Rapcabtagene autoleucel

The clue came, as they often do, from an unexpected source. Some sixteen months ago, a small study of five people in Germany pointed to a new direction for the high-profile field of cell therapy.The study showed a cellular medicine could drive a tough-to-treat form of lupus into remission. While early, the finding suggested a technique used to create powerful cellular treatments for cancer might also work against autoimmune conditions like lupus, too.Its very early days, but its exciting for the field to see this possibility, said cell therapy pioneer and University of Pennsylvania immunologist Carl June, in an interview at the time.The biopharmaceutical industry took note. Since the paper was published, a number of drugmakers have revealed plans to develop cell therapies for lupus, and nearly a dozen are now in clinical testing.Updated results from that German study, presented at a medical meeting in December, indicate they may be right to invest. Among 15 people who had lupus or one of two other autoimmune diseases and hadnt responded to prior treatment, all were in remission after receiving cell therapy. Some responses have lasted two years.Its the tip of the iceberg, but it looks extraordinary, said Andy Plump, Takeda Pharmaceuticals head of research, in a recent interview. The hope is that this can expand to not just other refractory autoimmune diseases, but to more common diseases.Challenges remain. Current cell therapies for cancer are associated with side effects that in rare cases can be fatal, a risk thats easier to accept for people with deadly tumors than those with chronic health conditions. Theyre also complex to produce and administer, and only available at major treatment centers, limiting their potential for wider use. Some believe newer off-the-shelf alternatives may be a better fit.Answers could come within the next few years from clinical trials just getting underway. At least a dozen studies run by startups, biotechnology companies and large pharmaceutical giants are either recruiting participants or soon will be. Heres where the field stands:How is lupus treated now?Lupus is a chronic autoimmune condition that occurs when the body attacks itself. The disease leads to pain and inflammation in many parts of the body, from the skin and joints to internal organs like the kidneys or lungs. About 1.5 million people in the U.S. and 5 million worldwide have a form of the disease, according to the Lupus Foundation of America, a patient advocacy group. For reasons that arent quite clear, many of those affected are women of childbearing age. Researchers arent certain what triggers the disease in the first place, either.Lupus has several types, the most common of which is known as systemic lupus erythematosus, or SLE. It affects multiple organs and can involve a constellation of symptoms, making it tough to diagnose. Lupus characteristic flares arrive unpredictably and can last days or weeks. While most people can manage their disease and live a long life, the condition can result in kidney failure or death from heart-related complications.There is no cure. Available treatments can help manage symptoms and counteract the immune response associated with the disease. They include repurposed anti-inflammatory or immunosuppressive therapies, steroids or antimalarials.More recently, three medicines specifically developed for lupus GSKs Benlysta, Aurinia Pharmaceuticals Lupkynis and AstraZenecas Saphnelo have reached market. Roches cancer drug rituximab is sometimes used off-label as well, despite disappointing clinical results.All have limitations, however. Not everyone responds to treatment and patients can continue to have flare-ups, requiring them to try different treatments. Additionally, drugs that blunt the immune system, like steroids, can leave patients vulnerable to infection.How could cell therapy be used?Six so-called CAR-T cell therapies are approved in the U.S. to treat leukemia, lymphoma and multiple myeloma. When they work, these therapies can lead to long-lasting benefit.Theyre made by genetically modifying a patients immune cells to spot proteins found on the surface of cancerous B cells. These cells, which normally make protective antibodies, are also implicated in an array of autoimmune diseases. In lupus, for example, B cells go haywire and make antibodies that damage healthy tissue.CAR-T therapies wipe out B cells, whether cancerous or not. That effect led Georg Schett and colleagues at the Friedrich Alexander University, Erlangen-Nurnberg, to test CAR-T therapy in people with lupus.Schetts team published a case report in The New England Journal of Medicine in 2021, following up one year later with results in four more study volunteers, which were presented in Nature. They found the drug depleted B cell counts and drove participants disease into remissions that persisted without using other drugs.Notably, treated individuals still responded to vaccines and their levels of infectious disease antibodies largely remained intact, wrote analysts at the investment bank William Blair, in a recent report. Side effects were mild.When B cells did regenerate, disease symptoms didnt return, which the authors suggested could support the idea that CAR-T therapy reboots the immune system.To drugmakers, the findings indicate cellular therapies, if engineered right, could potentially cure some autoimmune