Noah Stansfield

In recent years, cell therapy has begun integrating into the clinical trial landscape for autoimmune diseases. The shift, which began with an early push in lupus, has since expanded into early programs in several indications, including myasthenia gravis, multiple sclerosis, systemic sclerosis, myositis, stiff person syndrome, and others.

Thus far, no cell therapies have been approved for treating autoimmune diseases – or even entered phase 3 trials for such indications – but nonetheless, the possibility of curative-type therapies has generated great excitement in the field. Chimeric antigen receptor (CAR) T-cell therapies, for example, are able to target and eliminate B-cells, and are thus a promising mode of treatment for B-cell-driven autoimmune diseases. Years of experience with CAR-T therapy in oncology and long-term data supporting its durability and efficacy are supporting the move into autoimmune disease.

Companies leading the charge to bring cell therapy to autoimmune disease include 

 one of the first companies to investigate CAR-T therapy for lupus; 

, all of which have cell therapies in phase 2 trials for autoimmune diseases. These programs have produced life-changing results in many patients and disappointing results in others. As a wide array of other companies have launched and continue to launch phase 1 trials, experts in the field have pointed out that while cell therapies may be curative for certain patients, they will certainly not be for all.

“[Cell therapy] generates an enormous amount of hype. Some of that is justified, but we have to see the long-term data. We’ve had similar levels of excitement in the past, and long-term data sort of tempered our expectations. I don't want to seem like a denier with this, but I think we just need to sort of take it in the context of where it is. It will probably be a very effective therapy for a small portion of treatment resistant patients. How much that's generalized across the disease, we'll see. But we'll get the answer eventually,” Jack Arnold, a clinical research fellow and clinician treating lupus at Leeds Centre of Rheumatic and Musculoskeletal Medicine told 

Supporting the move into autoimmune disease now are years of experience with CAR-T therapy in oncology and long-term data supporting its durability and efficacy. 

spoke with experts, advocates, and companies engaged in the cell therapy autoimmune scene to learn more about what the field learned from hematology/oncology, continuing progress in the field, and unlocking cell therapy’s full potential for autoimmune disease in the rheumatological field.

Lessons Learned With Cell Therapy for Autoimmune Disease

Lupus, including systemic lupus erythematosus (SLE) and lupus nephritis (LN), was one of the first areas of investigation for cell therapies such as CAR-T therapy. Lupus Research Alliance and its clinical affiliate Lupus Therapeutics have helped to bring a number of cell therapies to the clinical stage through its Lupus Clinical Investigators Network (LuCIN) and partnerships with companies making progress in this area including Bristol Myers Squibb, Cabaletta, Caribou Bio, Nkarta, and others.

 As such, they are a key player in the space with a unique view on cell therapy’s potential and progress for autoimmune diseases.

Stacie Bell, PhD, executive vice president of Lupus Therapeutics, sat down with 

 during the American College of Rheumatology (ACR) 2024 Convergence in November to discuss the changing field of autoimmune disease.

ACR Bell Video: This Year in Medicine

“When the first major publication came out in November 2022

, for CAR T and the involvement with the lupus community, it was like something I'd never thought I would ever see in my career, you know, to see people basically have complete disease remission, not only relief of symptoms, but actually their lived disease course,” Bell said.

Bell discussed the growth of investigations into cell therapy since their initial introduction and how groups such as Lupus Research Alliance, Lupus Therapeutics, and the FDA have worked together since then to facilitate research in the space. She emphasized the importance of taking learnings from oncological experience with cell therapy and translating them to the rheumatology field, as well as the importance of supporting patient education and informed consent.

“...Translating the love language between hematology and oncology and the things that they've experienced into the rheumatology community and how that relates to those living with autoimmune disease is an important element,” Bell said.

Bell also reminded viewers that no one therapy is 100% effective for everyone and cell therapy is no exception, although it has acted as a curative therapy for a number of patients with lupus in the follow-up done thus far.

