Data Roundup: September 2024 Features Updates in Ophthalmology Gene Therapy, CAR-T for Lymphoma, and More

Last month, September 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 promising data updates in chimeric antigen receptor T-cell (CAR-T) therapy for diffuse large B cell lymphoma (DLBCL), gene therapy for X-linked retinitis pigmentosa (XLRP), and more. Our team has highlighted these updates below.

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

REGENXBIO’s MPSII Gene Therapy RGX-121 Continues to Show Efficacy in Long-Term Trial Data

September 4, 2024 - REGENXBIO’s RGX-121, an investigational adeno-associated virus vector-based gene therapy intended to treat mucopolysaccharidosis type 2 (MPSII, also known as Hunter syndrome), has continued to show signs of efficacy in long-term data from the pivotal phase 1/2/3 CAMPSIITE clinical trial (NCT03566043) that the company presented at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium 2024, held September 3-6, in Porto, Portugal.

REGENXBIO reported that among patients who received the pivotal dose level (dose level 3, DL3) in the study, a median reduction of 85% in heparan sulfate (HS) D2S6 levels was seen in the cerebrospinal fluid (CSF). The company noted that these levels of the biomarker approach normal levels and were sustained for up to 2 years.

It was also noted that 80% of patients treated at DL3 were not taking standard of care enzyme replacement therapy (ERT) as of the most recent time point, for up to 18 months after receiving the gene therapy. In addition, 71% of patients treated at DL2 were ERT-free at the most recent time point, for up to nearly 3 years after treatment with the gene therapy. Some participants in the trial had entered ERT-naive and others discontinued receiving ERT while on-study.

Biogen’s Nusinersen Shows Efficacy in SMA Compared With Sham Treatment at Experimental Higher Dose

September 5, 2024 - Biogen’s nusinersen (Spinraza), a marketed antisense oligonucleotide (ASO) therapy for the treatment of spinal muscular atrophy (SMA), has demonstrated efficacy compared with a sham treatment when evaluated at a higher dose than that approved for use by the FDA.

The data come from the pivotal part B cohort of the phase 2/3 DEVOTE clinical trial (NCT04089566), in which 75 patients with infantile-onset SMA who had not previously received treatment for their disease were randomly assigned in a 2:1 ratio to receive either the experimental higher dose or the FDA-approved dose of nusinersen. The experimental higher dose consists of a loading regimen of two 50-mg doses administered 14 days apart and maintenance doses of 28 mg given every 4 months. On the other hand, the FDA-approved dosing regimen consists of 4 loading doses at 12 mg and maintenance doses at 12 mg every 4 months.

DEVOTE’s primary end point compared the change from baseline on the Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) at 6 months posttreatment for patients treated at the higher dose in part B of DEVOTE to a matched, untreated sham control group from the phase 3 ENDEAR clinical trial (NCT02193074). Biogen reported that DEVOTE met this end point, with a statistically significant improvement on CHOP-INTEND observed in the patients treated at the experimental compared with those given the sham treatment (least squares mean difference: 26.19; P <.0001). Biogen also noted that, across secondary end points, the outcomes favored the experimental dose regimen versus the sham treatment. The company additionally stated that the outcomes for key biomarker and efficacy measures trended in favor of the higher dose regimen versus the FDA-approved regimen.

Allogeneic CAR-T Azer-Cel Achieves Complete Responses in Some Patients With Diffuse Large B-Cell Lymphoma

September 10, 2024 - Azercabtagene zapreleucel (azer-cel), an investigational allogeneic CAR-T therapy, has demonstrated the ability to produce complete responses (CRs) in some patients with relapsed/refractory (r/r) DLBCL treated in a trial run by Imugene, which licensed the therapy from Precision BioSciences.

The data comes from a phase 1/1b clinical trial (NCT03666000) that has treated 10 patients thus far across 2 cohorts. In cohort A, 6 patients received the CAR-T following lymphodepletion, and in cohort B, 3 patients received the CAR-T in combination with interleukin 2 (IL-2) following lymphodepletion. One of the 4 patients treated in cohort B has not yet reached the 28 days posttreatment scan, and thus was not evaluable for efficacy. Of the 3 other patients in cohort B, 2 achieved CRs (67%), one of which has been ongoing for more than 120 days and the other of which has been ongoing for more than 90 days. The other evaluable patient in cohort B has shown stable disease, although Imugene noted that in this patient tumor decrease was seen in conjunction with an increase in signal intensity; the company noted that this may be an example of pseudoprogression and that further analysis is ongoing.

