Noah Stansfield

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

Articles

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.