First Prime Editing Clinical Trial Expected in 2024

Abstract

David R. Liu, PhD, the genome editing pioneer whose Broad Institute laboratory developed both base editing and prime editing technologies over the past decade, told an audience of investors that prime editing is on track to join base editing in human clinical trials in less than a year.

“Likely the first clinical trial will be in 2024,” Liu said, speaking through video at the Chardan 7th Annual Genetic Medicines Conference, held in New York City. “Prime editors, we anticipate, will be in the clinic next year.”¹

Liu is a cofounder of Prime Medicine, the publicly traded company formed to commercialize prime editing by developing treatments based on applying the technology's “search and replace” approach to genome editing.

In releasing second-quarter results in August, Prime Medicine conveyed the possibility of a first trial for its gene editing technology next year by publicly including among its anticipated upcoming milestone: “First Investigational New Drug (IND) filing expected as early as 2024 and additional IND filings anticipated in 2025,” Prime Medicine said in a company presentation to investors last month.²

By contrast, base editing technology, first disclosed in 2016 by Liu's laboratory, is under investigation in six ongoing clinical trials.

Prime Medicine has not yet released which of its 18 pipeline programs will be selected as its first clinical-phase candidate.

According to Prime Medicine's presentation, only one of its programs has reached the phase of IND-enabling studies—a blood-targeting candidate for chronic granulomatous disease, designed to be administered ex vivo.

Three other programs are in lead optimization phases—a Wilson's disease candidate targeting liver tissue and using lipid nanoparticle delivery, a retinitis pigmentosa/rhodopsin candidate targeting eye tissue and using adeno-associated virus (AAV) vector delivery, and a neuromuscular tissue targeting candidate for Friedreich's ataxia also delivered through AAV.

The rest of Prime Medicine's pipeline programs are in preclinical discovery phases.

KYOWA KIRIN TO ACQUIRE ORCHARD THERAPEUTICS FOR UP TO $477.6M

Kyowa Kirin has agreed to acquire gene therapy developer Orchard Therapeutics for up to $477.6 million, in a deal designed to expand the buyer's gene and cell therapy portfolio with a rare disease treatment under FDA review after approvals in Europe and the United Kingdom.

That treatment, Libmeldy^® (atidarsagene autotemcel), is indicated for patients with early-onset metachromatic leukodystrophy (MLD). Libmeldy is approved by the European Commission and the U.K. Medicines and Healthcare products Regulatory Agency for the treatment of late infantile and early juvenile MLD patients.

Libmeldy is now under FDA Priority Review, with a target action date under the Prescription Drug User Fee Act of March 18, 2024. Libmeldy uses a patient's own genetically modified hematopoietic stem cells (HSCs) to potentially correct the underlying cause of a genetic disease using a single administration.

Using the same HSC gene therapy technology platform, Orchard is advancing two clinical-stage programs for forms of mucopolysaccharidosis (MPS): OTL-203, a treatment for mucopolysaccharidosis type I Hurler's syndrome (MPS-IH); and OTL-201 for mucopolysaccharidosis type IIIA (MPS-IIIA), also called Sanfilippo syndrome.

Orchard said its acquisition by Kyowa Kirin will enable the buyer to maximize the value of Libmeldy and accelerate the development of its next-in-line clinical programs for forms of MPS, plus other early research programs that include a severe genetic form of Crohn's disease and frontotemporal dementia.

“This is an exciting opportunity designed to accelerate the realization of our shared vision of ending the devastation caused by severe genetic diseases and deliver life-changing value in medical care,” Bobby Gaspar, MD, PhD, Orchard's cofounder and CEO, said in a statement.³

Kyowa Kirin agreed to pay at least $16 per American Depositary Share (ADS) cash for Orchard—∼$387.4 million—plus an additional contingent value right (CVR) of $1 per ADS tied to the FDA approving Libmeldy. Should that occur and the CVRs are exercised, the value of the deal at $17 per American Depositary Receipt would rise to ∼$477.6 million.

The boards of Kyowa Kirin and Orchard have approved the deal, which is expected to close in the first quarter of 2024 subject to Orchard shareholder approval, receipt of applicable regulatory approvals, and other customary closing conditions. Upon completion, Orchard Therapeutics will become a wholly owned subsidiary of Kyowa Kirin.

UNIQURE ELIMINATES 114 JOBS, SHRINKS RESEARCH, CLOSES LABORATORY

uniQure is eliminating 20% of its total workforce—114 jobs—halting more than half of its research and technology projects, closing a research laboratory, and consolidating some operations under a restructuring designed to save the gene therapy developer ∼$180 million over the next 3 years.

