GEN Edge presents 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.

Elliott Investment Management, a fund manager with approximately $60 billion in assets and a reputation for activist investing in underperforming companies, has taken a stake of more than $1 billion in BioMarin Pharmaceutical, according to a Reuters news report that cited two unnamed sources.

Elliott—which managed approximately $59.2 billion in assets as of June 30—has declined comment on its investment activity in BioMarin, while the company has not commented publicly. However, investors reacted positively to the November 7 report, sending BioMarin shares up 11%.

The reported investment by Elliot came a week after BioMarin scaled back its sales forecast for Roctavian® (valoctocogene roxaparvovec-rvox), its recently-approved gene therapy for adults with severe hemophilia A, for the second time this year.

In reporting third-quarter results November 1, BioMarin slashed its guidance to investors for 2023 revenues from Roctavian, now projecting the gene therapy to generate less than $10 million. BioMarin stated that the latest reduction came “as a result of global delays securing pricing and reimbursement, and other market preparations for Roctavian treatment, and proximity to the holiday season.”

BioMarin’s revised guidance for Roctavian falls well below the original forecast of between $100 million to $200 million in net product revenue, a range later halved to between $50 million and $100 million. Roctavian has generated just $800,000 in net product revenues this year, all of it in the third quarter.

BioMarin also narrowed its full-year total revenue outlook from a range of $2.38 billion to $2.5 billion to $2.39 billion to $2.47 billion. The company’s stock has declined by nearly 30% from its 12-month high of $117.27 at the close of trading on January 23.

The same day as its release of third quarter results, BioMarin also announced the planned retirement of its chairman and CEO Jean-Jacques Bienaimé, and his succession by Alexander Hardy effective December 1.

Bienaimé joined BioMarin as CEO in 2005 and became chairman 10 years later. He will be succeeded as chairman by Richard A. Meier, BioMarin’s lead independent director. Hardy is CEO of Genentech, a member of the Roche Group.

“Given recent mixed execution, we are not entirely surprised to see an activist potentially getting involved here,” RBC Capital Markets senior biotechnology analyst Luca Issi, PhD, said in a research note. “However, we are a bit surprised about the timing given the new CEO was announced last week and we wonder if he was aware of this.”

Sangamo defers Phase III Fabry gene therapy plans

Sangamo Therapeutics said it will defer additional spending on planning a future Phase III program for its Fabry disease gene therapy candidate isaralgagene civaparvovec (formerly ST-920) absent a collaboration partner or additional external funding.

Sangamo made the move as part of a restructuring that included a similar deferral of spending on chimeric antigen receptor-modified regulatory T-cell (CAR-Treg) therapies absent a collaboration partner or other external funding, the elimination of 40% of its U.S. workforce, and the narrowing of its pipeline.

Going forward, Sangamo will focus spending on developing epigenetic regulation therapies treating neurological diseases and novel adeno-associated virus (AAV) capsid delivery technologies.

“The process of streamlining Sangamo’s pipeline has been accelerated within today’s challenging economic environment and we have had to make difficult decisions to defer further investments and seek collaboration partners or direct investment in both our Fabry gene therapy and CAR-Treg cell therapy programs,” Sangamo CEO Sandy Macrae, MBChB, PhD said.

The pause in spending on isaralgagene civaparvovec comes despite the company trumpeting promising clinical data from its ongoing first-in-human Phase I/II STAAR trial (NCT04046224). Sangamo said all 25 patients dosed as of November 1 in the STAAR study have continued to show sustained, elevated α-Gal A levels, up to three years for the longest-treated patient.

The 25 dosed patients include 14 patients who were dosed at 5×1013 vg/kg, the dose planned for a future Phase III trial of isaralgagene civaparvovec.

Another Sangamo-developed gene therapy, giroctocogene fitelparvovec, is being developed with Pfizer for patients with moderately severe to severe hemophilia A. Sangamo said dosing has been completed in the Phase III AFFINE trial (NCT04370054), which is overseen by Pfizer.

A pivotal data read-out from AFFINE is expected in mid-2024, with Sangamo saying it anticipated submitting U.S. Biologics License Application (BLA) and European Marketing Authorization Application (MAA) submissions in the second half of 2024.

AstraZeneca inks $245M+ collaboration with Celectis

AstraZeneca has agreed to partner with Cellectis to develop up to 10 gene and cell therapy therapies in areas of high unmet need that include oncology, immunology, and rare diseases, through a collaboration that will pay $245 million initially—and could generate more than $1 billion—for the Paris-based gene-editing therapy developer.

AstraZeneca will apply Cellectis’ gene editing technologies and manufacturing capabilities to design the novel gene and cell therapies, selecting the up to 10 candidate therapies from 25 genetic targets that Cellectis agreed to exclusively reserve for AstraZeneca.

