Abstract
Pfizer marked a success, and a setback, in its ongoing effort to develop gene therapies. The company joined Sangamo Therapeutics to report positive Phase III data for their hemophilia A gene therapy candidate. The companies reported that giroctocogene fitelparvovec met its primary endpoint in the Phase III AFFINE trial (NCT04370054) by achieving non-inferiority, as well as superiority, of total annualized bleeding rate (ABR) from Week 12 through at least 15 months of follow up post-infusion compared with routine Factor VIII (FVIII) replacement prophylaxis treatment.
Giroctocogene fitelparvovec demonstrated a statistically significant 74% reduction in mean total ABR compared to the pre-infusion period (1.24 vs. 4.73) following a single 3e13 vg/kg dose, Pfizer and Sangamo shared.
Pfizer and Sangamo also announced results on secondary endpoints that showed superiority compared to prophylaxis: 84% of participants maintained FVIII activity >5% at 15 months post-infusion, with most participants having FVIII activity ≥15%. The mean treated ABR showed a statistically significant 98.3% reduction from 4.08 in the pre-infusion period to 0.07 post-infusion (from Week 12 up to at least 15 months [15–44 months].
“We look forward to advancing this latest innovation to help address the medical and treatment burden associated with frequent and time-consuming IV infusions or injections, building on Pfizer’s more than 40-year effort to advance hemophilia treatment,” said James Rusnak, MD, PhD, Senior Vice President, Chief Development Officer, Internal Medicine and Infectious Diseases, Research and Development, Pfizer. 1
A few days after giroctocogene fitelparvovec marked a step forward for Pfizer in gene therapy, the pharma giant acknowledged a setback when it disclosed plans to eliminate 150 jobs at its gene therapy facility in Sanford, NC.
The layoffs, which were disclosed through a Worker Adjustment and Retraining Notification (WARN) notice filed with the North Carolina Department of Commerce, took effect on July 31, 2024.
The layoffs came about a month after Pfizer terminated the development of its Duchenne muscular dystrophy (DMD) gene therapy candidate fordadistrogene movaparvovec after it failed the Phase III CIFFREO trial (NCT04281485). The trial missed its primary endpoint of improvement in motor function among boys treated with the gene therapy, compared to placebo, as measured by change in the North Star Ambulatory Assessment (NSAA) one year after treatment.
“At this time we are focused on conducting a more detailed review of these data, which will be shared at future medical and patient advocacy forums, Pfizer’s DMD gene therapy team stated. 2
In May, Pfizer paused enrollment in the CIFFREO trial after acknowledging the sudden death of a young boy who received the treatment last year. The boy, whose age has not been disclosed, was among patients dosed with the gene therapy in the Phase II DAYLIGHT trial (NCT05429372), which has been evaluating fordadistrogene movaparvovec in 10 boys ages two to less than four years old.
SANGAMO, GENENTECH FOCUS ON NEURODEGENERATIVE DISEASE IN UP-TO $1.9B COLLABORATION
Sangamo Therapeutics has granted Genentech, a member of the Roche Group, an exclusive license to develop intravenous genomic medicines for specified neurodegenerative diseases, launching a collaboration that could generate more than $1.9 billion for Sangamo.
The license grants Genentech exclusive access to Sangamo’s zinc finger repressors directed to the tau gene, which plays a critical role in Alzheimer’s disease and other tauopathies, as well as an undisclosed second neurology target. Sangamo also agreed to exclusively license its neurotropic adeno-associated virus (AAV) capsid, STAC-BBB, to Genentech.
Sangamo has agreed to complete a technology transfer and specified preclinical activities, while Genentech has agreed to oversee all clinical development, regulatory interactions, manufacturing, and global commercialization. Genentech also agreed to pay Sangamo $50 million in near-term upfront license fees and milestone payments, as well as up to $1.9 billion in payments tied to achieving development and commercial milestones across multiple potential products, plus tiered royalties on net sales of such products subject to specified reductions.
Sangamo added that continues to engage in business development discussions with additional potential collaboration partners about the STAC-BBB capsid delivery platform, its epigenetic regulation capabilities, and other assets that include its Fabry disease treatment candidate isaralgagene civaparvovec (ST-920). According to Sangamo, STAC-BBB has demonstrated potent blood-brain barrier penetration and brain transduction in nonhuman primates.
