Abstract
Beam Therapeutics has announced initial safety and efficacy data from a Phase I/II trial (NCT06389877) showing clinical proof of concept for its base editing therapy candidate BEAM-302 as a potential treatment for alpha-1 antitrypsin deficiency (AATD) and for in vivo base editing.
Preliminary results from the first three single-ascending dose cohorts demonstrated that BEAM-302 was well tolerated, with single doses of BEAM-302 leading to durable dose-dependent correction of the disease-causing mutation.
BEAM-302 is a liver-targeting lipid nanoparticle formulation of a guide RNA and an mRNA encoding a base editor designed to correct the disease-causing PiZ mutation. Patients homozygous for this mutation, the PiZZ genotype, have very low circulating levels of functional alpha-1 antitrypsin (AAT) protein, all of which is the mutant form known as Z-AAT, which accumulates and causes liver toxicity.
By correcting the PiZ mutation at the DNA level, Beam said, BEAM-302 could be a one-time therapy that simultaneously reduces the amount of Z-AAT in circulation, generates therapeutic levels of corrected protein (M-AAT), and increases total and functional AAT in circulation above the 11 µM protective threshold, thereby addressing the underlying pathophysiology of both the liver and lung disease. Approximately 100,000 individuals in the United States are estimated to have the PiZZ genotype.
Beam said its data showed durable dose-dependent increases in total and functional AAT, production of corrected M-AAT, and decreases in mutant Z-AAT across the trial’s initial three dose levels. Total AAT at Day 28 ranged from 7.0 µM in the three patients dosed with 15 mg of BEAM-302, 10.1 µM in the three patients dosed with 30 mg, and 12.1 µM in the three patients dosed with 60 mg.
The percentage change from baseline in circulating mutant Z-AAT at Day 28 was 11% lower in 15 mg patients, 38% lower in 30 mg patients, and 78% lower in 60 mg patients.
“This landmark result in medicine represents the first clinical evidence of precise correction of a disease-causing mutation by rewriting the genetic code. The correction of the PiZ mutation in AATD is a potentially optimal application of base editing to precisely and potently repair mutations in DNA,” Beam CEO John Evans said. “With a simple intravenous infusion, promising safety profile, sustainable increase of total AAT above the therapeutic threshold, and rapid reduction in toxic mutant Z-AAT, we believe BEAM-302 has the potential to be a transformative therapy that could treat the entire spectrum of disease manifestations in severely deficient AATD patients.” 1
U.S. FOOD AND DRUG ADMINISTRATION APPROVES NEUROTECH’S ENCELTO™ AS FIRST TREATMENT FOR MACTEL
Neurotech Pharmaceuticals has received approval from the U.S. Food and Drug Administration (FDA) to market ENCELTO™ (revakinagene taroretcel-lwey) as a treatment for macular telangiectasia type 2 (MacTel), the first therapy authorized by the agency to treat any form of the disease.
ENCELTO is based on Neurotech’s Encapsulated Cell Therapy (ECT) platform, a cell-based gene therapy delivery system designed to provide long-term, sustained delivery of therapeutic proteins for the treatment of chronic eye diseases. ECT is designed to continually deliver therapeutic doses of ciliary neurotrophic factor (CNTF) to the retina to assist in slowing the progression of the disease.
ECT consists of a small, semi-permeable capsule containing proprietary allogeneic retinal pigment epithelium (RPE) cells genetically engineered to produce specific therapeutic proteins for targeted disease treatment. The capsule is surgically implanted.
Once in place, the capsule’s semi-permeable exterior membrane allows essential nutrients to enter while also permitting therapeutic proteins to exit into the eye where they can travel to the retina located at the back of the eye. The exterior membrane protects the encapsulated RPE cells from the host’s immune system, contributing to their survival and functionality over time.
The FDA based its approval on data from two Phase III trials that showed ENCELTO to have significantly slowed the loss of macular photoreceptors in MacTel patients over 24 months. ENCELTO is expected to be available in the United States for patients starting in June.
The recommended dose for ENCELTO is one implant per affected eye containing 200,000–440,000 allogeneic retinal pigment epithelial cells expressing recombinant human CNTF.
“This is a historic moment for the MacTel community, as ENCELTO becomes the first-ever FDA approved treatment for this vision-threatening disease,” said Thomas M. Aaberg Jr, MD, Neurotech’s Chief Medical Officer. “For those who have been affected by MacTel and for all who have supported this journey, today we look forward to a future where vision loss from MacTel may be slowed.” 2
ROCHE BEGINS RESTRUCTURING SPARK THERAPEUTICS SUBSIDIARY
Roche Group said it has begun restructuring its Spark Therapeutics subsidiary focused on gene therapy, integrating some of Spark’s activities within Roche’s Pharmaceutical Division while keeping other activities based at Spark’s Philadelphia site.
