Data Roundup: November 2024 Features Updates for CAR-T in Renal Cell Carcinoma, Gene Therapy in Danon Disease, and More

Last month, November 2024, the CGTLive® team was diligently tracking the latest data readouts and published literature on cell and gene therapies within oncology, neurology, rare diseases, and more.

As more and more innovative therapies enter the clinical trial field, more data is accrued every month, buoying excitement in the field and sometimes making or breaking the fates of small biotech companies. Last month delivered data updates for an adeno-associated virus (AAV) vector-based gene therapy for Danon disease, an allogeneic chimeric antigen receptor T-cell (CAR-T) therapy for renal cell carcinoma (RCC), and more. Our team has highlighted these below.

Click the read more buttons for more details and information about each update.

Neurogene’s Rett Syndrome Gene Therapy NGN-401 Demonstrates Efficacy in Low-Dose Cohort, But Serious Adverse Event in High-Dose Group Raises Concerns

November 13, 2024 - Neurogene’s NGN-401, an investigational AAV vector-based gene therapy intended to treat Rett syndrome, has generated positive efficacy results in the low-dose cohort of aphase 1/2 pediatric clinical trial (NCT05898620), but an emerging treatment-related serious adverse event (SAE) was reported in a patient treated in the study’s high-dose cohort.

The low-dose cohort treated patients at a dose of 1×10¹⁵ total vector genomes (vg) of NGN-401 and the high-dose cohort treated patients at dose of 3x10¹⁵ vg. As of an October 17, 2024, data cut-off, 5 patients had received the low dose and 2 patients had received the high dose.

In the first 4 patients treated in the low-dose group, whose ages ranged from 4 to 7 years and who were assessed at 3, 9, 12, or 15 months posttreatment, all participants obtained a clinician-rated Clinical Global Impression Scale of Improvement score of 2 compared to baseline, constituting a rating of “much improved”. In addition, the patients improved from 28% to 52% from baseline on the caregiver-completed Rett Syndrome Behavior Questionnaire. Neurogene noted that the participants gained hand function/fine motor, language/communication, and/or ambulation/gross motor skills or developmental milestones, including complex skills rarely learned or relearned in the patient population represented.

Allogene’s CAR-T ALLO-316 Demonstrates Ability to Produce Responses in Renal Cell Carcinoma, but Safety Data Includes 3 On-Study Deaths

November 15, 2024 - Allogene Therapeutics’ ALLO-316, an allogeneic CD70-directed CAR-T therapy, has produced responses in patients with advanced or metastatic renal cell carcinoma (RCC) treated in the phase 1 TRAVERSE clinical trial (NCT04696731); notably, however, 3 on-study patient deaths were reported. The data were presented at the Society for Immunotherapy of Cancer’s (SITC) 39th Annual Meeting, held November 6-10, 2024, in Houston, Texas.

The study’s efficacy findings covered 26 patients who had confirmed CD70-positive RCC and were evaluable as of the October 14, 2024 data cutoff. Among 8 patients who were treated at dose-level 2 (80 million CAR T-cells) after a standard FC500 [fludarabine (30 mg/m2/day) and cyclophosphamide (500 mg/m2/d) for 3 days] lymphodepletion regimen, which was used as the dose for the phase 1b expansion cohort, the best overall response rate (ORR) was 38% (3/8). For patients in the group with a high CD70 Tumor Proportion Score (TPS), which was defined as a TPS of 50% or greater, the best ORR was 50% (3/6). Furthermore, the confirmed ORR, which unlike the best ORR required confirmation of a complete response or partial response at the subsequent visit, was 25% (2/8) for the group of 8 patients. For the 6 patients with a high CD70 TPS, the confirmed ORR was 33% (2/6). For the whole group of 26 evaluable patients, the best ORR was 27% (7/26), the best ORR in patients with a high CD70 TPS was 33% (7/21), the confirmed ORR was 19% (5/26), and the confirmed ORR in patients with a high CD70 TPS was 24% (5/21). Allogene pointed out that 16 of 21 patients (76%) who had a high CD70 TPS showed a decrease in tumor burden and that 2 of 6 patients (33%) with a high CD70 TPS who were treated with the phase 1b expansion regimen achieved durable responses that remained ongoing at 4 months posttreatment or later.

“ALLO-316, the leading ‘off-the-shelf' CAR-T product candidate currently in development for solid tumors, continues to show remarkable potency in the TRAVERSE trial,” Zachary Roberts, MD, PhD, EVP, research and development and chief medical officer of Allogene, said in a statement. “Data from the phase 1 study demonstrating significant antitumor activity in patients with metastatic disease resistant to multiple therapeutic classes, even with standard lymphodepletion, potentially marks a major advancement in the field. The unprecedented cell expansion and persistence driven by CD70 CAR-intrinsic Dagger technology, along with strong evidence of tumor infiltration by CAR T-cells, highlights the distinctive features of ALLO-316. We believe these findings from our phase 1 trial lay the groundwork for a new generation of allogeneic cell therapies.”

