladi show 100% survival and a “well-tolerated safety profile” in nine severe Leukocyte Adhesion Deficiency-I (LAD-I) patients treated with the lentiviral vector therapy, according to a presentation at ASGCT Friday. All patients enrolled at less than 12 months of age have surpassed 24 months without hematopoietic stem cell transplantation (HSCT), Rocket reported. The FDA has set a PDUFA date of June 30 for the treatment.

Rocket also presented updated data from the global Phase I/II pivotal studies of RP-L102, the company’s ex vivo LV gene therapy candidate for Fanconi anemia. “RP-L102 demonstrates sustained and progressively increasing genetic correction in eight of 12 patients with greater than 12 months of follow-up,” according to the press release.

Additionally, a Phase I study of two adult and two pediatric patients with severe pyruvate kinase deficiency treated with RP-L301 showed “sustained and clinically meaningful hemoglobin improvement,” with no patients requiring red blood cell transfusion following neutrophil engraftment.

Friday at ASGCT, Creyon Bio will present results from a proof-of-concept study of its novel antisense oligonucleotide (ASO) therapy for an ultra-rare and severe neurological disease in a baby. Over nine months, the young patient showed reduced seizures and restored developmental milestones, Creyon announced in a press release.

The San Diego and North Carolina–based company touted the use of its custom-designed dataset paired with artificial intelligence (AI) to engineer an investigational ASO within one year of the project’s initiation. “This proof-of-concept underscores the transformative potential of AI in OBM [oligonucleotide-based medicines] drug engineering to rapidly create new OBMs for common and rare diseases and target the genetic underpinning of disease anywhere in the body,” Chris Hart, the company’s co-founder, CEO and president, said in a statement.

Freeline Therapeutics announced at ASGCT Thursday that its AAV-based gene therapy for Gaucher disease, FLT201, reduced levels of a biomarker that the company called “one of the best predictors of clinical response” in an ongoing Phase 1/2 trial. Specifically, four patients who had stopped prior therapies as of February 19, 2024 and received a single dose of FLT201 had reduced glucosylsphinogsine (lyso-Gb1) and showed early signs of reduced bone marrow burden and fatigue, according to the announcement.

“Gaucher disease, the most common lysosomal storage disorder, is severe and progressive when not treated,” trial investigator Ozlem Goker-Alpan, founder and CEO of the Lysosomal and Rare Disorder Research and Treatment Center (LDRTC), said in the company statement. “A gene therapy that could deliver the same or better efficacy than currently available treatments, while freeing people from an ongoing treatment burden, would mark a significant advance in the treatment paradigm for Gaucher disease. I am very encouraged by the clinical data to date for FLT201.”

Freeline also announced Thursday that the FDA granted FLT201 the Regenerative Medicine Advanced Therapy designation intended to accelerate the review process for therapies addressing a serious or life-threatening disease. “FLT201 is a potentially first- and best-in-class gene therapy for Gaucher disease,” Pamela Foulds, Freeline’s chief medical officer, said in the statement.

San Diego–based Fate Therapeutics unveiled Phase I data at ASGCT for its off-the-shelf CD19-targeted CAR T-cell therapy, FT819, in patients with relapsed / refractory B-cell lymphoma. Blood samples from 23 patients showed “rapid and deep” CD19+ B cell depletion with sustained suppression of B cells in the 30 days following treatment and chemotherapy, Fate reported.

Fate also announced it has dosed the first patient with systemic lupus erythematosus (SLE) in an autoimmunity study of FT819. The candidate induced a “rapid and potent depletion” of the patient’s CD19+ B cells in an ex vivo cytotoxicity assay, the company noted. The patient, who is part of a Phase I trial investigating the candidate in moderate to severe SLE, was discharged after a three-day hospital stay and reported no adverse events.

The Bespoke Gene Therapy Consortium, a public-private collaboration involving the National Institutes of Health, FDA, industry and patient groups intended to help accelerate the delivery of AAV-based gene therapies for rare diseases, is making slow but steady progress, Courtney Silverthorn, vice president of strategic alliances and innovation at Foundation for the NIH’s  Accelerating Medicines Partnership, told a Wednesday session at ASGCT. Silverthorn noted that BGTC’s announcement last May at ASGCT 2023 identifying eight rare diseases for its clinical trial portfolio “really kicked things off” for the consortium.

“The first year-and-a-half was designed to narrow down and finalize the clinical portfolio that would serve as the proof-of-concept for the goals and aims of the consortium,” Silverthorn said.