“The differentiated capabilities Cellectis has in gene editing and manufacturing complement our in-house expertise and investments made in the past year,” said Marc Dunoyer, chief strategy officer, AstraZeneca, and CEO, Alexion, AstraZeneca rare disease.

During the fourth quarter of 2023, AstraZeneca will pay Cellectis an initial payment of $105 million, consisting of $25 million cash upfront and an $80 million equity investment at $5/share, representing an equity stake of about 22% in Cellectis.

AstraZeneca also agreed to make an additional $140 million equity investment in Cellectis at $5/share, set to close in early 2024 subject to the signing of a final binding agreement following completion of a consultation with Cellectis’ employee representative bodies, and customary closing conditions that include approval by Cellectis shareholders and regulatory clearances. Upon closing of the second investment, AstraZeneca’s stake in Cellectis will grow to about 44%.

Cellectis is also eligible to receive an investigational new drug (IND) option fee and payments tied to achieving development, regulatory, and sales-related milestones that range from $70 million up to $220 million for each of the 10 candidate products, plus tiered royalties.

AstraZeneca retains an option for a worldwide exclusive license for the candidate products developed under the research collaboration agreement, to be exercised before IND filing.

Ajinomoto to acquire Forge Biologics for $620M

Ajinomoto has agreed to acquire Forge Biologics for $620 million, in a deal designed to extend the buyer’s global capabilities in adeno-associated virus (AAV) and plasmid gene therapy manufacturing by adding the operations of the viral vector and plasmid contract development and manufacturing organization (CDMO) and clinical-stage therapeutics company.

Forge carries out all of its development and manufacturing operations at its 200,000-square-foot, custom-designed current Good Manufacturing Practice (cGMP) facility “the Hearth” in Columbus, OH, where the company has more than 300 employees and 20 custom-designed cGMP suites

Forge’s offerings include scalable, end-to-end manufacturing services including process and analytical development, cGMP viral vector manufacturing, final fill, plasmid DNA manufacturing, as well as regulatory consulting support designed to accelerate gene therapy programs from preclinical through clinical and commercial stage manufacturing.

“Forge’s unparalleled expertise in gene therapy development and manufacturing will be a transformative addition to our core growth area of healthcare as part of our ASV [Ajinomoto Shared Value] Initiatives 2030 Roadmap,” stated Yasuyuki Otake, corporate executive, general manager of Ajinomoto’s biopharma services department. “Forge brings to Ajinomoto an entirely new capability that will vitally enhance our biopharma services business and help create new value through innovative solutions for communities and society.”

The transaction is expected to be completed by the end of the fourth quarter, subject to customary closing conditions that include regulatory approvals. Upon completion, Forge will become a fully consolidated subsidiary of Ajinomoto.

Bluebird to sell $103M lovo-cel voucher tied to approval

Bluebird Bio has agreed to sell a Rare Pediatric Disease Priority Review Voucher (PRV), if received, to Novartis for $103 million—if the FDA approves Bluebird’s Biologics License Application (BLA) for the gene therapy lovotibeglogene autotemcel (lovo-cel) for sickle cell disease (SCD), and grants the PRV.

The BLA for lovo-cel was previously accepted for priority review by the FDA for patients with sickle cell disease ages 12 and older who have a history of vaso-occlusive events (VOEs). The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of December 20, 2023. Bluebird may be eligible for the PRV if lovo-cel is approved for patients under the age of 18.

“The potential sale of a priority review voucher would provide an important source of non-dilutive capital for bluebird ahead of the anticipated launch of lovo-cel,” said Chris Krawtschuk, Bluebird’s CFO.

Lovo-cel is specifically designed to treat the underlying cause of SCD through the addition of a functional gene that enables production of anti-sickling adult hemoglobin. The BLA for lovo-cel is based on efficacy results from 36 patients in the HGB-206 study Group C cohort with a median 32 months of follow-up and two patients in the HGB-210 study with 18 months of follow-up each.

The BLA submission also includes safety data from 50 patients treated across the entire lovo-cel program, including six patients with six or more years of follow-up, which according to Bluebird is the longest follow-up of any gene therapy program for SCD.

Lexeo Therapeutics launches $100M IPO

Gene therapy developer Lexeo Therapeutics has launched an initial public offering (IPO), raising approximately $100 million in gross proceeds through the sale of 9,090,910 shares of common stock at $11 per share on the Nasdaq Global Market.

Lexeo lowered its price from a range of $13 to $15 a share before proceeding with the offering. The IPO generated approximately $88.7 million in net proceeds—a figure that could rise to approximately $102.7 million if the IPO’s underwriters exercise in full their option to purchase up to 1,363,636 additional shares. The IPO had not closed at deadline.

Lexeo’s began trading its first public shares on November 3 under the symbol “LXEO.”

J.P. Morgan, Leerink Partners, Stifel, and RBC Capital Markets are acting as joint book-running managers for the offering. Chardan is acting as lead manager for the offering.