Among jobs being eliminated is that of Ricardo Dolmetsch, PhD, uniQure's Chief Scientific Officer. Dolmetsch is departing the company after the reduction in research activity, whereas Chief Business Officer Rich Porter, PhD, will add responsibilities for research as well as nonclinical and vector development while continuing to oversee business development and product planning as chief business and scientific officer.

uniQure said it also plans to end more than half its research and development (R&D) projects, including AMT-210 for the treatment of Parkinson's disease and multiple undisclosed programs. The company said it will focus its surviving R&D efforts on projects believed to have optimal risk, value, and speed attributes, including AMT-161 for c9orf72 amyotrophic lateral sclerosis (ALS), AMT-240 for autosomal dominant Alzheimer's disease, and next-generation AAV capsid development.

Also surviving, uniQure added, are four clinical-stage programs on track for near-term proof-of-concept data readouts:

AMT-130 for the treatment of Huntington's disease.

AMT-260 for the treatment of refractory mesial temporal lobe epilepsy.

AMT-162 for the treatment of SOD1-ALS.

AMT-191 for the treatment of Fabry disease.

Under its restructuring, uniQure plans to close a research laboratory in Lexington, MA, and sublease the space. The company will also consolidate all good manufacturing practice manufacturing into its Lexington, MA, manufacturing facility, and consolidate process and analytical development into its facility in Amsterdam, The Netherlands.

uniQure said the restructuring will cost it ∼$2.3 million in one-time costs, primarily incurred in the fourth quarter.

Not affected is uniQure's commercial manufacturing for CSL Behring of HEMGENIX^® (etranacogene dezaparvovec-drlb), the first gene therapy for hemophilia B to win approval by the U.S. Food and Drug Administration.

“We are taking important actions today to cut operating expenses while ensuring that we have the necessary resources to advance our prioritized clinical-stage programs as rapidly as possible to proof-of-concept,” uniQure CEO Matt Kapusta said.⁴

REGENERON, INTELLIA EXPAND IN VIVO CRISPR COLLABORATION

Regeneron Pharmaceuticals and Intellia Therapeutics have expanded their 3-year-old research collaboration by agreeing to develop additional in vivo CRISPR-based gene editing therapies focused on neurological and muscular diseases.

Under an expanded collaboration whose value was not disclosed, Regeneron and Intellia plan to initially research two in vivo nonliver targets. Intellia has agreed to lead the design of the editing methodology, whereas Regeneron has agreed to lead the design of the targeted viral vector delivery approach.

Each company will have an opportunity to lead potential development and commercialization of product candidates for one target. For that target, the company that is not leading development and commercialization will have the option to enter into a codevelopment and cocommercialization agreement.

The collaboration is designed to combine Regeneron's proprietary antibody-targeted AAV vectors and delivery systems and Intellia's proprietary Nme2 CRISPR/Cas9 (Nme2Cas9) systems adapted for viral vector delivery and designed to precisely modify a target gene.

“To date, the widespread use of genetic medicines has generally been limited by the inability to deliver a genetic payload to cells of interest in the body beyond the liver. This expansion of our longstanding and productive collaboration with Intellia is taking advantage of new technology and innovations to unlock these opportunities,” said Aris Baras, MD, senior vice president and cohead of Regeneron Genetic Medicines.⁵

THERMO FISHER TIES EXPANSION OF VIRAL VECTOR SITE TO DEMAND

Thermo Fisher Scientific has publicly discussed a possible future expansion of the $180 million viral vector manufacturing plant it opened last year in the Boston suburb of Plainville, MA, saying it will not proceed until it sees demand for the additional capacity.

Thermo Fisher can currently produce 12 to 13 products simultaneously at Plainville, depending on the product. The company has the ability to “double the production, or even triple the production” at its Plainville site, said Cédric Volanti, vice president and general manager of Viral Vector Services.⁶

Volanti added the company has the capacity to more than double its 55,000 square feet (5,110 square meters) of manufacturing space, while its current 290,000 square feet (26,942 square meters) of total space in Plainville could grow to >400,000 square feet (37,161 square meters) after expansion.

However, Volanti and other executives declined to discuss a timeline for the new project, adding that it will be ready when Thermo Fisher sees demand for the expansion.

Located 48 miles (77 km) southwest of Boston, and 37 miles (60 km) south of Thermo Fisher's headquarters in Waltham, MA, the Plainville viral vector plant has 180 employees. Thermo Fisher plans to grow that staff to >300 people over the next 2 years.