Future Goals for CAR-T in Autoimmune Disease

Schett Cell Therapy Video: This Year in Medicine

The first-in-human clinical study of CAR-T in autoimmune disease began around 3 years ago. At the time, not much was known about the potential safety and efficacy of CAR-T in patients with autoimmune disease, and as such the trial was carried out in patients with severe disease who had generally exhausted other treatment in options. Notably, an autologous CAR-T product was used, with the standard lengthy manufacturing time for such products.

Since this and other early trials have shown some promising signs of long-term safety and efficacy, experts are now thinking about the next steps to optimize the safety, efficacy, and accessibility of CAR-T for autoimmune disease, as well as ways to broaden eligibility. In December 2024, CGTLive spoke with Georg Schett, MD, vice president of research and chair of internal medicine at the University of Erlangen – Nuremberg, who served as an investigator on the earliest CAR-T trial for autoimmune disease. Schett discussed what has been learned from these early efforts, pointing out that the risk of high grade cytokine release syndrome and neurotoxicity was shown to be low, thus suggesting a strong safety profile for the modality in autoimmune disease. Schett also discussed key areas of innovation that may be a focus of future clinical research for CAR-T in autoimmune disease. For example, he discussed the technically challenging process of manufacturing autologous CAR T-cells and the need to streamline and shorten this process in order to utilize fewer resources and less space. He also spoke about the potential of using hypoimmunogenic allogeneic CAR T-cells in order to further improve scalability and time-to-treatment. 

Schett also noted that if CAR-T in autoimmune disease continues to demonstrate safety, it may eventually be able to be used as an earlier-line treatment in patients with severe autoimmune disease. He emphasized the potential benefits of CAR-T over other options in this scenario.
“Imagine you can abrogate the whole disease with a single infusion and do this early and prevent organ damage,” Schett told CGTLive. “I think that concept is very appealing. At the moment, I think we are not there because [earlier on] data on safety were basically not present, but now [those data] are actually coming up more and more. So at the beginning, actually, the therapy was limited to very resistant patients, but I think the concept to move earlier, if safety data look good, which they do so far, is extremely appealing to prevent organ damage.”
Schett also touched on the fact that most CAR-T trials for autoimmune disease are still in phase 1, but that in the future more CAR-T products will be brought into phase 2 and phase 3 studies. Although, he highlighted that recruiting patients for CAR-T trials poses some unique challenges compared to other modalities, and that even phase 3 trials for CAR-T in autoimmune disease may continue to include relatively lower numbers of patients compared to more conventional treatments like antibody therapies.

The Role of Established Pharmaceutical Companies in Bringing Cell Therapy to Autoimmune Disease

Van Eickels Cell Therapy in Autoimmune Disease

The earliest efforts exploring the use of CAR-T in autoimmune disease were carried out by academic institutions and small biotech companies. As the technology has shown promise, however, more and more companies have begun to show interest in launching trials for CAR-T products in autoimmune disease. Among these are large, well-established pharmaceutical companies, with previous experience developing and commercializing CAR-T in oncology and substantial resources to dedicate to new research in autoimmune disease. One such company is Bristol Myers Squibb (BMS), which already has an FDA-approved CD19-directed CAR-T product for oncology indications and is now also exploring the potential of CD19-directed CAR-T in autoimmune diseases including lupus, systemic sclerosis, idiopathic inflammatory myopathies, and multiple sclerosis. CD19 NEX-T, the company’s lead CAR-T candidate for autoimmune disease, is currently being evaluated in 2 clinical trials, data from one of which were presented at the 2024 ACR Convergence.

In the lead up to the conference, CGTLive spoke with Daniela van Eickels, MD, PhD, MPH, the vice president and head of medical affairs for BMS’s Cell Therapy Organization, about the company's plans for developing CAR-T products in autoimmune disease. Notably, BMS has formed the Autoimmunity Cell Therapy Network (ACTioN) Steering Committee in order to foster collaboration and facilitate the advancement of investigational candidates.