Based on the early success of BGTC, the Foundation for the NIH is currently developing a similar cell therapy consortium that will be launched in 2025, according to Silverthorn.

Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), sat down with Kristin Van Goor, U.S. head of global regulatory policy and innovation at Takeda and chair of the ASGCT Regulatory Affairs Committee, in a fireside chat on Wednesday morning to discuss regulatory issues facing cell and gene therapies. Van Goor asked Marks about the use of the accelerated approval pathway, ongoing staffing efforts at the FDA’s new Office of Therapeutic Products (OTP) and much more. More than anything, Marks emphasized that one of the mottos CBER follows is to be “transparent about what we’re doing. And that’s what we try to do.”

Regeneron’s investigational gene therapy has shown a “dramatic” hearing improvement in two young children with “profound genetic deafness” since birth, according to the biotech’s oral presentation at ASGCT on Wednesday.

Within 24 months, one child, dosed with DB-OTO at 11 months of age, had achieved normal levels of hearing as measured by auditory brainstem response and the gold-standard pure tone audiometry. The second patient, given the cell-selective, AAV-delivered gene therapy at four years of age, showed “initial hearing improvements” at the six-week follow-up. DB-OTO was well-tolerated with no treatment-related serious adverse events, according to the presentation.

The results “showcase the revolutionary promise of DB-OTO as a potential treatment for otoferlin-related deafness,” Lawrence Lustig, study investigator and chairperson of Columbia University’s Department of Otolaryngology-Head & Neck Surgery, said in a statement.

DB-OTO is being studied in the Phase I/II CHORD trial, a first-in-human open-label study, which is still currently enrolling patients from sites in the U.S., U.K. and Spain.

Fresh off last week’s FDA clearance of a clinical trial for an ex vivo prime editing candidate in patients with a rare disease, Prime Medicine on Tuesday laid out its vision for the next generation of one-time curative gene editing therapies at the ASGCT 2024 annual meeting.

At a Tuesday workshop on the delivery and development of precision genome editing technologies, the company presented preclinical data demonstrating the broad potential of prime editing technology. Prime Medicine’s approach leverages CRISPR technology to rewrite defective genes without breaking DNA double helix strands, while enabling a wide range of edits such as substitutions, insertions and deletions.

According to Jonathan Levy, principal scientist for platform delivery innovation at Prime Medicine, prime editors have the capability to repair almost all types of genetic mutations and work in many different tissues, organs and cell types, with potential opportunities across thousands of indications.

“Off-target editing is very low. In fact, for our lead programs, we show no detectable off-targets,” Levy said in his Tuesday presentation on the development and delivery of prime editors.

The company is working on a pipeline of investigational therapeutic programs in hematology, immunology, liver, lung, ocular and neuromuscular diseases.

Speakers from Roche, Spark Therapeutics, Oxford Biomedica and other biopharma firms on Tuesday afternoon discussed ongoing efforts to improve AAV purification and yield, aiming to improve both the safety and quality of these workhorse vectors of gene therapy.

AAV manufacturing is 15 years from where monoclonal antibodies are, Cirsium Biosciences’ Daniel Gibbs told BioSpace earlier in the day. And while that lag time is not unexpected considering monoclonal antibodies entered the biopharma scene well before cell and gene therapies (CGTs), Gibbs said that improvements to AAV manufacturing must outpace advances in producing monoclonal antibodies. “[We have to] take those learnings and go exponentially faster,” he said.

Presentations at the session addressed different approaches to improving separation of full capsids from empty ones and removing impurities. These included various chromatography methods and the use of additives such as brefeldin A. And while the results presented were positive, Roche’s Thuy Linh Do noted that there are often tradeoffs to consider. There’s a “balance between yield and quality,” she said.

Neurogene’s gene therapy NGN-401 was “generally well-tolerated” by all three patients dosed in a Phase I/II trial for Rett syndrome, the New York–based biotech reported Tuesday. There were no signs or symptoms of overexpression-related toxicity reported in any of the patients, who were followed for nine, six and three months after dosing.

NGN-401 was designed to “overcome the limitations of conventional gene therapy for Rett syndrome,” with Neurogene’s EXACTTM transgene regulation technology, which the company believes provides tolerable and therapeutic levels of protein expression to the key areas of the brain and nervous system that drive disease, Neurogene founder and CEO Rachel McMinn said in a statement.

Neurogene is on track to share interim efficacy data from the trial’s first cohort in the fourth quarter of this year, McMinn said. 


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