According to Thermo Fisher, the Plainville facility is designed to provide process and analytical development, characterization, validation, clinical and commercial manufacturing, as well as fill–finish services, all under one roof—which “eliminates the need for costly and time-consuming facility-to-facility transfers.”⁷

The plant's key capacities include flexible facility designs capable of supporting both adherent and suspension (up to 2,000-L stirred-tank bioreactors) processes; a bioprocess sciences laboratory for process/analytical development, characterization, and scale up to 2,000 L; 11 drug substance suites for viral vector production and purification; 2 fill–finish suites for final drug product production with up to 5,000 vial capacity; manufacturing support areas for solution preparation and component preparation; and quality control laboratories to support on-site bioanalytical testing needs.

COAVE NAMES SEVEN TO SCIENTIFIC ADVISORY BOARD

Coave Therapeutics has formed a scientific advisory board (SAB) whose members have been leaders in gene therapy, neurological diseases, adeno-associated viral, and nonviral vector technologies.

The following are the seven members named to the SAB:

Olivier Danos, PhD, the SAB's chair and chief scientific officer at REGENXBIO.

Alain Wagner, PhD, director of the Laboratory of Functional Chemosystems at the University of Strasbourg.

Anne des Rieux, PhD, professor at Université Catholique de Louvain (UCLouvain)'s Louvain Drug Research Institute.

Aravind Asokan, PhD, professor and director at the Duke University School of Medicine, and director of the Danaher Beacon for Gene Therapy Innovation.

Juliette Hordeaux, DVM, PhD, executive director of Translational Research at the Gene Therapy Program, University of Pennsylvania.

Mark Kay, MD, PhD, director of the Program in Human Gene Therapy, and professor in the Department of Pediatrics and Genetics at Stanford University School of Medicine.

Robert Kotin, PhD, adjunct professor at UMass Chan Medical School.

The SAB members will support Coave's R&D strategy by offering expert scientific and clinical guidance as the company progresses its pipeline of innovative genetic medicines based on its unique ALIGATER™ (Advanced Vectors-Ligand Conjugates) platform.

Coave added that the collective expertise of the SAB members will also contribute to enhancing the ALIGATER platform and expanding its potential across viral and nonviral vector-based therapeutics, unlocking the potential to develop novel genetic medicines targeting serious diseases.

“Bringing together such a diverse, esteemed and knowledgeable group of world-leading experts is a testament to the immense potential of Coave's pipeline, platform and strategic vision,” said Lolita Petit, Coave's chief scientific officer. “Their presence will undoubtedly catalyze our growth and move us closer to our mission of transforming the lives of patients with limited treatment options.”⁸

References

Philippidis

. At Chardan Conference, David Liu Foresees First Prime Editing Clinical Trial in 2024. Genetic Engineering & Biotechnology News. 2023. Available from: https://www.genengnews.com/gen-edge/at-chardan-conference-david-liu-foresees-first-prime-editing-clinical-trial-in-2024/ [Last accessed: October 15, 2023 ].

Prime Medicine. September 2023 Corporate Presentation. Available from: https://investors.primemedicine.com/static-files/415870f7-b7dc-475f-895f-fb243be27629 [Last accessed: October 15, 2023].

Kyowa Kirin and Orchard Therapeutics. Kyowa Kirin to Acquire Orchard Therapeutics. 2023. Available from: https://www.kyowakirin.com/media_center/news_releases/2023/pdf/e20231005_02.pdf [Last accessed: October 15, 2023 ].

uniQure. uniQure Announces Strategic Reorganization to Reduce Operating Expenses and Support Advancement of Multiple Clinical-Stage Programs. 2023. Available from: https://uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-strategic-reorganization-reduce-operating [Last accessed: October 12, 2023 ].

Regeneron Pharmaceuticals and Intellia Therapeutics. Regeneron and Intellia Announce Expanded Research Collaboration to Develop CRISPR-Based Therapies for the Treatment of Neurological and Muscular Diseases. 2023. Available from: https://investor.regeneron.com/news-releases/news-release-details/regeneron-and-intellia-announce-expanded-research-collaboration [Last accessed: October 15, 2023 ].

DeFeudis

. Thermo Fisher Is Ready to Expand Its Viral Vector Production Site in Massachusetts Once There's ‘Demand for It’. Endpoints News. 2023. Available from: https://endpts.com/thermo-fisher-is-ready-to-expand-its-viral-vector-production-site-in-massachusetts-once-theres-demand-for-it/ [Last accessed: October 15, 2023 ].

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Coave Therapeutics. Coave Therapeutics appoints Leading World Experts to Newly Formed Scientific Advisory Board dedicated to its Genetic Medicine Delivery Platform. 2023. Available from: https://coavetx.com/coave-therapeutics-appoints-leading-world-experts-to-newly-formed-scientific-advisory-board-dedicated-to-its-genetic-medicine-delivery-platform/ [Last accessed: October 12, 2023 ].