AAV-RPGR(University of Oxford)

John Tlumacki/The Boston Globe via Getty Images Less than two weeks after Ginkgo Bioworks announced a merger with special purpose acquisition company (SPAC) Soaring Eagle Acquisition Corp., it announced a collaboration partnership with Biogen. The two companies, they claim, “aim to redefine the industry standard for manufacturing recombinant adeno-associated virus (AAV)-based vectors.” This is a hot area in gene and cell therapies. Gingko Bioworks is known as “the organism company.” Its focus is on using microorganisms to engineer various products in a vast swath of markets. This includes fragrances, food and agriculture, antibiotics, vaccines, therapeutics and enzymes. In November 2020, Gingko was offered a $1.1 billion loan from the U.S. government for COVID-19 testing and manufacture of raw materials for possible therapies. After its merger with Soaring Eagle and the resultant initial public offering (IPO), it is expected to have a market value of $15 billion. Under the terms of the deal with Biogen, the company will have access to Ginkgo’s cell programming platform. Gingko will use its technology and resources to improve the AAV production titers of Biogen’s gene therapy manufacturing. Biogen is paying Ginkgo $5 million up front, with milestone payments up to another $115 million. “We believe that Ginkgo’s unique combination of cell programming expertise, proprietary tools and knowledge of biological systems make them an ideal collaboration partner to explore a large number of design ideas with the goal of optimizing constructs,” said Alphonse Galdes, Head of Pharmaceutical Operations and Technology at Biogen. “They share our goal of ensuring approved therapies are not delayed by manufacturing constraints and are available to patients worldwide.” Biogen has a big date just around the corner. The U.S. Food and Drug Administration (FDA) has a target action date of June 7 for Biogen’s aducanumab for Alzheimer’s disease. The drug has had a complex history, with a significant amount of controversy. The drug was initially dropped in March 2019 after data suggested it would not meet its primary endpoint. Further data analysis found the drug was promising at the highest dose in a subpopulation. After further investigation, they submitted the application to the agency. If approved, analysts have projected annual sales of about $4.8 billion by 2026. However, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted against the drug. The most optimistic analysts have the odds for approval at about 50/50. And earlier this month, Biogen reported that its gene therapy for X-linked retinitis pigmentosa (XLRP), cotoretigene toliparvovec, missed the primary endpoint of the Phase II/III XIRIUS trial. XLRP is a rare, inherited disease of the retina. The company otherwise observed positive trends in some of its secondary endpoints. The therapy is an AAV8 vector-based gene therapy administered by subretinal injection. It allows for delivery of a full-length functioning retinitis pigmentosa GTPase regulator (RPGR) protein in XLRP patients whose disease is the result of RPGR gene mutations. But the Gingko deal is only the latest in a stream of agreements that show Biogen is working seriously on developing its gene therapy capabilities. Only a week before the trial announcement, Biogen signed a strategic collaboration deal with Capsigen to engineer novel AAV capsids for gene therapy. Washington-based Capsigen uses a proprietary TRADE platform and technologies to find and develop novel AAV capsids for disease-specific transduction profiles. And in March, Biogen announced plans to build a new gene therapy manufacturing facility in North Carolina to support its manufacturing for itself and its partners. Earlier in the year, the company signed a licensing deal with Germany’s CEVEC Pharma for its ELEVECTA Technology to manufacturing AAV vectors for gene therapies. And in January, Biogen and Germany’s ViGeneron GmbH inked a gene therapy collaboration focused on AAV therapies for inherited eye diseases. Jason Kelly, chief executive officer of Ginkgo Bioworks, said, “We are excited to collaborate with Biogen as they aim to develop treatments that may potentially slow, halt or cure neurological and neurodegenerative diseases and seek to enhance the industry standard for AAV manufacturing. Synthetic biology is leveraging the power of living cells to develop the next generation of therapeutics, everything from CAR-T, to CRISPR and gene therapies, which we believe will have a material impact on the lives of many.”

Biogen’s gene therapy aspirations have been dealt a setback after one of the assets acquired as part of an $800 million deal failed a key clinical trial testing it as a treatment for a rare, inherited eye disease. On Friday, Biogen announced that cotoretigene toliparvovec, a gene therapy candidate for X-linked retinitis pigmentosa (XLRP), failed to meet the main goal of showing improvement according to a test that assesses the retina. But the Cambridge, Massachusetts-based biotech isn’t giving up on the gene therapy yet, pointing to “positive trends” in other clinical trial endpoints, such the measure of vision sharpness under low light. Biogen said it is continuing to evaluate the clinical trial data before determining what to do next with this gene therapy program. XLRP is an inherited disease that causes the deterioration of photoreceptors, the light-sensing cells of the retina. The disease is caused by mutations in genes that encode proteins key to various retinal functions. Patients who have the rare disease experience progressive vision loss, typically leading to blindness by age 40. There are no FDA-approved treatments for XLRP. Cotoretigene toliparvovec was developed to address XLRP caused by a mutations to the RPGR gene. Injected into the eye, the gene therapy uses the adeno-associated virus 8 (AAV8) to deliver a functioning version of that gene to retinal cells, potentially slowing or even stopping further degeneration of photoreceptors. It’s intended to be a one-time treatment. Biogen is testing its gene therapy in a 50-patient Phase 2/3 study that enrolled males who have a genetically confirmed diagnosis of XLRP. The first part of the clinical trial was a 24-month dose-escalation study in 18 men. The second part was a 12 month dose expansion study in 32 patients age 10 and older, with high and low doses selected from the first part of the study. A third group of patients remained untreated as a control. According to the preliminary results reported by Biogen, the improvement in the treated eyes was not enough to be statistically significant, as assessed by microperimetry, a visual field test that assesses how much light is perceived by certain parts of the retina. Biogen said that this assessment was done 12 months after treatment and was compared to the study eye of patients who were randomly assigned to the untreated control group. Biogen said most of the adverse events reported in the XLRP clinical trial were related to the eye, were mild to moderate in severity, and they resolved. Analysis of the clinical trial data is ongoing and the company said it will share detailed results at a future scientific forum. The Biogen portfolio is dominated by multiple sclerosis drugs, which together accounted for $7.8 billion of the company’s nearly $10.7 billion in 2020 product sales. Efforts to expand the company’s scope include deals that address additional therapeutic areas with new types of treatments, such as gene therapies. In 2018, Biogen terminated a three-year gene therapy alliance with Applied Genetic Technologies Corporation (AGTC) following the clinical trial failure of a gene therapy for X-linked retinoschisis, a rare, inherited eye disease that degeneration of the retina and vision loss. Meanwhile, AGTC has continued its gene therapy research, including an XLRP gene therapy candidate. Last week, the company reported positive results for the highest dose of its gene therapy candidate in a Phase 1/2 study. Cotoretigene toliparvovec is one of two clinical-stage gene therapies that came to Biogen via its 2019 acquisition of Nightstar Therapeutics. The other gene therapy in that deal, timrepigene emparvovec, is currently in Phase 3 testing as a potential treatment for choroideremia, another rare inherited retinal disease. Nightstar also brought to Biogen preclinical assets. Biogen has placed other bets on gene therapies for the eye. Last year, Biogen licensed from Massachusetts Eye and Ear a gene therapy candidate that addresses mutations in the PRPF31 gene, which causes autosomal dominant retinitis pigementosa. Early this year, Biogen inked an alliance with German gene therapy company ViGeneron. Neither the financial terms nor the eye disease target were disclosed. Photo by Flickr user Ken Teegardin via a Creative Commons license