Data Roundup: October 2024 Features Update for TCR-Based Autologous Cell Therapy in Melanoma, the First Clinical Demonstration of Therapeutic RNA Editing in Humans, and More

Last month, October 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 a promising data update in TCR-based autologous cell therapy for melanoma, the first clinical demonstration of therapeutic RNA editing in humans, and more. Our team has highlighted these updates below.

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

Immatics’ TCR-T Therapy Shows Good Phase 1 Safety and Survival Data, Phase 3 Plans Confirmed

October 29, 2024 - Treatment with the investigational TCR-based autologous cell therapy, ACTengine IMA203 (Immatics), has been shown to demonstrate a response rate exceeding 50% while maintaining a favorable tolerability profile across all dose levels tested, according to newly presented data. Additionally, the company reported progression-free survival (PFS) and overall survival (OS) data for the first time among patients with melanoma in the trial.

The median PFS in the dose-escalation phase for patients with melanoma (n = 11) in the trial was 2.6 months, increasing to 6.0 months in the dose-expansion phase (n = 28; P <.0001). Likewise, the median OS value in the dose-escalation phase was 6.3 months, and was not reached in the dose-expansion phase (n = 28; P = .0003). Among those with deep responses (n = 12), defined as a 50% or greater tumor reduction, the median PFS was 13.4 months (P = .0033). Those with a less than 50% tumor reduction (n = 14), including tumor size increase, still observed a mPFS more than twice as long as those treated in dose-escalation who had suboptimal doses, at 5.7 months.

Responses were considered durable as well, with both the total phase 1b melanoma (n = 28) and the phase 1b cutaneous melanoma (n = 13) populations reporting a confirmed objective response rate of 54% (total, n = 14; cutaneous, n = 7) and objective response rate of 62% (total, n = 16; cutaneous, n = 8). Tumor shrinkage was reported by 88% of the total melanoma population (n = 23) and 85% of the cutaneous population (n = 11), with duration of response being 12.1 months for both groups. Median OS was 15.9 months for the cutaneous population, and median PFS was 6.1 months.

Hematological Malignancies Detected in Some Patients Treated With bluebird bio’s Active Cerebral Adrenoleukodystrophy Gene Therapy Eli-Cel

October 15, 2024 - Seven of 67 patients treated with bluebird bio's elivaldogene autotemcel (eli-cel; marketed as Skysona), a gene therapy product comprised of engineered autologous CD34+ hematopoietic stem cells, for early, active cerebral adrenoleukodystrophy (CALD) across multiple clinical trials have developed hematologic malignancies, according to a study published in The New England Journal of Medicine.

The data comes from the phase 2/3 ALD-102 (NCT01896102), phase 2/3 ALD-104 (NCT03852498), and LTF-304 (NCT02698579) clinical trials. Notably, LTF-304 is an ongoing long-term follow-up study for patients treated in ALD-102 and ALD-104.

One of 32 patients treated in ALD-102 and 6 of 35 patients treated in ALD-104 were diagnosed with hematologic malignancies following treatment with eli-cel. One patient developed myelodysplastic syndrome (MDS) with unilineage dysplasia at 14 months posttreatment and another was diagnosed with the same at 26 months posttreatment. Another 3 patients were diagnosed with MDS with excess blasts at 28 months, 42 months, and 92 months posttreatment, respectively. Another patient was diagnosed with MDS at 36 months posttreatment. A single patient developed acute myeloid leukemia at 57 months posttreatment. Among the 7 patients, 6 remain alive, with 1 patient having died 49 months after treatment with eli-cel. This patient had received allogeneic hematopoietic stem-cell transplantation (HSCT) for treatment of their MDS, and their death 20 months after receiving HSCT was attributed to presumed graft-versus-host disease (GvHD).

Wave Life Sciences Achieves RNA Editing in Trial for WVE-006 in Alpha-1 Antitrypsin Deficiency

October 17, 2024 - Wave Life Sciences’ WVE-006, an investigational RNA editing oligonucleotide intended to treat alpha-1 antitrypsin deficiency (AATD), has demonstrated the ability to edit targeted RNA molecules in the first 2 patients treated in the phase 1b/2a RestorAATion-2 clinical trial (NCT06405633).

The data come from the first 2 patients with “ZZ” AATD (Pi*ZZ AATD) to have been treated with WVE-006 and to have reached 57 days of follow-up. Both were treated in the study’s first single dose cohort received 200 mg of WVE-006. The patients, who normally would not produce any wild-type alpha-1 antitrypsin (M-AAT) protein because of their disease, showed a mean of 6.9 micromolars of wild-type M-AAT protein circulating in plasma at 15 days posttreatment, thus confirming that the intended editing of mutant Z-AAT mRNA had occurred. Furthermore, the M-AAT protein at this time point constituted more than 60% of the total AAT circulating in plasma. Neutrophil elastase inhibition also increased from baseline in a manner Wave deemed consistent with production of M-AAT. According to the company, this is the first time therapeutic RNA editing has been clinically demonstrated in humans.