diseases.There's a huge potential for patients to really benefit, said Samit Hirawat, the chief medical officer of Bristol Myers Squibb, in a recent interview.Yet its still unclear how long responses will last, or whether people may need to be re-treated later. The results may not be replicated as CAR-T therapies are studied in large groups of people with lupus, either.CAR-T also involves a chemotherapy conditioning regimen to prepare patients for therapy. And treatment can cause serious immune and neurological side effects that, in an autoimmune disease setting, will not be acceptable to patients and physicians, wrote William Blair analysts.More seriously, the Food and Drug Administration recently issued safety warnings for all six available CAR-T therapies, following a review of reports of patients developing secondary malignancies after treatment.Those risks will require developers to mitigate CAR-Ts known safety issues. Companies working on adapting the therapies say their goal is to fine-tune the approach for use in autoimmune diseases.I think the whole industry is asking: how can we work on the benefit-risk profile and the conditioning process so that, ideally, you can [treat patients] earlier and earlier and not wait until they have severe, refractory disease? said Victor Bulto, head of Novartis U.S. division.Which companies are working on cell therapies?About a dozen companies have launched trials testing cell therapies in lupus, according to a federal database. At least another six have received Food and Drug Administration clearance to begin initial studies and could soon follow, while others still have disclosed plans for testing.Two cell therapy leaders, Novartis and Bristol Myers Squibb, started Phase 1 trials last year. Theyre each testing newer versions of the products they brought to market for cancer, tweaking them to cut manufacturing times, boost safety and raise potency.Bristol Myers Hirawat noted how Schetts research suggests developers can deliver benefit in lupus with lower and, theoretically, safer doses than in cancer. Thats partly because there are fewer B cells to target in lupus than there are cancerous cells in lymphoma or leukemia.We don't anticipate, or want to see, the same safety profile as you saw in malignancies, he said.Select lupus cell therapies in federally listed clinical trialsCompanyCell therapyDevelopment phaseTrial numberIndicationKyverna TherapeuticsKYV-101Phase 1NCT05938725Lupus nephritisGracell BiotechnologiesGC012FPhase 1NCT05858684SLENovartisYTB323Phase 1/2NCT05798117SLEBristol Myers SquibbCC-97540Phase 1NCT05869955SLECartesian TherapeuticsDescartes-08Phase 2NCT06038474SLEMiltenyi BiomedicineMB-CART19.1Phase 1/2NCT06189157SLEImmPACT BioIMP-514Phase 1/2NCT06153095SLE and lupus nephritisiCell Gene TherapeuticsBCMA-CD19 cCAR-TPhase 1NCT05474885SLECabaletta BioCABA-201Phase 1/2NCT06121297SLE and lupus nephritisJW TherapeuticsRelma-celPhase 1NCT05765006SLESOURCE: clinicaltrials.gov, companiesAlongside Bristol Myers and Novartis is Kyverna Therapeutics, a well-funded biotech startup that filed for an initial public offering earlier this month. Kyvernas lead program was licensed from the National Institutes of Health and, like that of its larger rivals, targets the protein CD19.Also in testing are Gracell Biotechnologies, which AstraZeneca acquired last year, Cartesian Therapeutics and startups Cabaletta Bio and ImmPACT Bio. Behind them are an array of cell therapy companies that have said they will go after lupus and other autoimmune diseases, like Fate Therapeutics, CRISPR Therapeutics and Autolus Therapeutics.China-based biotechs and academic researchers are investing in lupus research, too. A federal database shows nearly a dozen academic or industry-backed trials underway, including studies run by JW Therapeutics, Shanghai GeneChem and Chongqing Precision Biotech.Some that havent publicly announced trial plans, like Takeda, are interested: Even though we're very far behind, we still think that we have a path, Plump said.One reason: Not everyone is pursuing the same approach. Some companies have cell therapies that target BCMA, another protein on B cells, as well as CD19. Some are looking at different targets. And others are changing out components to boost potency, or are tweaking conditioning regimens.Meanwhile, companies like Artiva Biotherapeutics, Fate, and Sana Biotechnology are trying approaches that rely on the cells of healthy donors. These so-called allogeneic treatments have struggled as cancer therapies. But some developers claim they may have an edge over personalized, or autologous, treatments in autoimmune conditions. Here, they say, the advantages of donor-derived therapies like cheaper production costs or lower rates of side effects will be more important.Autologous cell therapy for autoimmune [disease] is going to be pretty challenging, said Carlo Rizzuto, managing director at Versant Ventures, a venture firm that invested in allogeneic cell therapy developer Century Therapeutics. I do think that allogeneic off-the-shelf approaches, especially the stem cell-based approaches, will have an advantage.Cell therapies could also face competition from newer antibody drugs designed to better deplete B cell counts. Roche and Johnson & Johnson, for instance, have drugs in mid- or late-stage testing for lupus.We will have to see how science evolves across all these modalities