Recurrent Adult Acute Lymphoblastic Leukemia

Phoenix, Arizona/ iStock, Sean Pavone Stephen Majors from the Alliance for Regenerative Medicine, which hosts the conference, spoke with BioSpace about what the more than 2,000 attendees can expect to learn next week in Phoenix about the pressing issues confronting the industry. The 2024 Cell & Gene Meeting on the Mesa has a new location this year—held Oct. 7–9 in Phoenix, having moved from Carlsbad, Calif. Despite the change in venue, the industry continues to face the same regulatory, manufacturing and commercialization challenges as the sector hits an inflection point. BioSpace will provide on-site coverage of the three-day event, where more than 2,000 attendees will get an update from key stakeholders on the industry’s progress and the stumbling blocks that are impeding the advancement of cell and gene therapies (CGTs). One of the biggest business challenges for the sector is the investment headwinds that have continued this year, according to the Alliance for Regenerative Medicine (ARM), the Washington, DC–based advocacy organization that represents the industry and hosts the annual Meeting on the Mesa. Stephen Majors, global head of communications at ARM, told BioSpace that capital markets “have been really tough” the past few years for CGT. “There’s a lot of companies in the space pursuing a smaller amount of money,” he observed. “Inflation projections were, of course, a driver of this because the gene therapy companies tend to be the furthest away from commercialization and therefore inflation concerns hit them hardest,” Majors said. “We’re hopeful that with the reduction of interest rates and a better inflation outlook going forward, we’ll start to see more money flow into the sector.” Manufacturing, Commercialization Hurdles Majors said that manufacturing is also a major challenge for the industry due to a lack of standardization and the fact that scale-up has often been an obstacle to regulatory approval and commercialization. “There are still some manufacturing challenges and the ability to produce these therapies at scale at the demand that they’re needed. That’s something that the sector’s still working through,” according to Majors. A Government Accountability Office report last year found that while regenerative medicine technologies—including gene therapies, cell therapies and tissue-engineered products—are highly promising, they are being held back by the lack of widely accepted standards and guidelines to govern their use, development and manufacture. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), provided a sobering assessment in May at the 2024 American Society of Gene & Cell Therapy conference about the opportunities and challenges facing the CGT industry. He said that while it’s “an exciting time” for gene therapies in particular—including the approval of competing therapies for sickle cell disease —there are “some real challenges” including manufacturing, clinical development timelines and different global regulatory requirements . After their groundbreaking approvals in late 2023, infusions of Vertex-CRISPR Therapeutics’ and bluebird bio’s sickle cell gene therapies have recently begun, offering hope to patients and the companies, which are looking to jumpstart revenues. “Those of us who have been watching this for a while were always expecting these launches to be kind of slow with steady uptick over time, because of the length of time involved in the identification of eligible patients and in the consultation process they have with their doctors about whether this is the right therapy for them,” Majors said. A panel session at Meeting on the Mesa on commercializing cell and gene therapies in today’s “dynamic market” environment will be a “hot” session given other recent product launches, according to Majors. He expects “some lessons learned from that, maybe some wisdom and advice for launches yet to come.” For the second year at the conference, ARM CEO Tim Hunt will lead a session on the importance of ethics in cell and gene therapies. Majors said it is meant to be a broad-based look at several issues, including “the pricing and value” of CGT, global access such as “how long it will be” before therapies reach patients in developing and low- and middle-income countries, and ultra-rare diseases in which the sizes of patient populations “fall outside what usually works from a commercialization perspective.” According to market research and consulting firm Nova One Advisor, the global CGT market was valued at more than $18.1 billion in 2023 and is expected to reach approximately $97.3 billion by 2033. While CGT developers face challenges along several key stages of the product life cycle, the firm notes that “key success factors such as enabling patient access, managing supply chain and manufacturing operations, evidencing compliance with increasingly complex regulatory requirements and alternate business models impose a greater burden” for CGTs than for chemical-based pharmaceuticals. Regulatory Environment Takes Center Stage On the regulatory front at Meeting on the Mesa, the conference will hear from Nicole Verdun, director of the FDA’s Office of Therapeutic Products within CBER. According to Majors, Verdun will “give us an update on where the FDA is in terms of how they’re looking at cell