“ACTioN is a BMS initiative where we are providing a platform that should enable deep connectivity and the building of a network between the different stakeholders that are involved in cellular therapies and how to bring them into the field of autoimmunity,” van Eickels 

. “We understand from our past that the patient journey will touch on different disciplines, and it is very important that this is a seamless connectivity along the patient journey.”

An important factor in the application of CAR-T to autoimmune disease has been the need for collaboration at the level of individuals between oncology specialists who have practical experience using CAR-T therapies in the clinic and autoimmune disease specialists who are disease area experts. Van Eickels also discussed more generally how this concept applies on the institutional level, as well.

“I think, generally speaking, we are very, very excited about the concept of deep immune reset,” van Eickels told CGTLive. “It's something that we are driving with utmost urgency, knowing that there are currently patients that are really suboptimally treated. We hope that by accelerating [this approach] we will really bring a real value to those patients. This is something that we really need to execute together with scientific experts, clinicians, and the patients that go on our studies. This is where we see the biggest value of an established player like BMS bringing that all together and also using our expertise in cellular therapies from other areas.”

Translating CAR-T Therapy from Oncology to Autoimmune Disease

Zachary Roberts NDA Plans ACR 2024

Another, smaller company that has begun to integrate rheumatological targets into an oncology-focused pipeline is Allogene Therapeutics, with its ALLO-329, an allogeneic CD19/CD70 dual CAR-T. Allogene presented preclinical data from the program at the ACR Convergence that demonstrated the therapy’s dual targeting and elimination of targeted B-cells in mouse models.

Zachary Roberts, MD, PhD, executive vice president of Research & Development and Chief Medical Officer of Allogene, spoke with HCPLive during the ACR Convergence and shared that the company plans to file an investigational new drug (IND) application for the therapy in early 2025. He also discussed Allogene’s experience developing cell therapies for oncology and now rheumatology.

“We are very good at dealing with toxicities that we expect to see with CAR-T,” Roberts said. “...We have direct clinical experience with that CAR molecule in patients with oncologic disease... we have encountered several of the same kind of toxicity profiles that others have seen with CD19 and BCMA CARTs. And so, we feel very prepared.”

Allogene’s pipeline is still comprised mostly of oncological allogeneic CAR-T therapies, with lead candidate cemacabtagene ansegedleucel currently in phase 2 trials for large B-cell lymphoma.

Roberts discussed how Allogene and other companies investigating CAR-T for autoimmune disease, most of which began their pipelines with oncologic indications, are able to take their experience developing, investigating, and managing CAR-T and its treatment in this new group of patients. Of course, there are many differences in patients with malignancies compared with autoimmune diseases, and approaches will need to be adapted and tailored to these patients.

“Rheumatologists are not oncologists, and autoimmune patients are not cancer patients. And so, you really have to come at this with a point of view that is tailored to the target audience... We plan to... further reduce the intensity of the lymphodepletion and ideally, we'll be able to get rid of it all together. So, this product design really was founded on this idea of tailoring this towards a group of physicians and a group of patients whose needs are different than oncologists and patients with malignant disease,” Roberts said.

Further commenting on the interplay between cell therapy for cancers and autoimmune diseases, Roberts mused that CAR-T's quick expansion in the rheumatological field feels the same as CAR-T's initial launch in the oncology field. He shared his excitement over what he believes will be an exciting new couple of years for the field.

The field of CAR-T for autoimmune disease has made substantial progress over the past few years. Following promising early results from academic institution-led clinical research in lupus, biotech companies began jumping into the race to bring CAR-T to autoimmune diseases beginning in late 2022, with a flurry of new trials being launched by companies from that point onward 

Now, in 2024, as this trend continues, and companies such as Cabaletta and Cartesian have begun to announce positive early efficacy and safety 

, some experts are beginning to think about the longer-term future.

The possibility of bringing CAR-T into earlier lines of treatment for autoimmune disease, the need to improve manufacturing processes, the potential of allogeneic approaches, and benefits of collaboration and knowledge-sharing across disciplines and would-be competitors are all relevant considerations on the horizon now. With that in mind, the need for vigilance and cautious optimism also remains, as the ultimate proportion of patients with autoimmune diseases who may actually stand to benefit from cell therapy continues to be uncertain. Regardless of how things play out, the field will likely need to make adjustments and accommodations as the landscape develops.