Wave additionally pointed out that at 15 days posttreatment, mean total AAT protein was 10.8 micromolar, in contrast to the patients’ baseline measurements, at which point it was below the level of quantification. The company stated that increases from baseline in both AAT in general and M-AAT were seen as early as 3 days posttreatment and through 57 days posttreatment.

Intellia’s CRISPR Gene Editing Therapy NTLA-2002 Appears to Eliminate Hereditary Angioedema Attacks in Some Patients Following One-Time Treatment

October 27, 2024 - Intellia Therapeutics’ NTLA-2002, an investigational CRISPR/Cas9-based gene-editing therapy that is delivered systemically as a single-dose and is being evaluated in a phase 1/2 clinical trial (NCT05120830) for the treatment of hereditary angioedema (HAE), has eliminated HAE attacks in some patients through their most recent follow-up, according to data the company is presenting at the 2024 American College of Allergy, Asthma & Immunology (ACAAI) Scientific Meeting, held October 24 to 28, in Boston, Massachusetts.

Participants in the trial received either a single dose of 25 mg of NTLA-2002, a single dose of 50 mg of NTLA-2002, or a placebo. As of the April 4, 2024, data cutoff, monthly HAE attacks for patients who received the 50 mg dose were reduced by 77% in comparison to the placebo group for weeks 1 to 16 posttreatment and by 81% during weeks 5 to 16 posttreatment. For the patients who received the 25 mg dose, HAE attacked were reduced by 75% in comparison to the placebo group for weeks 1 to 16 posttreatment and by 80% during weeks 5 to 16 posttreatment. Furthermore, Intellia noted that 8 of the 11 patients who received the 50 mg dose of the therapy achieved a complete response—defined as experiencing no HAE attacks at all during the 16 week observation period and beyond—with a median follow-up time of 8 months, during which no additional treatment was necessitated. On the other hand, complete responses were achieved by just 4 of 10 patients who received the 25 mg dose, and there were 0 complete responses in the placebo group. In addition, at 16 weeks posttreatment, the patients in the 50 mg group showed an 86% mean decrease in kallikrein protein levels from baseline, while patients in the 25 mg group showed a 55% reduction.

“These positive NTLA-2002 Phase 2 results underscore the tremendous potential of our in vivo CRISPR gene editing therapy to be a functional cure and redefine the treatment paradigm for HAE,” John Leonard, MD, the president and chief executive officer of Intellia, said in a statement. “The phase 2 data demonstrated that a majority of patients in the 50 mg arm experienced a complete response—no attacks at all and no further treatment needed—after a one-time infusion of NTLA-2002 through the latest follow-up, consistent with the long-term phase 1 data. We are highly encouraged by these results, which we believe sets NTLA-2002 apart from other prophylaxis treatments. What was previously an unimaginable potential to be free of chronic therapy is one step closer to becoming a reality for the HAE community.”

MeiraGTx’s Parkinson Disease Gene Therapy AAV-GAD Improves Motor Scores and Patient-Reported Quality of Life in Sham-Controlled Study

October 21, 2024 - MeiraGTx’s AAV-GAD, an investigational adeno-associated virus (AAV) vector-based gene therapy, has improved MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 3 and Parkinson’s Disease Questionnaire (PDQ-39) scores compared to baseline in some patients with idiopathic Parkinson disease (PD) treated in the phase 1/2 MGT-GAD-025 clinical trial (NCT05603312).

MGT-GAD-025 treated 5 patients with a low dose of AAV-GAD (7.0×10¹⁰ vg), 5 patients with a high dose of AAV-GAD (21×10¹⁰ vg), and 4 patients with a sham procedure. For the patients treated at the high dose, an average improvement of 18 points from baseline was observed in UPDRS Part 3 “off” medication score at 26 weeks posttreatment (P = .03). On the other hand, there was no significant change in this score recorded in the same timeframe for the patients treated with the low dose and the patients treated with the sham procedure.

Furthermore, at 26 weeks posttreatment, an 8 point improvement from baseline on PDQ-39 score was recorded for patients treated at the high dose (P = .02), a 6 point improvement from baseline was recorded for patients treated at the low dose (P = .04), and a statistically insignificant worsening of 0.2 points was recorded for the patients treated with the sham procedure. MeiraGTx noted that the dose response for PDQ-39 was 100% for the high dose group, 60% for the low dose group, and 25% in the sham group. In terms of safety, AAV-GAD was characterized as “well-tolerated”. No serious adverse events related to the gene therapy were reported.