“We are excited to share this powerful combination with Genentech to advance potential treatment options for devastating neurodegenerative disorders, and we are hopeful this could be the first of multiple capsid collaborations to come with other partners,” said Sangamo CEO Sandy Macrae, MB ChB, PhD. 3
VERTEX TO APPLY ORUM PLATFORM TOWARD CONDITIONING AGENTS FOR GENE EDITING THERAPIES
Vertex Pharmaceuticals will use Orum Therapeutics’ dual-precision targeted protein degradation (TPD2®) technology platform to discover targeted conditioning agents for use with gene editing therapies, the companies said, through a collaboration that could generate up to $945 million-plus for the degrader antibody conjugate (DAC) developer.
Orum has granted Vertex rights to conduct research using its TPD2 approach to developing DACs, next-generation versions of antibody-drug conjugates (ADCs) which use antibodies to precisely deliver small molecule targeted protein degrader payloads to cancer cells and other targeted biological therapies.
Following a research period for each target, Vertex will have the option to obtain a worldwide, exclusive license to research, develop, manufacture, and commercialize DACs developed with Orum’s TPD2 technology for that target.
Vertex has agreed to pay Orum $15 million upfront, plus option payments and milestones potentially totaling up to $310 million per target for up to three targets—up to $930 million total—as well as tiered royalties on potential future global annual net sales. Vertex has agreed to oversee all research, development, and commercialization for the collaboration. 4
The collaboration comes at a time when researchers across industry and academia are seeking less toxic alternatives to busulfan as a bone conditioning regimen, a crucial component of cell and gene therapy protocols. That effort is of keen interest to Vertex, which made history last December when Casgevy® (exagamglogene autotemcel, or “exa-cel”), which the company co-developed with CRISPR Therapeutics, became the first-ever CRISPR-based gene editing therapy to win U.S. Food and Drug Administration (FDA) approval to treat sickle cell disease, followed a month later by agency approval of Casgevy to treat transfusion-dependent beta thalassemia.
“You can view this collaboration in the context of looking for more targeted and safer conditioning agents,” said Sung Joo Lee, PhD, Orum’s CEO and founder. “Before getting this genetic treatment Casgevy, these patients need a preconditioning agent, and that traditionally has been chemotherapy. What we’re targeting through this collaboration is to replace that chemotherapy with a more targeted conditioning agent, using our degrader ADC approach or TPD2 approach.” 5
EVOTEC ELIMINATES 400 JOBS WORLDWIDE
Evotec said it plans to eliminate approximately 400 jobs worldwide as part of a restructuring that included the end of its gene therapy program and is intended to return the company to profitability.
The restructuring was unveiled by Christian Wojczewski, PhD, who was appointed Evotec’s CEO effective July 1. Wojczewski succeeded interim CEO Mario Polywka, DPhil, who had led the company from January 3 until the end of June.
“H1 2024 revenues and profitability have been more challenging for the company than expected. We are operating in a more difficult market environment, most notably the slowdown of early-stage R&D spending. This has required us to accelerate our transformation towards sustainable profitable growth, leveraging better on our strengths, driving productivity, reducing complexity and making the organization stronger for its next growth phase,” Wojczewski said. 6
Wojczewski acted after Evotec finished the first half of 2024 with adjusted group earnings before interest taxes, depreciation, and amortization (EBITDA) of —€0.5 million (about $550,000), compared with positive EBITDA of €33.9 million (about $37 million) in January–June 2023.
Evotec recorded an overall 2% year-over-year revenue increase in the first half of €390.8 million ($430 million), compared with €383.8 million ($422 million) in the first six months of 2023. However, total Shared R&D [research and development] revenues decreased by 7% to €302.4 million (about $333 million), compared with €324.8 million ($357 million) in the year-ago period.
Evotec said its results were impacted by a high fixed-cost base in its Shared R&D business segment, as well as costs related to the ramp-up of the new J.POD® biomanufacturing facility in Toulouse, France by the company’s Just-Evotec Biologics business, a contract development and manufacturing organization offering development and manufacturing services for antibody and antibody-related therapeutics.