“We have the deep belief that this is a true innovation so it will require some adaptations in the healthcare environment,” van Eickels additionally told CGTLive. “We are trying to enable early conversations on what needs to change and what needs to happen, so that these new therapies can actually really benefit a wide array of patients if the data prove that to be beneficial.”

Mackensen, A., Müller, F., Mougiakakos, D. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. 

28, 2124–2132 (2022). doi: 10.1038/s41591-022-02017-5

Current Collaborations and Initiatives. Lupus Therapeutics. 2024. Accessed December 24, 2024. https://lupustherapeutics.org/current-partner-studies/

Taking ACTioN. Bristol Myers Squibb. Website. Accessed December 24, 2024. 

https://www.bms.com/researchers-and-partners/areas-of-focus/our-research-in-immunology/taking-action.html

Allogene Therapeutics to Present Pre-Clinical Data Highlighting the Potential of ALLO-329, an Allogeneic CD19/CD70 Dual CAR T for the Treatment of Autoimmune Diseases, at the American College of Rheumatology (ACR) Convergence. Allogene Therapeutics. September 26, 2024. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-present-pre-clinical-data-highlighting

Cabaletta Bio presents positive clinical safety and efficacy data on CABA-201 at ACR Convergence 2024. News release. Cabaletta Bio, Inc. November 18, 2024. Accessed December 24, 2024. 

https://www.cabalettabio.com/news-media/press-releases/detail/119/cabaletta-bio-presents-positive-clinical-safety-and

Cartesian Therapeutics announces positive updated results from phase 2b trial of Descartes-08 in participants with myasthenia gravis and outlines design of planned phase 3 trial. News release. Cartesian Therapeutics, Inc. December 3, 2024. Accessed December 24, 2024. 

https://ir.cartesiantherapeutics.com/news-releases/news-release-details/cartesian-therapeutics-announces-positive-updated-results-phase

Articles

Cell therapy is emerging in clinical trials for autoimmune diseases, with CAR-T therapies showing promise, particularly in B-cell-driven conditions. Despite no approvals or phase 3 trials yet, the potential for curative treatments is generating excitement. Companies like Kyverna Therapeutics and Bristol Myers Squibb are leading phase 2 trials, though results vary. Experts emphasize the need for long-term data and caution against overhyping. Future goals include optimizing CAR-T safety, efficacy, and accessibility, with potential earlier-line use. Collaboration between oncology and autoimmune specialists is crucial for advancing these therapies.

Cell therapy, particularly CAR-T, is expanding into autoimmune diseases like lupus and multiple sclerosis. While promising, safety, efficacy, and broad applicability remain uncertain.

Leveling Up: Cell Therapy Research Expands Horizons in Autoimmune Disease

In continuation of a trend that initially got rolling at the tail-end of last year, 2023 saw a record number of investigational chimeric antigen receptor T-cell (CAR-T) therapies enter clinical trials for the treatment of autoimmune diseases.

 These newly initiated studies, many of which are recruiting patients with 

 and lupus nephritis (LN), seek to push the boundaries of a therapeutic modality that originally proved itself in the field of oncology.

Currently, there are 6 FDA-approved CAR-T therapies, all of which are currently indicated exclusively for the treatment of hematological malignancies like large B-cell lymphoma and multiple myeloma.

 When it comes to B-cell malignancies, CAR-T therapies function by targeting antigens typically found on B-cells and releasing cytokines to destroy them; the intention is to wipe out cancerous B-cells, though healthy B-cells will inevitably be destroyed as well. This mode of action thus has potential to be repurposed for the treatment of B-cell driven autoimmune diseases like SLE.