Genethon’s Gene Therapy GNT0004 Stabilizes or Improves Motor Functions in Patients With Duchenne Muscular Dystrophy

November 25, 2024 - Genethon’s GNT0004, an investigational recombinant AAV vector-based gene therapy intended to treated Duchenne muscular dystrophy (DMD), has demonstrated the ability to stabilize or improve motor function in patients treated in the phase 1/2 portion of a phase 1/2/3 clinical trial.

The phase 1/2 portion of the study treated 2 patients a lower dose level (1x10¹³ vg/kg) and 3 patients at a higher dose level (3x10¹³ vg/kg). The patients were aged between 6 and 10 years old.

All 3 patients who received the high dose showed stabilization of motor function, as assessed by the 34-point North Star Ambulatory Assessment, at 1 to 2 years posttreatment. Notably, 1 of these patients showed improvement with a maximum score of 34 recorded 12 months after dosing. This improvement was later confirmed at the 18 month time point. By contrast, untreated patients followed in a natural history studied being carried out by Genethon showed a rapid decline in motor function over the same course of time.

Cabaletta Bio’s CAR-T CABA-201 Effects Clinical Responses in Autoimmune Diseases

November 27, 2024 - Cabaletta Bio’s CABA-201, an investigational CD19-directed CAR-T therapy intended to treat various indications, has effected responses or possible emerging responses in some patients treated in the phase 1/2 RESET-SLE clinical trial (NCT06121297) for systemic lupus erythematosus (SLE) and lupus nephritis (LN), the phase 1/2 RESET-Myositis clinical trial (NCT06154252) for active idiopathic inflammatory myopathy (IIM), and the phase 1/2 RESET-SSc clinical trial (NCT06328777) in systemic sclerosis (SSc). These data were presented at the 2024 American College of Rheumatology (ACR) Convergence, held November 14 to 19 in Washington, DC.

Cabaletta reported that in RESET-Myositis, a patient with immune-mediated necrotizing myopathy (IMNM) who has 6 months of follow-up showed a sustained and improved clinical response without flares, and was off of immunosuppressants. Another patient with IMNM and 1 month of follow-up showed a total improvement score in line with the aforementioned patient and was also off immunosuppressants at 1 month posttreatment. A patient with dermatomyositis achieved a major total improvement score response and was off immunosuppressants at 1 month posttreatment. This patient also showed an improvement to normal in muscle strength and improved from 25 to 9 on the Cutaneous Dermatomyositis Disease Area and Severity Index – Activity.

In RESET-SLE, 3 patients with nonrenal SLE had no clinical symptoms on the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000 at their latest follow-up. The first patient in this group to have been treated also finished tapering off of prednisone. A patient with LN improved from 22 to 8 on SLEDAI from baseline to 4 months of follow-up. The patient’s proteinuria also approached normal levels, constituting an improvement of greater than 90%. This patient, who is off immunosuppressants, is in the process of tapering off prednisone.

Gene Therapy RP-A501 Shows Promising Phase 1 Results in Danon Disease

December 1, 2024 - Rocket Pharmaceuticals has announced the long-term safety and efficacy results from the phase 1 RP-A501 study (NCT03882437) of its investigational gene therapy RP-A501, noting that the treatment was well tolerated on the whole, and that all the patients with Danon disease demonstrated sustained LAMP2 protein expression after 1 year and up to 60 months, among other positive indicators.

The data were presented at the American Heart Association (AHA) Scientific Sessions 2024 by Joseph Rossano, MD, MS, FAAP, FACC, the Jennifer Terker Endowed Chair in Pediatric Cardiology, codirector of the Cardiac Center, and chief of the Division of Cardiology at the Children's Hospital of Philadelphia; and simultaneously published in the New England Journal of Medicine. Gaurav Shah, MD, the CEO of Rocket Pharma, said in a statement that the data represented a “critical milestone” for the program “and cardiac gene therapy in general, demonstrating for the first time that AAV conferred long-term efficacy in a cardiac indication. This program represents the most comprehensive investigational gene therapy dataset for any cardiac condition.”

Shah continued, “As is true for many other recent internal and peer company programs, when gene therapy works, it is life changing. RP-A501 is being developed as a potential one-time gene therapy and the results of the long-term Phase 1 study show the promise of gene therapy across cardiac diseases, including PKP2-ACM, BAG3-DCM and others.”