Trehalose

Roberto Caricchio has studied lupus for nearly three decades. Hes witnessed steady, but slow, progress in how the frustratingly complex autoimmune disease is understood and treated.The past few years have been different. Promising early research from a team of German scientists has shown that cellular medicines can drive lupus into remission in ways other drugs cant. The findings have sparked a surge in industry interest, leading to the start of about a dozen clinical trials. Many more are on the way.Its unprecedented, said Caricchio, head of UMass Chan Medical Schools rheumatology department. Sometimes I have to sit down and take a deep breath.The latest evidence was on display last week, when leading scientists and physicians in autoimmune disease research gathered in Austria for the European Alliance of Associations for Rheumatologys annual meeting. Georg Schett, whose team at Friedrich Alexander University, Erlangen-Nurnberg in Germany set off the current bonanza, opened the meeting with new results from his teams study. The data show cell therapy continued to benefit almost all treated participants with several autoimmune conditions. Some remissions have lasted three years.Im very excited, said Schett, during a press conference Friday. When we started this three years ago, we did not know where it would go.A bevy of companies, including Kyverna Therapeutics, Cabaletta Bio and Novartis, aim to show that Schetts findings are just the start. At the meeting, they shared updates from clinical studies of these so-called CAR-T therapies in lupus and other autoimmune conditions, like myositis and systemic sclerosis.The new results are from small clinical trials and represent very early steps in what will likely be a yearslong effort to prove these treatments engineered from a patients own cells and proven against certain cancers can rewire the immune systems of people with inflammatory diseases. They hint at the approachs potential, but also the high bar drugmakers will have to clear to succeed.For instance, Cabaletta said that, of the first two people it treated with CAR-T therapy, one no longer needs other drugs and the other is weaning off steroids. Kyverna, which has accumulated the most data of any company in the field so far, reported similar results in six of seven lupus patients given CAR-T, some of whom were treated more than six months ago. Another, with the disease myasthenia gravis, hasnt had evidence of disease or needed other medications for one year following treatment.We are showing that this story about an immune reset is taking some shape and form, said Kyverna CEO Peter Maag, in an interview.Similarly encouraging responses to CAR-T were reported in other tests by Novartis as well as biotechs iCell Gene Therapeuticsand JW Therapeutics.Across these trials, participants have mostly experienced mild forms of the immune and neurological side effects associated with CAR-T a relief to researchers as patients risk tolerance in autoimmune disease is lower than in people with deadly cancers.Before beginning testing in 2021, we were pretty scared by potential safety issues, Schett, who serves on Kyvernas and Cabalettas scientific advisory boards, said on Friday. Now we are much more relaxed.Still, effective autoimmune disease treatments already exist, so the bar is higher to introduce cell therapy. And CAR-T drugs remain costly, complex to manufacture and largely only available at specialized treatment centers. Its unclear whether long-term health issues, such as the secondary malignancies that have been reported in rare cases among cancer patients whove received CAR-T, will also occur in people with autoimmune disease.Cell therapy is very promising, but I'm not sure that I would use it as my first, second or even third option, said Daniel Wallace, chief of rheumatology at City of Hope and Cedars Sinai Medical Center. He isnt involved with any of the companies currently conducting autoimmune cell therapy research.The therapies are only worth it if we can put somebody who has life-threatening organ disease in remission for years, he said.To that end, analysts are watching how well these therapies free people from needing the many immunosuppressive drugs they typically take. At EULAR, Schett revealed one myositis patient relapsed after 18 months of follow-up, while Kyverna said one lupus patient treated with its therapy relapsed after five months. Nine people who received Kyvernas therapy across trials in different diseases, including that lupus patient, are still on some sort of immune medicine. They have either experienced recurrence or have more advanced disease. In the latter case, it may take longer for CAR-T therapy to show benefit, said Chief Medical Officer James Chung.Cabaletta reported some symptom improvement in the two treated lupus and myositis patients, but neither are disease free yet.Wall Street analysts were generally impressed by the results. Jefferies Kelly Shi said Cabalettas data fulfilled the goal of replicating Schetts results. Thomas Smith, of Leerink Partners, noted the majority of patients treated with Kyvernas therapy have had a significant response, and the numbers could improve with time. Yet shares of both companies fell double digits Friday, with Kyvernas stock plummeting by 34%.Kyverna claims the one reported relapse was partly due to the lower dose level the participant received. Maag also noted how, in lupus patients, often multiple things are going on that require therapy. Some investigators prefer to keep their patients on a low dose of an oral steroid and they are allowed to do so in Kyvernas trials. With more time, more patients may eventually stop taking other drugs, Maag said.Ultimately, the goal is to taper people off of steroids completely, he said.We will have side effects, said Cabaletta CEO Steven Nichtberger, on a conference call with analysts on Friday. We will have failure to treat effectively in some patients, and that's fine, as long as what we have is at least as good, if not better, than any other company in the industry.There are still many unanswered questions about autoimmune cell therapy. Caricchio, of UMass, notes the treatments havent been tested in many Black people, who are more likely to have aggressive forms of lupus. He pointed out that people with particularly significant kidney damage, a hallmark of the condition, may not respond as well. And infections observed in testing, while mild so far, bear watching, he said.Personalized cell therapies are also being joined in clinical trials by treatments made from donor cells or natural killer cells, as well as by dual-targeting antibody drugs called T cell engagers. All are seen as more convenient and easier-to-manufacture options that some analysts think could challenge CAR-T therapy. A similar pattern has played out in oncology, where enthusiasm for CAR-T has been tempered by success with other technologies.This is the first CAR-T approach. Its a proof of concept and shows this can work in systemic autoimmunity, said Caricchio. I do truly believe that the next decade will be a life-changing experience for physicians and for patients. '

With a growing number of CAR-T developers having recently shifted focus from cancer to inflammatory diseases, the first early clinical data are starting to emerge. On Friday, Cabaletta Bio reported results from the first two patients treated with its anti-CD19 CAR-T therapy CABA-201 for lupus and myositis, demonstrating what the company called an “emerging clinical benefit” and well-tolerated safety profile. Findings were presented at the European Congress of Rheumatology (EULAR) annual meeting.Cabaletta is investigating CABA-201 in the Phase I/II RESET-SLE study for systemic lupus erythematosus and the Phase I/II RESET-Myositis trial of patients with the muscle-weakening autoimmune disease. The drugmaker noted that as of May 28, one patient has been treated in each study with a single infusion of CABA-201 at 1 x 106 cells/kg, with one month of follow-up in the lupus trial and three months of follow-up in the myositis study.Immune system resetAccording to Cabaletta, complete B-cell depletion was observed within 15 days post-infusion with CABA-201 in both patients, who also demonstrated improvements in specific disease measures. In the myositis study, B-cell repopulation was observed at week 8 in the participant – who is being treated for immune-mediated necrotising myopathy (IMNM) – which the company said suggests a “potential immune system reset.”Cabaletta added that no evidence of cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) was seen in either patient. Meanwhile, both participants discontinued all chronic maintenance therapy or concomitant medications, other than a planned prednisone taper for the lupus patient.David Chang, chief medical officer of Cabaletta, suggested that the data “provide important early validation” of the selected CABA-201 dose to reset the immune system. The therapy is also being studied in Phase I/II trials for systemic sclerosis and generalised myasthenia gravis, with initial data expected in the second half.