In November 2022, Kyverna Therapeutics announced that KYV-101, its investigational autologous CD19-directed CAR-T therapy, had been cleared for the phase 1 KYSA-1 trial (NCT05938725) clinical trial in patients with LN. Throughout 2023, several other companies reached the same milestone with their CAR-T and other cell therapy products for lupus. Among these were investigational new drug application clearances for Cabaletta Bio’s CABA-201, a CD19-directed CAR-T, in SLE and LN; ImmPACT Bio’s IMPT-514, a bispecific CD19/CD20-directed CAR-T in active, refractory SLE (rSLE); Artiva Biotherapeutics’ AlloNK (AB-101), an unengineered allogeneic natural killer (NK) cell therapy forming part of a combination therapy with antiCD20 monoclonal antibody rituximab, in SLE and active LN; Nkarta’s NKX019, an allogeneic CD19-directed CAR NK cell therapy, in LN; and Gracell Biotechnologies’ GC012F, an autologous BCMA/CD19-directed CAR-T, in rSLE.

“Despite advances over the last few decades, treatment options for SLE remain inadequate,” David J. Chang, MD, the chief medical officer of Cabaletta Bio said in a May 2023 statement.

 “There are currently no curative options available that achieve durable disease remission. Existing therapies typically result in general immunosuppression, require chronic administration, and are often administered in conjunction with steroids and other immunosuppressive medications to reduce disease burden, which can leave patients with continued disease activity, treatment-associated side effects, and impaired quality of life.”

Several of the aforementioned therapeutics have been previously evaluated for the treatment of hematological malignancies or use constructs similar to those previously used for that purpose.

 Although most of these companies initially made the leap to autoimmune disease clinical trials with SLE and/or LN, several of them have now expanded their investigations into other autoimmune diseases. For example, KYV-101 was subsequently cleared by the FDA for trials in diffuse cutaneous systemic sclerosis (scleroderma) and myasthenia gravis, CABA-201 was cleared for trials in active idiopathic inflammatory myopathy (also referred to as myositis), systemic sclerosis, and generalized myasthenia gravis.

In response to this rising interest in cell therapy for autoimmune diseases, 2023 also saw the birth of a new medical conference dedicated specifically to the topic: the inaugural Cell Therapy for Autoimmune Disease Summit, held November 28-30 in Philadelphia, Pennsylvania. 

™ attended the emerging conference in order to speak to experts in the space and learn more about the promise and challenges presented by this novel treatment modality for autoimmune disease. During the course of the meeting several themes emerged.

One of these motifs was the need for an increased focus on safety during autoimmune disease trials in comparison to trials that evaluate CAR-T for patients with late-stage cancers. “I think [an] aspect that physicians will find very important is the safety of these cell therapies since that has become a big question as a whole for cancer,” Tiffany Chen, PhD, the vice president of discovery at GentiBio, told 

“The risk tolerance is just better there because patients have cancer—they have limited time—and so they're willing to take these,” Chen continued. “[For] autoimmune disease patients, that might not necessarily be the case. As such, ensuring there's really good safety in these cell therapies is very important.”

Another important theme emphasized by multiple attendees at the conference was the increased need for collaboration between different parties during the development of these therapeutics. The input of oncologists, who have experience treating patients with the use of CAR-T, and input from doctors who treat patients with autoimmune diseases but lack experience with CAR-T, will both be essential for biotech companies, academic institutions, and treatment centers to consider during the early stages of this field’s development.

“We're very used to working within a group of oncologists, hematologists, and blood and marrow transplant physicians to treat patients with cancer,” David Porter, MD, the director of cell therapy and transplant at Penn Medicine, told 

at CTADS. “But historically, our cell therapy group doesn't necessarily work with the physicians and their staff that treat autoimmune diseases: the rheumatologists, the nephrologists, dermatologists, neurologists, etc. We certainly have relationships—we know each other, and we share patients back and forth—but we don't have the same experience having a joint program.”