Among the 6 patients treated in cohort A, all of whom were evaluable, the overall response rate was 33%, with 1 patient (17%) achieving a CR and 1 patient achieving a partial response. It was noted that the durability of response was less than 60 days and that none of the 6 patients in this cohort remain onstudy.

Beacon Therapeutics’ XLRP Gene Therapy AGTC-501 Continues to Show Favorable Benefit-Risk Profile at 36 Months

September 24, 2024 - Beacon Therapeutics’ AGTC-501, an investigational AAV vector-based gene therapy being evaluated for the treatment of XLRP, has continued to show a favorable benefit-risk profile in the view of the company, based on newly updated data from the phase 1/2 HORIZON clinical trial (NCT03316560). The data were presented at the 24th EURETINA Congress held September 19 to 22, 2024, in Barcelona, Spain.

In terms of safety, there were no suspected unexpected serious adverse reactions (SUSARS) and no endophthalmitis observed among 29 patients treated in the study. Furthermore, most treatment-emergent adverse events (TEAEs) were characterized as not serious. There were 7 ocular serious AEs (SAEs) in total, including 4 cases of retinal detachment, 1 case of subcapsular cataract, and 1 case of reduced visual acuity, all of which were considered related to the injection procedure, and 1 case of glaucoma considered related to perioperative steroids. Notably, participants in the trial were treated with AGTC-501 either centrally or peripherally; 3 of the 4 cases of retinal detachment occurred in patients who received the gene therapy peripherally. There were no SAEs deemed related to AGTC-501 itself. Beacon additionally pointed out that according to Kaplan-Meier survival curves, approximately 73% of the ocular TEAEs took place during the first 3 months posttreatment and the majority of TEAEs resolved within a month after appearing.

Nonserious AEs reported in the study included cataract nuclear, conjunctival hyperaemia, increased intraocular pressure, lens disorder, and retinal depigmentation, all of which occurred in 1 patient each. Of these, only retinal depigmentation was deemed possibly related to AGTC-501 and possibly related to the injection procedure. All grade 3 or higher AEs were reported to have resolved, excepting the cases of retinal depigmentation, reduced visual acuity, and cataract nuclear.

Biomarker Data from Oncology Trial for Adicet Bio’s Gamma Delta T-cell Therapy ADI-001 Indicates Potential for Use in Autoimmune Disease

September 25, 2024 - Biomarker data collected in the phase 1 GLEAN clinical trial (NCT04735471) evaluating Adicet Bio’s ADI-001, an investigational CAR-engineered gamma delta T-cell therapy, for the treatment of B-cell malignancies, indicates the therapy’s potential to treat autoimmune disease, according to the company.

In lymph node biopsies from patients treated in the study, a mean exposure of 236,701 CAR T-cells per million across all dose levels was observed. Furthermore, CAR T-cells comprised 27% to 64% of total cellular material as measured by ddPCR in evaluable biopsies from patients treated at the 1x10⁹ dose level. In situ detection of granzyme B also indicated a “robust” activation profile. Analysis of secondary lymphoid tissue also revealed complete depletion of CD19+ B-cells alongside ADI-001 tissue trafficking and activation.

“These results clearly support the potential of ADI-001 and Adicet’s off-the-shelf gamma delta CAR T-cell platform, by demonstrating robust trafficking and complete B-cell depletion in tissue, while providing superior exposure of ADI-001 in secondary lymphoid tissue compared to published third-party data reported for alpha-beta CAR T therapies,” Blake Aftab, PhD, the chief scientific officer of Adicet Bio, said in a statement. “Together, the totality of our findings provide multiple levels of evidence highlighting the significant advantages of our approach and present a compelling opportunity for ADI-001 to extend B-cell targeting into tissues, as we look to address a range of autoimmune diseases in the clinic.”