and see which one works best for which patients, said Bulto, of Novartis.Select cell therapies for lupus cleared for testing by FDA*CompanyCell therapyDevelopment phaseTrial numberIndicationNkartaNKX019To be confirmedNot yet listedLupus nephritisSana BiotechnologySC291Phase 1Not yet listedLupus nephritisArtiva BiotherapeuticsAB-101To be confirmedNot yet listedSLE and lupus nephritisCentury TherapeuticsCNTY-101Phase 1Not yet listedSLELuminary TherapeuticsLMY-920Phase 1Not yet listedSLEFate TherapeuticsFT-819Phase 1Not yet listedSLE*Describes instances when the FDA has cleared an Investigational New Drug application, but no trial is listed in clinicaltrials.gov database. SOURCE: companiesWhats next?Several clinical trial readouts this year and next could build on Schetts study. The tests underway are enrolling patients with SLE or lupus nephritis, when the condition affects the kidneys. Some developers are recruiting people with other autoimmune conditions as well, which could provide more clues as to how broadly cell therapy might be applied.Kyverna presented early results from a lupus nephritis study last year and is recruiting patients. A fuller readout could come in 2025, according to a federal database. The company is planning to test its treatment in systemic sclerosis, myasthenia gravis and multiple sclerosis, too.Novartis shared preliminary findings last year in a study testing its therapy, YTB323, in SLE. More data are expected in the second half of 2024. Bristol Myers should provide an early look at its programs potential this year, too, and intends to expand into MS, myositis and other conditions.Cabaletta has said it will share results from three patients with lupus or myasthenia gravis in the first half of 2024. ImmPACT and Sana could also report initial data in 2024.Others, such as Fate, Nkarta and CRISPR intend to start dosing patients in 2024. Startups with different approaches, like Luminary Therapeutics, could follow afterwards.Some of these efforts will need to bear fruit for investment to continue at such a torrid pace. CAR-Ts potential in lupus alone can't sustain this massive energy in the industry, Plump said. There are pieces that we're just starting to work through, but it's an area of a lot of excitement. '

LB2102 will mark the first time Novartis has turned the power of its T-Charge platform to a solid-tumor-focused cell therapy. Novartis will give a solid-tumor-focused cell therapy the T-Charge treatment, after paying $100 million upfront to Legend Biosciences for a selection of CAR-T candidates. The therapies in question all target Delta-like ligand protein 3 (DLL3), including an autologous CAR-T dubbed LB2102 that Legend has taken into the clinic for lung cancer. What makes this deal especially noteworthy is Novartis’ decision to incorporate its T-Charge platform in the manufacturing process of these therapies. The T-Charge process involves a significant portion of CAR T-cell expansion taking place within the patient’s body. By minimizing the time the cells spend outside the body (ex vivo), it aims to preserve naive and stem cell memory T cells. According to the theory, this preservation may result in better responses, improved long-term outcomes and a reduced risk of severe adverse events. Last year, Jennifer Brogdon, Ph.D., head of cell therapy research in the Department of Exploratory Immuno-Oncology of the Novartis Institutes for BioMedical Research, told Fierce Biotech that CAR-T-focused biotechs had already been in contact with the Swiss pharma to explore the possibility of giving their own candidates the T-Charge treatment. LB2102 will mark not only the first time Novartis has turned the power of its T-Charge platform onto an externally-developed CAR-T but also the first time it has been used on a solid-tumor-focused cell therapy, the Big Pharma said. Legend will oversee a phase 1 trial of LB2102 in the U.S., before Novartis takes over all further development. "We have explored CAR-T in solid tumors previously and believe that our T-Charge platform coupled with Legend Biotech’s unique CAR design may add a level of potency and persistence needed to provide transformative benefit for patients," Brogdon told Fierce Biotech via email this morning. Beyond the hefty $100 million upfront payment, the New Jersey-based biotech is also in line for over $1 billion in potential milestone payments as well as tiered royalties. “We believe LB2102 has an innovative CAR design and armor mechanism that increases its anti-tumor activity,” Legend’s chief scientific officer Guowei Fang, Ph.D., said in the release. “We are excited that a major pharmaceutical company with deep roots in oncology and cell therapy has chosen to further this product candidate in the clinic.” Novartis already has two homegrown CAR-T therapies in the clinic that were produced by the T-Charge platform. Rapcabtagene autoleucel, also known as YTB323, has been shown to produce a 63% complete response rate after three months among 26 patients with relapsed/refractory diffuse large B-cell lymphoma in a phase 1 trial. The other asset, PHE885, has demonstrated a 96% overall response rate among the 23 patients with relapsed/refractory multiple myeloma. Since then, Novartis has remained loyal to the platform’s potential. T-Charge can only be used for autologous therapies, and Novartis has so far resisted the hype around so-called "off-the-shelf" CAR-Ts.