“I think it’s a very exciting time seeing cellular therapies, in particular CAR T-cells, transition from the oncology setting into the autoimmune setting,” Tom Van Blarcom, PhD, the senior vice president and head of research at Kyverna Therapeutics, told 

 in a separate interview at the conference. “One of the main things we're learning is that this [effort] has to be a really big partnership between oncology physicians who've been treating patients with CAR T-cells and these new physicians in rheumatology and neurology who have less or little-to-no experience with cellular therapies. Bringing both those communities together, as well as companies like [Kyverna] who are trying to develop these drugs, is a huge 3-way partnership...”

Peter A. Merkel, MD, MPH, the chief of the Division of Rheumatology and a professor of medicine and professor of epidemiology at Penn Medicine, concluded his interview with 

at CTADS with a word of cautious optimism for the future of this emerging field. “I think we are certainly hopeful that some forms of cell-based therapy will help some forms of autoimmune disease and hopefully substantially,” Merkel told 

"We need to do this right, we need to move it forward, but I think we're very enthused,” Merkel continued. “We need to see how this plays out and this will take some time. I also think patients will be interested. We need to remember that the goal is to help patients and that's what we're trying to do. We want to be able to raise the bar and help our patients even more than we've been able to so far.”

Kyverna Therapeutics announces FDA clearance of IND for KYV-101, a novel fully human CD19 CAR T-cell therapy to treat lupus nephritis. News release. Kyverna Therapeutics. November 11, 2022. Accessed December 20, 2023. https://kyvernatx.com/press-releases/kyverna-therapeutics-announces-fda-clearance-of-ind-for-kyv-101-a-novel-fully-human-cd19-car-t-cell-therapy-to-treat-lupus-nephritis/

Approved Cellular and Gene Therapy Products. FDA. Website. December 8, 2023. Accessed December 20, 2023. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products

Kyverna Therapeutics submits IND for novel CAR T-cell therapy to treat lupus nephritis. News release. Kyverna Therapeutics. October 18, 2022. Accessed December 20, 2023. https://kyvernatx.com/press-releases/kyverna-therapeutics-submits-ind-for-novel-car-t-cell-therapy-to-treat-lupus-nephritis/

Cabaletta Bio receives FDA clearance of IND application for CABA-201 for treatment of systemic lupus erythematosus. News release. Cabaletta Bio, Inc. March 31, 2023. Accessed December 20, 2023. https://www.cabalettabio.com/news-media/press-releases/detail/81/cabaletta-bio-receives-fda-clearance-of-ind-application-for

ImmPACT Bio announces FDA clearance of IND application for bispecific CD19/CD20 CAR T therapy IMPT-514 for the treatment of refractory systemic lupus erythematosus. News release. ImmPACT Bio USA, Inc. August 15, 2023. Accessed December 20, 2023. https://immpact-bio.com/news-and-events/immpact-bio-announces-fda-clearance-of-ind-application-for-bispecific-cd19-cd20-car-t-therapy-impt-514-for-the-treatment-of-refractory-systemic-lupus-erythematosus/

Artiva Biotherapeutics announces FDA clearance of IND for AlloNK cell therapy candidate in combination with rituximab in lupus nephritis. News release. Artiva Biotherapeutics, Inc. August 16, 2023. Accessed December 20, 2023. https://www.artivabio.com/artiva-biotherapeutics-announces-fda-clearance-of-ind-for-allonk-cell-therapy-candidate-in-combination-with-rituximab-in-lupus-nephritis/

Nkarta receives FDA clearance of IND application for NKX019 in lupus nephritis. News release. Nkarta Inc. October 17, 2023. Accessed December 20, 2023. https://ir.nkartatx.com/news-releases/news-release-details/nkarta-receives-fda-clearance-ind-application-nkx019-lupus

Gracell Biotechnologies announces FDA clearance of IND application for phase 1/2 clinical trial of FasTCAR-T GC012F for the treatment of refractory systemic lupus erythematosus. News release. Gracell Biotechnologies Inc. November 27, 2023. Accessed December 20, 2023. https://ir.gracellbio.com/news-releases/news-release-details/gracell-biotechnologies-announces-fda-clearance-ind-0

