Abstract
The global Phase III CIFFREO trial (NCT04281485), designed to evaluate the safety and efficacy of fordadistrogene movaparvovec in boys with DMD, has been ongoing in 11 countries. It was paused in August 2021 after three “severe adverse events of muscle weakness, two of which involved myocarditis (inflammation of the heart tissue),” Pfizer wrote in a September 28 letter to the DMD community. 1
Pfizer first amended the Phase III protocol in November 2021 by excluding individuals with mutations (exon deletion, exon duplication, insertion, or point mutation) affecting exons 9 through 13, inclusive, or a deletion that affects both exon 29 and exon 30.
In December, Pfizer further amended the protocol to include a 7-day hospitalization period to enable close monitoring and management of patients after administration of gene therapy. That protocol amendment was implemented after Pfizer had acknowledged the death of a young male participant in the Phase Ib trial (NCT03362502), a first-in-human/first-in-patient, multicenter, nonrandomized, ascending dose, safety, and tolerability study.
The patient participated in the nonambulatory cohort of the trial, designed to assess a single intravenous infusion of fordadistrogene movaparvovec in ambulatory and nonambulatory subjects with DMD.
“Like many non-ambulatory DMD patients, the participant had more advanced disease with underlying cardiac dysfunction,” Pfizer stated. 2
Fordadistrogene movaparvovec is an investigational recombinant adeno-associated virus serotype 9 (AAV9) capsid carrying a shortened version of the human dystrophin gene (minidystrophin) under the control of a human muscle-specific promoter. According to Pfizer, the AAV9 capsid has been chosen as the delivery mechanism because of its potential to target muscle tissue.
TESSERA COMPLETES $300M+SERIES C FINANCING ROUND
According to Tessera, gene writing uses mobile genetic elements (MGEs) to overcome the limitations of gene editing and gene therapies by writing short and long therapeutic sequences of DNA into human cells.
The company said it has designed, built, and tested tens of thousands of engineered and synthetic MGEs to create programmable gene writing systems that can change any base pair to any other, make small insertions or deletions, and write entire genes into the genome with delivery of only RNA. Those features, according to Tessera, give the platform its potential to cure nearly any genetic disease, create life-changing medicines for other serious conditions, and prevent still other illnesses with curative, scalable, and easily administered genetic medicines.
“It is our belief that genetic medicine will be the most important next epoch in medicine—offering the ability to cure genetic diseases and to someday even prevent disease from occurring,” said Geoffrey von Maltzahn, PhD, cofounder, CEO, and a board director of Tessera Therapeutics. 3
Investors in the Series C round included a wholly owned subsidiary of the Abu Dhabi Investment Authority (ADIA); Alaska Permanent Fund Corp.; Altitude Life Science Ventures; ARTIS Ventures; Cormorant Asset Management; Tessera's founder, Flagship Pioneering; and Hanwha Impact Partners.
Also, Longevity Vision Fund; March Capital; SALT Fund; SoftBank Vision Fund 2; funds and accounts advised by T. Rowe Price Associates, Inc., and other investors that included all of Tessera's existing institutional shareholders.
ASTELLAS SCRAPS GENE THERAPIES INCURS $170M IMPAIRMENT CHARGE
The company plans to book an impairment charge of $170 million for loss of intangible assets among other expenses when the company reports results for the first quarter of its 2022 fiscal year (April, May, and June).
The three gene therapies treat separate groups of patients by targeting different DMD gene exons. AT702 is an adeno-associated virus (AAV)-antisense candidate designed to induce exon 2 skipping for DMD with duplications of exon 2 and mutations in exons 1–5 of the dystrophin gene.
AT702 was originally developed by researchers at the National Children's Hospital (NCH), which licensed the gene therapy to Audentes Therapeutics in 2019. After showing a dose-dependent increase in dystrophin levels and improvements in muscle function in a mouse model with a DMD exon 2 duplication, Audentes and the NCH launched a Phase I/II trial of AT702 (NCT04240314).
Astellas acquired Audentes for ∼$3 billion, in a deal completed in 2020.
AT751 and AT753 are also vectorized exon skipping candidates designed to treat DMD patients with genotypes amenable to exon 51 and exon 53 skipping, respectively.
CARIBOU SHOWS POSITIVE INITIAL DATA FOR CB-010
“These excellent initial outcomes represent important steps toward validating our chRDNA genome-editing platform as well as our plans for future development of CB-010 and our broader pipeline,” Rachel Haurwitz, PhD, Caribou's president and CEO, said in a statement. 5
The initial data are set to be shared at the European Hematology Association (EHA) 2022 Hybrid Congress, to be held during June 9–17 in Vienna, Austria. At EHA, Caribou is scheduled to share longer follow-up data from patients in Cohort 1 of the ANTLER trial who received a single administration of CB-010 at the first dose level of 40 × 106 CAR-T cells.