and gene therapies, their staffing levels to ramp up with the submissions,” as well as accelerated approvals and “other details about the regulatory frameworks they’re looking at” for CGT. Scott Gottlieb, former FDA commissioner, will participate in a fireside chat at the conference. In 2019, as the head of the agency, Gottlieb predicted that the regulator would be approving 10 to 20 cell and gene therapy products annually by 2025. Early next year, his book The Miracle Century: Making Sense of the Cell Therapy Revolution is slated to be published. In it, he “tackles the issues that must be addressed to enable wide adoption of these treatments,” according to the publisher’s description . Majors said that Gottlieb will provide Meeting on the Mesa with an overview of “where we are in the field right now” and “what we can expect over the next few years.” “Historically, we haven’t seen much of a difference between the U.S. and Europe in approvals,” according to Majors. “There were a handful of gene therapies that got approved in Europe first before they got approved here. But what we’re seeing more recently is the U.S. starting to have more approvals.” ARM in its annual Cell & Gene State of the Industry Briefing in January predicted that the sector could see up to 17 regulatory approvals in the U.S. and European Union this year. However, Majors in an update to BioSpace said the organization has cut its forecast a bit and is now predicting up to 14 approvals, with eight in the U.S.—including the FDA’s first approval in March for an autologous gene therapy from Orchard Therapeutics to treat the rare metabolic disease metachromatic leukodystrophy in children, and the FDA nod in April for Pfizer’s hemophilia B gene therapy Beqvez. “If we looked at last year as kind of the breakthrough year of gene therapy, which it certainly was, this year we’re seeing a lot of advances in cell therapy,” Majors said. “There’s been a number of really impressive fundraises from cell therapy companies. There’s been a lot of excitement and progress in autoimmune diseases. And there’s been expansion of CAR T therapies into earlier lines of treatment.” In February, the FDA granted approval to Iovance Biotherapeutics’ li as the first one-time cell therapy for a solid tumor and the first tumor-infiltrating lymphocytes therapy. In April, the regulator greenlit two CAR T cell therapies for the earlier treatment of multiple myeloma —BMS and 2seventy Bio’s Abecma, and J&J and Legend Biotech’s Carvykti. And in August, Adaptimmune Therapeutics’ Tecelra became the first FDA-approved engineered cell therapy for solid tumors and the first new synovial sarcoma therapy in more than a decade. Majors sees Autolus Therapeutics’ FDA application for its next-generation CAR T therapy obe-cel in relapsed/refractory adult acute lymphoblastic leukemia as an important milestone, with a PDUFA target action date of Nov. 16. According to Autolus, obe-cel is a CD19 CAR T cell investigational therapy designed to overcome the limitations in clinical activity and safety compared to current CD19 CAR T cell therapies. The FDA in January pushed for a class-wide boxed warning on all commercial BCMA- and CD19-directed CAR T cell immunotherapies due to the “risk of T cell malignancies, with serious outcomes, including hospitalization and death.” “There was correlation but there wasn’t necessarily causation,” Majors said about the regulator’s findings on CAR T therapies and secondary cancers, noting that “the benefits of these therapies continue to outweigh the risks” providing an “important tool at the disposal of physicians for patients with serious, aggressive forms of cancer.”

Pictured: A collage representing cell and gene therapy/Taylor Tieden for BioSpace In 2023, cell and gene therapy saw an unprecedented surge with seven FDA approvals, and this year, an even greater number of these treatments could reach the market. So far in 2024, the regulator has given the green light to three new CGTs, and at least seven additional cell and gene therapy products are expected to receive approval by year’s end, according to a March report from the Alliance for Regenerative Medicine. “All signs point to 2024 surpassing 2023 as a landmark year for cell and gene therapy,” David Barrett, CEO of the American Society of Gene & Cell Therapy (ASGCT), told BioSpace. The first approval this year belonged to Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy, which won the FDA’s nod in January for use in transfusion-dependent beta thalassemia. This followed the agency's December 2023 approval of Casgevy as one of the first two cell-based gene therapies to treat patients with sickle cell disease. It also represented the first FDA approval of a therapy using CRISPR/Cas9 technology. Then, in February, Iovance Biotherapeutics’ Amtagvi was approved as the first one-time cell therapy for a solid tumor and the first tumor-infiltrating lymphocytes therapy, for advanced melanoma patients who have worsened after being treated with certain other therapies failed. Finally, last month, the FDA greenlit Orchard Therapeutics’ Lenmeldy, which entered the U.S. market as the first gene therapy for children with metachromatic leukodystrophy, and the word’s most expensive drug, with a $4.25 million price tag. Looking forward, the FDA has upcoming PDUFA dates for