JIM WILSON EXITS PENN GPT FOR RARE DISEASE DEVELOPER, CRO
James M. Wilson, MD, PhD, director of the Gene Therapy Program (GTP) at the Perelman School of Medicine at the University of Pennsylvania (Penn), announced he will step down to oversee two new companies he will be founding in part to continue work he spearheaded at Penn GPT.
The two companies are GEMMA Biotherapeutics (GEMMABio), a therapeutics company specializing in accelerating research and global access to advanced therapies for rare diseases; and Franklin Biolabs, a new genetic medicines contract research organization (CRO) formed to provide comprehensive solutions from discovery to development and distribution for the global genetic medicines industry. Both companies will be based within the greater Philadelphia area with an international network of partners stretching to countries that include the United Kingdom., Brazil, and South Korea.
GEMMABio will be funded through a syndicate of investors and investment groups, while the funding for Franklin Biolabs will come from a single undisclosed investor.
“Forming these two new entities is the next step to accelerate the future of gene therapy and deliver therapeutics to patients significantly faster,” said Wilson, who will serve as CEO of GEMMABio and Chairman of Franklin Biolabs. 7
Most of Penn GTP’s current employees will be offered positions at GEMMABio or Franklin Biolabs, which plan to hire additional staffers over the next 18+ months.
GEMMABio has agreed to in-license from Passage Bio three clinical-stage pediatric lysosomal storage disease programs. Passage Bio has granted GEMMABio exclusive, worldwide rights for the development and commercialization of PBGM01 for the treatment of GM1 gangliosidosis; PBKR03 for the treatment of Krabbe disease; and PBML04 for the treatment of metachromatic leukodystrophy.
GEMMABio agreed to pay Passage Bio initial payments of $10 million for the purchase of clinical product supply and up to an additional $10 million contingent on completing specified GEMMABio business milestones. GEMMABio also agreed to pay Passage Bio up to an additional $114 million tied to achieving development and commercial milestones, as well as future royalties in exchange for sublicenses to relevant intellectual property and the transfer of clinical trial materials and product supply related to the licensed programs.
“We are excited to have out-licensed our pediatric lysosomal storage disease programs to a company deeply committed to advancing these promising therapies for underserved patient communities,” said Will Chou, MD, president and CEO of Passage Bio. 8
Wilson was recruited to Penn in 1993 and created the first and largest academic-based program in gene therapy. His laboratory discovered AAV capable of being engineered into effective gene transfer vehicles. Wilson has also facilitated the clinical and commercial development of gene therapy platforms by establishing eight biotechnology companies.
At Penn Perelman, Wilson is also Rose H. Weiss Professor and Director of the Orphan Disease Center, and professor in the Departments of Medicine and Pediatrics. Wilson is a former editor in chief and clinical development editor of Human Gene Therapy.
BIOMARIN NARROWS ROCTAVIAN FOCUS, ENDS HEART MUSCLE DRUG DEVELOPMENT
BioMarin Pharmaceutical has narrowed the focus of its commercial, research and manufacturing programs for its marketed gene therapy Roctavian® (valoctocogene roxaparvovec-rvox, “val rox”) in three countries, the United States., Germany, and Italy, actions that the company said will enable the gene therapy to help BioMarin reach long-term profitability.
BioMarin said it expects Roctavian to be profitable by the end of 2025 as a result of its narrower activity focus, which the company anticipated will reduce annual direct Roctavian expenses to approximately $60 million, beginning in 2025.
During the quarter, BioMarin treated 3 patients in the United States. and 2 in Italy with Roctavian, generating $7 million in revenue. BioMarin said its global commercial team will continue to focus on elements deemed to be critical toward supporting the uptake of Roctavian in the United States, Germany, and Italy.
The narrowing of Roctavian’s programs is among cost cutting measures announced by BioMarin in reporting second quarter results. The company said it was limiting its investment approach to only those assets deemed to have the highest potential impact for patients. To that end, BioMarin said, it has ended development of BMN 293, a gene therapy for hypertrophic cardiomyopathy, saying in a statement that “the time and resources anticipated to bring BMN 293 through development and to market no longer met BioMarin’s high bar for advancement.” 9