Cabaletta Bio receives FDA fast track designation for CABA-201. News release. Cabaletta Bio, Inc. May 1, 2023. Accessed December 20, 2023. https://www.cabalettabio.com/news-media/press-releases/detail/84/cabaletta-bio-receives-fda-fast-track-designation-for

Kyverna Therapeutics announces FDA clearance of IND for KYV-101, a novel fully human CD19 CAR T-cell therapy to treat scleroderma. News release. Kyverna Therapeutics. October 11, 2023. Accessed December 20, 2023. https://www.prnewswire.com/news-releases/kyverna-therapeutics-announces-fda-clearance-of-ind-for-kyv-101-a-novel-fully-human-cd19-car-t-cell-therapy-to-treat-scleroderma-301953561.html

Kyverna Therapeutics announces FDA Clearance of phase 2 IND for KYV-101, a fully human CD19 CAR T-cell therapy to treat Myasthenia Gravis. News release. Kyverna Therapeutics. November 13, 2023. Accessed December 20, 2023. https://www.prnewswire.com/news-releases/kyverna-therapeutics-announces-fda-clearance-of-phase-2-ind-for-kyv-101-a-fully-human-cd19-car-t-cell-therapy-to-treat-myasthenia-gravis-301986135.html

Cabaletta Bio receives FDA clearance of IND application for CABA-201 for treatment of myositis. News release. Cabaletta Bio, Inc. May 16, 2023. Accessed December 20, 2023. https://www.cabalettabio.com/news-media/press-releases/detail/87/cabaletta-bio-receives-fda-clearance-of-ind-application-for

Cabaletta Bio receives FDA clearance of IND application for treatment of systemic sclerosis with CABA-201. News release. Cabaletta Bio, Inc. November 6, 2023. Accessed December 20, 2023. https://www.cabalettabio.com/news-media/press-releases/detail/97/cabaletta-bio-receives-fda-clearance-of-ind-application-for

Cabaletta Bio receives FDA clearance of CABA-201 IND application for treatment of generalized myasthenia gravis. News release. Cabaletta Bio, Inc. November 6, 2023. Accessed December 20, 2023. https://www.cabalettabio.com/news-media/press-releases/detail/99/cabaletta-bio-receives-fda-clearance-of-caba-201-ind

Throughout 2023, interest in the application of CAR-T and other cell therapies to autoimmune disease skyrocketed, with a multitude of clinical trials being initiated by various companies.

The Lupus Approach: CAR-T Begins the Jump from Blood Cancers to Autoimmune Disease

This article was originally published on CGTLive.

A draft report was released from the Institute for Clinical and Economic Review (ICER) comparing clinical benefit and cost effectiveness of CSL’s etranacogene dezaparvovec (EtranaDez), an investigational gene therapy intended for the treatment of hemophilia B, and BioMarin’s valoctocogene roxaparvovec (val-rox; BMN-270) gene therapy for the treatment of hemophilia A, to current standards of care.

EtranaDez was examined alongside factor IX prophylaxis, and the report noted an initial positive success rate for EtranaDez for patients who receive a full dose and do not have high antibody titers to the adenovirus vector. It was additionally noted that bleeding rates of all types were lower in years 4 and 5 of long-term follow-up for the initial cohort of treated patients (n=5).

“It is not yet clear that the initial increase in factor IX levels will be maintained for decades, though the results are encouraging...,” the report concluded. “Because of the uncontrolled study design, small numbers of patients studied and relatively short follow-up, there is still considerable uncertainty about the long-term net benefits of EtranaDez compared with factor IX prophylaxis. In particular, there are uncertainties about the long-term impact of the therapy on liver function and the risk for hepatocellular carcinoma. However, the short-term results clearly favor EtranaDez and the harms seem relatively modest."

Val-rox was compared with factor VIII prophylaxis. It was acknowledged that patients in the GENEr8-1 trial (NCT03370913) experienced a relative risk reduction of 84% for treated joint bleeds and 85% for treated bleeds compared with baseline annualized bleeding rates (ABR) during the 6-month run-in phase on factor VIII prophylaxis. 