CB-010 is an allogeneic, anti-CD19 CAR-T cell therapy derived from healthy donor T cells. CRISPR-Cas9 chRDNAs designed to significantly reduce off-target editing were used to generate three genome edits in the manufacture of CB-010, according to an abstract of the presentation: Knockout of the TRAC gene to eliminate T-cell receptor expression to reduce the risk of graft versus host disease; site-specific insertion of an anti-CD19 CAR into the TRAC locus; and knockout of the gene encoding PD-1, designed to limit CAR-T cell exhaustion.
CB-010 “demonstrated promising preliminary safety and efficacy in pts [patients] with r/r B-NHL at the initial dose level,” according to the abstract. 6
REGENXBIO DELAYS DOSING IN TRIAL OF DMD GENE THERAPY
The company blamed the delay on an unspecified “unexpected observation” seen during the final stages of manufacturing the gene therapy candidate at one of its third-party manufacturers, which was also not disclosed.
REGENXBIO said that work was continuing toward preparation for the AFFINITY DUCHENNE trial, including readying clinical trial sites and manufacturing additional clinical supply.
“REGENXBIO anticipates dosing the first patient in this trial in the first half of 2023,” the company stated. 7
RGX-202 is an investigational AAV therapeutic designed as a one-time treatment for DMD (Duchenne). RGX-202 uses the NAV AAV8 vector to deliver a transgene for a novel microdystrophin that includes the functional elements of the C-Terminal domain as well as a muscle-specific promoter to support a targeted therapy for improved resistance to muscle damage associated with Duchenne.
RGX-202 has received the Orphan Drug Product Designation from the U.S. FDA.
SCRIBE THERAPEUTICS EXPANDS COLLABORATION WITH BIOGEN
The second target and disease area of interest were not disclosed. Also undisclosed is how much more Biogen will pay Scribe if the second target leads to a successful therapy.
The first target is a genetic cause of amyotrophic lateral sclerosis, the companies announced when they launched their collaboration in October 2020.
“We remain excited about pushing forward in that area,” Benjamin L. Oakes, PhD, Scribe's cofounder, president, and CEO, told Genetic Engineering & Biotechnology News. “We've also been developing ways of using genome editing and additional genome modification technologies, as well as significantly improving delivery. In all those areas, the collaboration has been really fruitful.” 8
Biogen originally agreed to pay Scribe $15 million upfront, and up to $400 million tied to achieving milestones. The companies also said at the time that Biogen had an option for a second neurological disease target with high unmet need.
Headquartered in Alameda, CA, Scribe develops CRISPR-based treatments through its genetic modification platform, designed to build and apply its suite of CRISPR technologies in therapeutic areas that include neurodegenerative diseases; ophthalmological diseases; multisystem, muscle, and metabolic disorders; and hematopoietic disorders. That platform aims to address safety, delivery, poor editing outcomes, and the long-running bitter legal battle over who invented CRISPR-Cas9.
To avoid intellectual property uncertainty, Scribe has engineered its own CRISPR effectors—CasX enzymes—that are more capable of delivering CRISPR packaged in a viral vector because the protein is <1,000 amino acids (aa), compared with the 1,200–1,400-aa size of Cas9. Those “X-Editing” (XE) molecules are highly engineered CRISPR-based enzymes designed to provide combined aspects of greater efficacy, specificity, and deliverability than current CRISPR genome editing technologies.
“Scribe's custom-designed CRISPR platforms, molecules, and delivery technologies are overcoming the technical hurdles that challenge many genetic targeting technologies and we are thrilled to continue to drive forward a new era of truly transformative genetic medicines,” Oakes stated. 9
APERTURA GENE THERAPY LAUNCHES WITH $67M
Apertura said it was established to develop genetic medicines, through platform technologies designed to address limitations of genetic medicine delivery and expression. The company was founded to commercialize a pair of platform technologies developed in the laboratories of Ben Deverman, PhD, senior director of Vector Engineering and institute scientist at the Broad Institute of MIT and Harvard, and Michael Greenberg, PhD, the Nathan Marsh Pusey professor of neurobiology and chair of the department of neurobiology at Harvard Medical School.
Apertura has exclusive rights to AAV capsids developed in the Deverman Lab at the Broad Institute.
Through a separate sponsored research and licensing agreement with Harvard University, spearheaded by the Harvard Office of Technology Development, Apertura has been granted exclusive access to methods of identifying cell type-specific genetic regulatory elements, including access to the Paralleled Enhancer Single-Cell Assay platform, developed in the Greenberg Lab.
The company's platform is designed to engineer novel capsids, gene regulatory elements such as promoters and enhancers, and payloads to simultaneously enhance multiple functions of gene therapies for greater translational potential, by applying machine learning and high-throughput assays.
“Deerfield saw an opportunity to bring together and support a unique and comprehensive platform that could address technical challenges that have prevented gene therapy from reaching its full potential,” said Dave Greenwald, PhD, Apertura's acting CEO and vice president, Business Development at Deerfield Management Company. “While next-generation approaches to gene therapy have largely focused on the innovation of delivery vectors, Apertura has the potential to innovate simultaneously across delivery, expression, and payloads.” 10
Deerfield Management has also committed to further strengthening the company's ability to advance gene therapy discoveries, through unspecified additional operational support.