several more novel CGTs, including a traditional in vivo gene therapy delivered via viral vector, a couple of gene-corrected cell therapies in which a patient’s cells are modified by gene therapy outside of the body and then reinfused, and a new CAR-T. Two Q1 reports, from ASGCT and the Alliance for Regenerative Medicine, highlight some of these regulatory actions as potential catalysts for the sector, with approvals poised to propel the CGT space. The ASGCT report includes a list of noteworthy events in Q1 2024, while ARM’s report makes the case that 2024 could be a banner year for cell therapy. Here, BioSpace reviews five products under regulatory review that were highlighted by both organizations. Pfizer’s Beqvez Indication: Hemophilia B Therapy type: In vivo gene therapy Action date: April 27 Later this month, the FDA will rule on Pfizer’s gene therapy for hemophilia B, Beqvez. This engineered version of the factor IX coagulation gene carried by an adeno-associated virus is administered via a single infusion. Beqvez has been approved by Health Canada to treat adults with hemophilia B based on positive data from the Phase III BENEGENE-2 study, which showed a significant reduction in bleeding rate and infusion frequency. The Big Picture An FDA approval would put Pfizer in competition with CSL Behring, whose gene therapy Hemgenix, which is also administered via a single intravenous infusion, became the first FDA-approved gene therapy for hemophilia B in November 2022. Pricing details for Beqvez are not yet available, but Hemgenix costs $3.5 million per dose. Chris Boshoff, Pfizer’s chief oncology officer, told BioSpace the company aims to leverage its experience to ensure smooth market entry and efficient delivery to eligible patients. Abeona Therapeutics’ pz-cel Indication: Recessive dystrophic epidermolysis bullosa Therapy type: Gene-corrected cell therapy Action date: May 25 Next up is Abeona Therapeutics’ pz-cel, which delivers a functional collagen-producing COL7A1 gene into a patient’s own skin cells using a retroviral vector, for the treatment of patients with recessive dystrophic epidermolysis bullosa (RDEB). RDEB, a rare connective tissue disorder, causes severe skin wounds, pain and life-threatening complications stemming from compromised immunity due to a deficiency in the COL7A1 gene, preventing the production of functional type VII collagen. In November 2023, the FDA granted priority review to pz-cel based on clinical data from the Phase III VIITAL study and long-term results from a Phase I/IIa study, which demonstrated sustained wound healing and pain reduction. The Big Picture Ira Leiderman, managing director of healthcare at Cassel Salpeter, underscored the importance of evaluating therapeutic options against the rarity and impact of the disease. A positive decision on Abeona’s pz-cel will help address the high unmet need of RDEB patients and may lead to transformative interventions in this challenging rare genetic disorder, Leiderman told BioSpace. If approved, pz-cel would follow Krystal Biotech’s Vyjuvek, the first gene therapy approved for recessive or dominant DEB in May 2023. Abeona said in March it is actively preparing for the potential U.S. launch of pz-cel, including discussions with treatment sites and payer engagement. Rocket Pharmaceuticals’ Kresladi Indication: Leukocyte adhesion deficiency-1 Therapy type: Ex-vivo vector gene therapy Action date: June 30 While Rocket Pharmaceuticals initially anticipated a decision on its gene therapy for leukocyte adhesion deficiency-I (LAD-I) by March, the FDA requested more review time and extended the deadline to June 30. Severe LAD-I, a rare genetic disorder affecting children, is caused by mutations in the ITGB2 gene that lead to life-threatening infections. Without regular bone marrow transplants, survival beyond childhood is rare. Kresladi contains patient-derived hematopoietic stem cells genetically modified with a lentiviral vector to carry functional copies of the ITGB2 gene, crucial for leukocyte adhesion and infection-fighting. In November 2023, the FDA accepted Rocket’s BLA for Kresladi with priority review, following positive efficacy and safety data from a global Phase I/II study, in which all nine LAD-I patients were alive 12 to 24 months post-infusion. Significant reductions in infection rates were observed compared to pre-treatment levels, along with the resolution of LAD-I–related skin lesions and restoration of wound healing capabilities. Kresladi also holds the FDA’s Regenerative Medicine Advanced Therapy, Rare Pediatric, Fast Track and Orphan Drug designations. The Big Picture This marks Rocket’s inaugural product filing and is a notable advancement for patients, offering an alternative to bone marrow transplant, which carries significant risks and may not be readily accessible. Rocket is enhancing its commercial infrastructure in preparation for a potential product launch, including center initiation, channel strategies, education and payer engagement. Rocket CEO Gaurav Shah told BioSpace the FDA is reallocating reviewers to focus on rare diseases and complex biologics, necessitating changes and a transition period. Shah noted that the delayed decision, based on the FDA’s request for clarity on chemistry, manufacturing and controls information submitted by Rocket, is common among