Abstract
The patient was one of three who were previously disclosed to have received AT132 at the trial's high dose of 3 × 1014 vg/kg, and who began to demonstrate signs of liver dysfunction within 3 to 4 weeks after dosing. According to Audentes, preliminary findings indicated that the immediate cause of death was gastrointestinal bleeding. 1
In a presentation to investors, Audentes said that all three patients who died showed notable features that included older age, heavier weight, and evidence of pre-existing hepatobiliary disease. 2
Twenty-three ASPIRO patients have received AT132: 6 at the 1 × 1014 vg/kg dose and 17 at the 3 × 1014 vg/kg dose.
AT132 is an adeno-associated virus serotype 8 vector containing a functional copy of the MTM1 gene. Audentes said it remained committed to the AT132 development program and the XLMTM patient community.
“These deaths require all of us to determine how to use high-dose AAVs safely—if at all,” Nicole Paulk, PhD, Assistant Adjunct Professor, University of California, San Francisco, asserted in a commentary published in Genetic Engineering & Biotechnology News. 3
In the short term, Dr. Paulk wrote, additional preclinical studies are needed to better predict safer doses and biomarkers of toxicity, as well as the influence of parameters such as empty capsid levels, impurities resulting from manufacturing methods, and different purification strategies.
“In the long term, we need to shift our focus from ‘how can we safely use high doses' to ‘how can we design the vector so we don't have to’” added Paulk, who is an editorial board member of Human Gene Therapy. 3
Despite FDA Setback, BioMarin Stands by Severe Hemophilia a Gene Therapy
The FDA requested 2 years of data from BioMarin's ongoing Phase III 270-301 trial (NCT03370913), to provide “substantial” evidence of a durable effect using annualized bleeding rate as the primary endpoint. In a statement, BioMarin said the recommendation was new and that the company and agency previously agreed on the extent of data necessary to support the BLA.
“We are surprised and disappointed that the FDA introduced new expectations for the first time in the Complete Response Letter. We are confident in valoctocogene roxaparvovec gene therapy and its potential to redefine the treatment paradigm for people with hemophilia A,” stated Jean-Jacques Bienaimé, Chairman and CEO of BioMarin. 4
Guy Young, MD, a professor of pediatrics at the Keck School of Medicine of the University of Southern California and director of the Hemostasis and Thrombosis Program at the Children's Hospital of Los Angeles, said: “I'm honestly shocked. I've been working in hemophilia for 22 years now, and this is the first product that I can recall that came through the FDA specifically for hemophilia, that was not approved right away.” 5
BioMarin said it planned to meet with FDA officials in coming weeks to agree on next steps to obtain approval. The BLA had been based on an interim analysis of Phase III study participants treated with investigational product manufactured by BioMarin's to-be-commercialized process, and by 3-year data from an earlier Phase I/II study (NCT02576795).
Fujifilm Diosynth Biotechnologies Breaks Ground on Innovation Center
The 60,000-square-foot (5,574-square-meter) facility will house dedicated process development and innovation laboratories designed to support advanced therapy projects. The building will be part of a 22-acre parcel acquired by FDB from Lake Walk Town Center in June.
The laboratories will have BSL-2 capabilities with advanced upstream, downstream, and analytical development technologies, according to FDB. The building will triple the site's advanced therapies process development capabilities.
The Advanced Therapies Innovation Center is projected to bring ∼100 jobs to the College Station area, and is to be operational by fall 2021.
“We remain committed to provide leading, future proofed end-to-end gene therapy solutions, from pre-clinical to commercial launch. This is aligned with core purpose to be a Partner for Life as we support our customers in the advancement of tomorrow's medicines,” said Gerry Farrell, chief operating officer at FDB, Texas. 6
Sorrento's Smart Purchase
San Diego-based Sorrento agreed to give SmartPharm equity holders up to $19.4 million of shares of Sorrento common stock, subject to certain adjustments, based on a price per share calculated in accordance with the merger agreement.
Sorrento and Cambridge, MA-based SmartPharm, have launched an R&D collaboration to encode and express in vivo Sorrento's proprietary SARS-CoV-2 neutralizing monoclonal antibodies using SmartPharm's Gene Mab plasmid nanoparticle platform. Through SmartPharm's platform, Sorrento has identified STI-2020dna (DNA plasmid injection), an antibody-encoded DNA plasmid candidate derived from Sorrento's proprietary STI-1499 (COVI-GUARD™) and matured and optimized for DNA plasmid delivery to generate antibodies in vivo directed against SARS-CoV-2 and its D614G variant.