However, the report highlighted that efficacy of val-rox for individual patients varies, with some patients getting a significant benefit while others receive minimal benefit or no benefit. No direct comparison between val-rox and emicizumab prophylaxis, which is in the process of replacing factor VIII prophylaxis as a standard of care, could be made due to the lack of head to head data.

“Indirect evidence suggests that the short-term reduction in bleeding rates compared with factor prophylaxis with valoctocogeneroxaparvovec is at least as great as that observed with emicizumab compared with factor prophylaxis,” the report stated. 

“However, differences in the patient populations studied in the trials could be responsible for the observed benefits. Furthermore, there are clear initial adverse events with valoctocogene roxaparvovec (high risk of elevated liver enzymes requiring prolonged corticosteroid therapy)… Finally, as factor levels have been observed to decline over time, the benefits of valoctocogene roxaparvovec could be relatively short-lived. The lack of direct data comparing [val-rox and Emicizumab], the small number of treated patients, and the modest long-term follow-up leave considerable uncertainty about the net health benefits," according to the report.

A substantial benefit noted for both gene therapies is that they are delivered as a single-dose, reducing the burden for patients who currently require dosing with current standards of care monthly or multiple times weekly. It was also concluded that both gene therapies are associated with large cost savings compared with standards of care. However, in a model of a capped cost savings scenario, val-rox was not determined to be cost effective, while EtranaDez was.

EtranaDez’s biologics license application (BLA) was 

 in May of 2022, with a projected PDUFA date in November 2022. The BLA is supported by positive data from the pivotal phase 3 HOPE-B trial (NCT03569891), which met its primary end point of reduction in annualized bleeding rate (ABR) post-treatment compared with baseline FIX prophylactic therapy. 

Previous data showed that mean FIX activity was 39.0 IU/dL (standard deviation ±18.7; minimum 8.2, maximum 97.1) at 6 months post-treatment and 36.9 IU/dL (±21.4; 4.5, 122.9) at 18 months. Among participants who received a full dose of EtranaDez, FIX prophylaxis was discontinued by all whose AAV5 NAbs were undetected or who had pre-dosing NAbs up to a titer of 678, constituting an overall 97% reduction in mean unadjusted annualized FIX consumption. The 52-week adjusted ABR for all bleeds was reduced by 64% (

 = .0002) from 4.19 during the ≥ 6-month lead-in period to 1.51 during months 7-18.

Val-rox has been approved in the European Union and is expected to begin commercial sales before the end of 2022, but it remains an investigational therapy in the United States. The approval in the EU was supported by results from GENEr8-1, which were published earlier this year in the 

, demonstrating a statistically significant increase in mean factor VIII activity level at weeks 49 through 52 (41.9 IU per deciliter; 95% CI, 34.1-49.7; 

 <.001) as well as a 98.6% and 83.8% decrease in rates of factor VIII concentrate use and treated bleeding after week 4, respectively (

All participants experienced at least 1 adverse event (AE), with 16.4% experiencing a serious AE. Elevations in alanine aminotransferase levels occurred in 85.8% of participants, with other common AEs including headache, nausea, and elevations in aspartate aminotransferase levels. BioMarin intends to re-submit a BLA to the FDA for val-rox before the end of September 2022. A BLA was previously 

rejected in August 2020 with requests for 2-year follow-up data

 of B-cell acute lymphoblastic leukemia in a patient who received val-rox.

"BioMarin is pleased that ICER recognizes the potentially transformative impact of Roctavian as possibly the first gene therapy treatment for severe hemophilia A, and potential to not only deliver profound patient benefit, but also potential long-term healthcare savings," Jeff Ajer, executive vice president, chief commercial officer, BioMarin, said in a statement regarding the new ICER draft report.

A draft report released from the Institute for Clinical and Economic Review (ICER) compared the benefits of etranacogene dezaparvovec (EtranaDez) and valoctocogene roxaparvovec (val-rox) to current treatments.