The restructuring follows a reassessment of Spark’s strategic future that began in the second half of 2024. The reassessment and onset of restructuring activities at Spark cost Roche CHF 162 million ($183 million) in 2024, the pharma giant stated in its Finance Report 2024.
Roche has offered a preliminary estimate of CHF 300 million (about $339 million) for restructuring costs and other potential obligations and commitments deemed as reasonably identifiable as of January 28, when the finance report was completed.
“There was no surplus from the estimated future revenues of the Spark Therapeutics business to support the carrying value of the goodwill, neither were there any significant future synergistic benefits to other products within the Pharmaceuticals Division,” Roche added. 3
As a result, Roche has completely written off Spark, recording a full impairment of CHF 2.122 billion ($2.397 billion) as goodwill from its $4.3 billion acquisition of Spark, completed in 2019.
Two years later, Spark unveiled plans for a $575 million gene therapy innovation center in Philadelphia within Drexel University’s campus within the University City neighborhood. The 500,000-square-foot center, which remains under construction, was envisioned to serve as a Roche global center of excellence for gene therapy manufacturing, facilitating collaborations with Drexel and other stakeholders in Greater Philadelphia’s life sciences cluster, which has focused on recent years on cell and gene therapy.
Roche cannot yet say how many employees will be affected or whether it will retain the Spark Therapeutics brand because details of the restructuring are still being finalized, according to a Roche spokesperson. 4
VERTEX ENDS LIVER DISEASE COLLABORATION WITH VERVE
Vertex Pharmaceuticals has ended its nearly 3-year-old research collaboration with Verve Therapeutics to discover and develop an in vivo gene editing program for a single undisclosed liver disease—a program Verve said it will pursue on its own.
“Vertex notified the company of its decision to terminate the research collaboration due to changing priorities within its development portfolio. Verve has now regained all rights to develop this nonclinical-stage program,” Verve stated in its announcement of fourth-quarter and full-year 2024 results. 5
Vertex and Verve launched their collaboration in July 2022, with Vertex paying Verve $60 million upfront, consisting of a $35 million equity investment and $25 million cash. In return, Verve agreed to advance the discovery, research, and specified preclinical development of the in vivo gene editing program for the undisclosed target of interest, with Vertex funding all program costs.
Vertex also agreed to oversee subsequent development, manufacturing, and commercialization of any program stemming from Verve’s research efforts. Vertex committed as well to paying Verve up to $66 million (up to $22 million per product candidate) “that achieves the applicable development criteria,” up to $340 million in payments tied to achieving development and commercial milestones, and tiered royalties on future net sales for any products resulting from the collaboration. 6
Verve recognized $8.7 million of revenue associated with the collaboration related to research services in the 9 months ending September 30, 2024, in addition to $5.9 million recognized in the nine months ended September 30, 2023, the company stated in its Form 10-Q quarterly report for the third quarter of 2024. 7
REGENERON GENE THERAPY SHOWS IMPROVED HEARING IN CHILDREN
Regeneron Pharmaceuticals has presented updated data from its Phase I/II CHORD trial (NCT05788536) assessing its gene therapy candidate DB-OTO in 12 children with profound genetic hearing loss due to variants of the otoferlin (OTOF) gene.
Regeneron said the 72-week results showed clinically meaningful improvement in nearly all children dosed with the gene therapy—namely speech and development progress in the first child dosed at 10 months of age, plus initial results in 11 children (aged 10 months to 16 years old), 3 of whom received DB-OTO in both ears.
“A year after treatment in one ear with DB-OTO, a child born profoundly deaf was able to enjoy music, engage in imaginative play and participate in bedtime reading when the cochlear implant on their other ear was removed,” said Jay T. Rubinstein, MD, PhD, a CHORD trial investigator who is Virginia Merrill Bloedel Professor of Otolaryngology and Bioengineering and Director, Bloedel Hearing Research Center at University of Washington School of Medicine. “These seemingly small interactions are life-changing for these children as well as their families and these results continue to underscore the revolutionary promise of DB-OTO as a potential treatment for otoferlin-related hearing loss.” 8
Of the 12 participants who received DB-OTO, 9 were administered an intracochlear injection in one ear and 3 received it in both ears. The surgical procedure to administer DB-OTO leverages an approach similar to cochlear implantation, thus enabling its use in young infants.
The results were presented orally at the Association for Research in Otolaryngology’s (ARO) 48th Annual MidWinter Meeting.