STI-2020dna is undergoing preclinical in vivo studies, and could generate long-lasting antiviral protection with a single intramuscular administration, Sorrento and SmartPharm said.
The transaction is expected to close in early September, subject to customary closing conditions.
“The merger with Sorrento presents a tremendous opportunity to advance our next-generation, non-viral gene therapy technology and combine it with Sorrento's significant R&D and manufacturing capabilities,” said SmartPharm CEO Jose Trevejo MD, PhD. 7
Forging ahead with $40M
Forge said it will use proceeds from the financing to expand adeno-associated virus (AAV) manufacturing CDMO capabilities this year, with cGMP production capacity available by mid-2021, as well as toward the development of a novel gene therapy pipeline.
Forge is located in Columbus, OH, within The Hearth, a 175,000-square-foot facility that houses a custom-designed cGMP facility dedicated to AAV vector manufacturing, now capable of up to 50L scale research and toxicology grade AAV manufacturing. By mid-2021, The Hearth is expected to host end-to-end cGMP AAV manufacturing services at 500L scale, enabling biotech and pharma clients to accelerate their gene therapy programs from preclinical development through clinical and commercial stage manufacturing. 8
Forge's lead gene therapy program is a novel AAV and umbilical cord transplant combination approach to treat infantile Krabbe disease. The combination treatment was pioneered in the laboratory of Maria Escolar, MD, who joins Forge as chief medical officer. She is a professor of pediatrics and director, Program for the Study of Neurodevelopment in Rare Disorders at University of Pittsburgh.
The management team also includes cofounders Timothy J. Miller, PhD, president and CEO; Jaysson Eicholtz, chief operations officer; and Erandi De Silva, PhD, chief strategy officer. Chris Garabedian, manager of the PXV Fund for Perceptive Advisors and CEO of Xontogeny, will join Forge's board as chairman.
Biocompatibility Questions Lead to Clinical Hold
“We are confident that we can efficiently and successfully address the FDA clinical hold questions related to biocompatibility of our proposed ICM delivery device so that we can begin to dose patients before the end of this year or early next year,” Passage Bio Chief Medical Officer Gary Romano, MD, PhD said. “We continue to believe that the initial [30-day] clinical safety and biomarker data from this trial will be available late in the first half of 2021.” 9
Passage Bio disclosed in its quarterly Form 10-Q, filed August 13 with the U.S. Securities and Exchange Commission that the clinical hold was imposed “pending additional biocompatibility risk assessments and/or testing of the proposed ICM delivery device.” 10
The company also said it was working with external medical device and regulatory experts to evaluate options for additional risk assessment and testing that could be conducted to further demonstrate the compatibility of the device with the intra-cisterna magna (ICM) injection procedure.
PBGM01 is designed to treat infantile GM1 by using a next-generation AAVhu68 viral vector to deliver a single dose of modified DNA encoding the b-gal enzyme to a patient's cells, through intracisterna magna injection. The vector and delivery approach of PBGM01 is intended to increase levels of the b-gal enzyme in both the central nervous system and the peripheral nervous system.
“Marginal” Impact from Change of Endpoint
The FDA told AGTC to change its primary endpoint to a change in visual sensitivity of 7 decibels or greater in at least five gene loci, calling the revised endpoint clinically meaningful—consistent with how other XLRP gene therapy developers are analyzing data. AGTC previously reported visual sensitivity as a mean over an entire treated area—a standard that had been applied to its ongoing Phase I/II trial (NCT03316560) of the gene therapy candidate.
AGTC CEO Sue Washer told GEN the change will not hurt the development program, despite the start of the trial being pushed back a few months from AGTC's earlier estimate of a planned launch by the end of 2020.
“In the grand scheme of things, we just needed to adjust for statistics, to account for the revised endpoint that the FDA requested. But we think that the delay is marginal,” Washer said. 11
Washer said no new testing will be needed for patients evaluated in the Phase I/II trial, which is being expanded with dosing of ∼20 additional patients to collect additional data, including a mobility test that will serve as a supplemental endpoint. In July, researchers from AGTC and the University of Pennsylvania published preclinical data in Human Gene Therapy showing validation of the transgene hRPGRco, which is being evaluated in the company's Phase I/II clinical trial in patients with XLRP. 12