CGTs and does not raise significant concerns beyond ensuring the regulator has sufficient resources for the approval process. Adaptimmune’s afami-cel Indication: Advanced synovial sarcoma Therapy type: T cell receptor therapy Action date: August 4 Adaptimmune is gearing up for the potential launch of its inaugural product in the sarcoma franchise, afami-cel, intended for treating advanced synovial sarcoma, with a PDUFA date set for August 4. Afami-cel received FDA priority review in January. Synovial sarcoma, which makes up 5% to 10% of soft tissue sarcomas, typically affects individuals under 30, with a five-year survival rate of 20% for metastatic cases. Recurrence is frequent, necessitating multiple lines of therapy and potential exhaustion of treatment options. Afami-cel is a single-dose engineered T cell receptor therapy targeting MAGE-A4-posititive tumor cells. The therapy’s clinical data from the SPEARHEAD-1 trial revealed that about 39% of patients experienced clinical responses, with a median response duration of around 12 months. Median overall survival was about 17 months, contrasting with historical data of less than 12 months for those who received two or more prior lines of therapy. Some 70% of responders to afami-cel were alive two years post-treatment. The FDA granted afami-cel Orphan Drug Designation for the treatment of soft tissue sarcomas and Regenerative Medicine Advanced Therapy designation. The Big Picture If approved, afami-cel would become the first approved engineered T cell therapy for this type of cancer. In November 2023, the Investigational New Drug (IND) for another T cell therapy, lete-cel, was transferred from GSK to Adaptimmune for the pivotal IGNYTE-ESO clinical trial, following an interim analysis showing a 40% response rate in synovial sarcoma or myxoid/round cell liposarcoma patients. Adaptimmune CEO Adrian Rawcliffe said that the clinical results from the pivotal trial position lete-cel as a complement to afami-cel, potentially allowing the company’s sarcoma franchise to significantly expand its reach. He noted that leveraging the same commercial infrastructure intended for afami-cel could facilitate the efficient delivery of lete-cel to the market. Afami-cel would become the first engineered T cell therapy for a solid tumor. The franchise, including both afami-cel and lete-cel, “is projected to deliver up to $400 million in U.S. peak year sales,” Rawcliffe said in March. Autolus Therapeutics’ obe-cel Indication: B cell acute lymphoblastic leukemia Therapy type: CAR-T cell therapy Action date: November 16 In accepting Autolus Therapeutics’ BLA for its lead next-generation CAR-T therapy obe-cel for relapsed/refractory adult acute lymphoblastic leukemia (ALL) in January, the FDA set a PDUFA target action date of November 16. Obe-cel, an investigational CD19 CAR-T cell therapy, is designed to enhance clinical activity and safety compared to existing therapies by incorporating a fast target binding off-rate, minimizing T cell activation. In December 2022, Autolus hailed the Phase II FELIX trial as a success, as interim analysis showcased an overall remission rate of 70% for obe-cel in leukemia patients. CAR-T cell concentration peaked and persisted at 75% in peripheral blood after a median of 166.5 days post-infusion. The trial also demonstrated positive safety findings. Obe-cel holds the FDA’s Orphan Drug and Regenerative Medicine Advanced Therapy status. Earlier this month, the company;’s obe-cel marketing application was accepted by the European Medicines Agency. The Big Picture The potential approval of a second cell therapy for solid tumors this year suggests breakthroughs in treating these cancers may be near, Stephen Majors, a spokesperson for the ARM, told BioSpace. There is an “increasing focus on solid tumors,” a previously elusive area for cell and gene therapy, he said. A recent $250 million deal granted BioNTech access to obe-cel, with the partner to aid in the launch and development program expansion and receive royalties based on net sales. Autolus expects obe-cel peak sales to exceed $300 million. Autolus could face competition from Gilead Sciences subsidiary Kite, which in 2021 gained FDA approval for its CAR-T therapy Tecartus, the first such treatment for ALL, achieving a 65% complete remission rate. Ana Mulero is a freelance writer based in Puerto Rico. She can be reached at anacmulero@outlook.com and @anitamulero on X.

BioNTech is enlisting CAR-T biotech Autolus Therapeutics on a partnership aimed at pushing both of their CAR-T programs toward commercialization, with an eye on its new partner’s programs as well as manufacturing capabilities. As part of the wide-ranging agreement, BioNTech will purchase $200 million of Autolus’ shares in a private placement, plus dish out a cash payment of $50 million. In exchange, BioNTech will receive up to mid-single digit royalty on net sales of Autolus’ lead CD19 therapy, obe-cel, which is now under review at the FDA for relapsed/refractory adult B cell acute lymphoblastic leukemia. It will also have an option to get a profit share on Autolus’ other CAR-T therapies, AUTO1/22 and AUTO6NG, in any cancer type, if it co-supports development and commercialization. Autolus will be eligible to receive an option exercise fee, milestone payments and co-funding of development expenses.