Also at ARO, researchers presented 48-week results from the first participant dosed in the trial, who showed improvement of hearing to near-normal levels across key speech frequencies. This included hearing thresholds that were within normal limits (0.25–2.0 kHz) in most speech-relevant frequencies and corroborated with positive auditory brainstem responses.
Particularly encouraging, according to Regeneron, were results from formal speech perception tests in which the child demonstrated improvement from week 48 to week 72 and correctly identified words—such as mommy, cookies, and airplane—that were presented at a conversational level without any visual cues. Among 11 participants with at least one post-treatment assessment, 10 showed improved hearing at various decibel hearing levels (dBHL).
In addition, among five participants with 24-week assessments, three showed improvements in average hearing thresholds, with one at nearly normal (≤40 dBHL) and two at normal (≤25 dBHL) hearing levels. One participant had not experienced a change from their baseline hearing at 24 weeks post-dosing.
ASKBIO ADVANCES TRIAL FOR LGMD2I/R9 GENE THERAPY AFTER SAFETY DATA REVIEW
AskBio has advanced its Phase I/II LION-CS101 clinical trial (NCT05230459) assessing its gene therapy candidate AB-1003 in limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9) to a second cohort, in which the first patient has been dosed, after a review of safety data by the study’s Data Safety Monitoring Board determined it was safe to proceed.
“The dosing of the first participant in cohort two marks an important milestone for the trial as enrollment continues for LION-CS101,” said Canwen Jiang, MD, PhD, Chief Development Officer and Chief Medical Officer of AskBio, a wholly owned and independently operated subsidiary of Bayer. 9
AB-1003 is an investigational recombinant adeno-associative virus–based gene therapy designed to restore FKRP enzyme activity, primarily inside muscle cells, for the treatment of LGMD2I/R9 as a one-time intravenous infusion.
LION-CS101 is a double-blind, randomized, placebo-controlled, dose-escalation clinical trial to evaluate the safety of AB-1003 gene therapy in adult participants (18–65 years) who have genetic confirmation of LGMD2I/R9. The trial includes two sequential, dose-level cohorts. Adults diagnosed with LGMD2I/R9 will be given a single intravenous infusion of AB-1003 or placebo.
Launched in 2023, the trial will include up to 14 participants at six sites throughout the United States. Participants in the first cohort remain in the study until completion. Enrollment in cohort two is ongoing.
AskBio has received the rare pediatric disease designation, orphan-drug designation, and fast track designation for AB-1003 for the potential treatment of LGMD2I/R9 from the U.S. Food and Drug Administration. There is no approved therapy for LGMD2I/R9, a rare form of LGMD caused by mutations in the FKRP gene and is associated with weakness and wasting of arm and leg muscles.
FUSE VECTORS WINS $5.2M IN PRE-SEED FINANCING
Fuse Vectors, a Copenhagen-based gene therapy startup, has raised $5.2 million in pre-seed financing toward development of its cell-free viral vector platform and resulting pipeline of novel gene therapies.
Rather than use living cells, Fuse Vectors’ technology uses controlled chemical reactions to create viral vectors, a process the company says allows for precise production as partners only need to provide a gene sequence. Fuse’s modular production process is intended to turn the sequence into an adeno-associated vector quickly, with higher quality and efficiency compared with traditional approaches.
Fuse Vectors reasons that its approach will enable patients to need only a fifth of the dose currently required from gene therapies, thus enhancing patient safety. The approach will also allow a new viral vector to be developed for testing in only 4 h, compared with 4 weeks for conventional production approaches, thus lowering treatment costs that have reached seven figures for the priciest gene therapies.
“If we want to develop new treatments faster, more safely and more cheaply, we need to solve the manufacturing problem,” said Benjamin Blaha, a co-founder of Fuse Vectors. “Traditional methods of manufacturing gene therapies are akin to asking a blacksmith to build a jet plane.” 10
Fuse Vectors has signed up about a dozen partners ranging from pharmaceutical companies to academic institutions, all of which plan to trial the startup’s technology in coming months. The co-founders hope to convert some of those partners into paying customers before the end of the year.
Fuse Vectors plans both to develop its own gene therapies and to give access to its manufacturing process to other developers.
The pre-seed financing was led by HCVC, an early-stage venture capital firm whose portfolio includes companies in Europe and North America. Fuse Vectors also won support for the financing from BioInnovation Institute, an international non-profit foundation supported by the Novo Nordisk Foundation, and the Export & Investment Fund of Denmark.
“We are thrilled to support Fuse Vectors in their mission to revolutionize gene therapy,” stated Alexis Houssou, founder and managing partner of HCVC. “With their unique cell-free viral vector solution, expert founding team and strong business model, Fuse Vectors has the potential to overcome significant challenges in the field, and we believe in their ability to bring transformative treatments to patients.” 11