As of September 30, 2023, Lexeo reported an estimated cash and cash equivalents balance of $35.4 million. In its IPO prospectus, the company detailed how it intended to use the net proceeds from the IPO, together with existing cash and cash equivalents:

  • Approximately $45 million to fund ongoing and planned clinical development of its most advanced cardiovascular product candidate LX2006 for the treatment of Friedreich’s ataxia (FA) cardiomyopathy, including completion of an ongoing Phase I/II study and readiness for the registrational study start.
  • Approximately $40 million to fund ongoing and planned clinical development of LX2020 for the treatment of arrhythmogenic cardiomyopathy, or ACM, caused by mutations in the PKP2 gene (PKP2-ACM), including completion of the ongoing Phase I/II study.
  • Approximately $10 million to fund ongoing and planned clinical development of LX1001 to treat Alzheimer’s disease in apolipoprotein E4 (APOE4) homozygous patients, including completion of an ongoing Phase I/II study.
  • Approximately $15 million to fund continued development of Lexeo’s other programs and cardiac discovery efforts, including advancing LX2021 for the treatment of desmoplakin (DSP) cardiomyopathy.
  • The remainder will be used for working capital and other general corporate purposes, Lexeo said.

“We are targeting diseases that have seen limited penetration of precision medicine, which we define as medications that treat the underlying molecular mechanism of a disease, and where we believe there is significant opportunity for gene therapy to play a role as a key therapeutic option,” Lexeo stated.

FDA advisory panel weighs exa-cel off-target effects

The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee set the stage for an expected decision in December on whether to grant its first-ever approval for a CRISPR-Cas9 gene-edited therapy.

At issue is the BLA submitted by Vertex Pharmaceuticals and CRISPR Therapeutics for exagamglogene autotemcel (exa-cel) as a treatment for SCD in people ages 12 and older with recurrent VOCs. The FDA granted priority review for exa-cel for SCD and assigned a Prescription Drug User Fee Act (PDUFA) action date of December 8.

The advisory committee sided with FDA staff reviewers, who concluded in their briefing document to the panel that despite limitations that included its small patient population and the absence of a control, “FDA does not believe that the study design limitations call the efficacy of exa-cel into question.”

However, the panel was charged with assessing specific questions regarding the potential clinical significance of so-called off-target genome edits and to consider recommendations for additional studies that the sponsor might be asked to perform to assess the risk of off-target editing.

Nicole Verdun, MD, super office director, Office of Therapeutic Products at FDA’s Center for Biologics Evaluation and Research (CBER), said any additional off-target studies could be conducted in the post-market setting. Fyodor Urnov, PhD, director of technology & translation at the Innovative Genomics Institute, told the panel that the success of genome editing depends on a host of variables besides off-target editing. They include the type of Cas9 nuclease, choice of guide RNA (gRNA), nature of the target sequence, mode of delivery, handling of transfected cells, and more.

During the October 31 hearing, a series of short presentations hosted by Vertex reviewed the exa-cel trial data and made a clinical case for approval. William Hobbs MD, Vertex vice president of clinical development, said the exa-cel therapy resulted in a “transformational clinical benefit” for patients.”

Moreover, Hobbs added, the results were consistent in both adults and adolescents, and have been shown to be durable in the first treated patient, Victoria Gray, for four years. Only two of the patients in the original cohort experienced any VOCs: one had a single pain crisis more than 12 months post treatment that occurred during a parvovirus infection.

Sanofi invests $30M in MeiraGTx

Sanofi has invested $30 million in MeiraGTx by purchasing four million shares of its stock at $7.50 per share, saying the investment reflected its interest in MeiraGTx’s Riboswitch gene regulation technology platform.

As a result of the investment, Sanofi will receive a right of first negotiation (ROFN) for the use of Riboswitch for immunology and inflammation (I&I) and central nervous system (CNS) targets, as well as for GLP-1 and other gut peptides for metabolic disease, and for MeiraGTx’s Phase II xerostomia program.

“We welcome technological innovations that help us chase the scientific miracles of the future. We believe that MeiraGTx’s Riboswitch platform, supported by its unique manufacturing capabilities, is such a technology,” said Sanofi CEO Paul Hudson. “We look forward to working alongside MeiraGTx as this innovative science moves forward to create a new generation of breakthrough medicines for immune-mediated and neurological diseases.”

Alexandria Forbes, PhD, MeiraGTx president and CEO, said Sanofi’s investment also reflected the breadth of interest over the past several months shown by multiple entities in acquiring assets of her company—potential deals that MeiraGTx is actively pursuing.

Forbes said MeiraGTx has hired Evercore Group to serve as financial advisor, and the law firm Wachtell, Lipton, Rosen & Katz as legal advisor to work with its management and Board of Directors to execute one or more additional potential strategic transactions, with the aim of maximizing value for shareholders.

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