Nanoscope Therapeutics presented positive data from their phase 1/2 study (NCT04919473) of 

MCO-010 in patients with retinitis pigmentosa

 (RP) at the 2021 Annual Meeting of the American Society of Retina Specialists (ASRS), October 8-12.

The presentation was given by Sai H. Chavala, MD, professor, Texas Christian University and University of North Texas Health Science Center School of Medicine. The study evaluated the multi-characteristic opsin (MCO) therapy’s effect on ON-bipolar cells in patients with RP and ABCA4 mutations.

“Optogenetics offers the potential for vision restoration in RP by photosensitizing higher order bipolar neurons. It is ‘gene-agnostic’, focusing on disease phenotype in a mutation independent manner, and applicable to a wide population of patients with retinal degenerations. This therapy differs by not requiring an external device for stimulation,” Chavala said in his presentation.

In the study, 4 participants with severe RP received a single intravitreal injection of MCO-010. The therapy consists of MCO-encoded genes delivered by adeno-associated virus vector 2 (AAV2) which reprograms ON-bipolar neurons to be activated by ambient light.

Gene Therapy for Retinal and Neurological Diseases

Investigators found that visual acuity improved from a mean of 1.95 logMAR at baseline to 1.46 logMAR at 52 weeks post-treatment. Additional improvements were also seen in mobility score, shape discrimination accuracy, and visual field at a dose of 3.5 x 10

vg per eye. Patient-reported outcomes supported the therapy’s efficacy, as patient scores improved on the Visual Function Questionnaire.

“We have very promising data in our phase 1/2 study in patients with retinitis pigmentosa... with a single intravitreal injection, in 2 different doses and groups, we see improvements in activities of daily living measured by visual function and mobility tests we did. The high dose group, especially, improved in visual equity tremendously,” Samarendra Mohanty, PhD, founder and president, Nanoscope Therapeutics, 

In terms of safety, the therapy was well-tolerated and no serious adverse events (AEs) were reported. There were mild –to moderate increases in intraocular pressure (IOP), but these resolved with topical IOP-lowering medications without sequelae. Similarly, mild self-limited ocular inflammation was observed and subsequently controlled with topical steroids. At the end of the study, no patient required medications for AEs.

Chavala concluded that MCO-010 had a positive trend in visual improvements for patients with RP regardless of underlying gene mutations. Therefore, this proof-of-concept study provides a rationale for further investigation of the therapy for both RP and other inherited retinal degenerative diseases.

A randomized, double-blind, multi-center phase 2b trial (NCT04945772) assessing MCO-010 is currently recruiting. Results are expected in the fourth quarter of 2022. MCO-010 previously received orphan drug designations from the FDA for RP and Stargardt disease.

“In our next trial, we are combining different cone-rod dystrophies: choroideremia, Leber congenital amaurosis, and Stargardt disease, in 1 trial. That's the second trial we’re planning in our pipeline that will be with a viral vector delivery. Also, we are advancing the non-viral delivery method of nano-enhanced optical delivery for geographic atrophy in dry AMD or wet AMD,” Mohanty previously told 

1. Positive data from Nanoscope's phase 1/2a trial of gene therapy to restore vision in patients blinded by retinitis pigmentosa to be featured at 2021 ASRS meeting. News release. Nanoscope Therapeutics. October 8, 2021. 

https://starlocalmedia.com/news/state/positive-data-from-nanoscopes-phase-1-2a-trial-of-gene-therapy-to-restore-vision-in/article_933f549d-e74a-5d85-aee4-14ef18f76ec6.html


2. Chavala SH, Singer MA, Mahapatra S, et al. Intravitreal AAV2 Optogenetic Vision Restoration in retinal degenerative patients with ABCA4 mutation. Presented at ASRS 2021 Annual Meeting. October 8-12, 2021. San Antonio, TX. 

Articles

Results from a phase 1/2 study from Nanoscope Therapeutics were presented at the 2021 ASRS meeting.

Optogenetic Therapy Shows Efficacy in Autosomal Recessive Retinitis Pigmentosa 

This content originally appeared on our sister site, 

spoke with Doris Hansen, MD, assistant member, department of blood and marrow transplant and cellular immunotherapy. Moffitt Cancer Center, about the progression-free survival (PFS) benefit yielded by idecabtagene vicleucel (ide-cel; Abecma).

The phase 2 KarMMa trial (NCT03361748) demonstrated an overall response rate of 73% in patients with pretreated relapsed/refractory multiple myeloma. Median PFS was 8.6 months in patients with R/R MM.

The study examined the safety and efficacy of ide-cel in this patient population and was pivotal because it provided a new novel therapy to those who otherwise have limited options, according to Hansen. Patients with relapsed/refractory multiple myeloma often have a median PFS of 2 to 3 months, according to Hansen. However, patients who receive a BCMA-targeted CAR T-cell therapy experience improved outcomes, Hansen continues.

For example, results from the KarMMa study showed that patients who achieved a deep response with ide-cel, or a complete remission or better, had a median PFS of approximately 22 months, and a duration of response of 21 months. These results held up with a longer follow-up, Hansen concludes.

Videos

The hematologist from Moffitt Cancer Center discussed the survival benefit of ide-cel in the phase 2 KarMMa trial.

Ide-Cel's Benefit on PF Survival: Doris Hansen, MD

 Weekly Rewind! We’ve compiled 5 highlights from this week’s coverage of advances in gene and cell therapies, including FDA actions, notable research, and interviews with experts across the field.

Natural Killer Cell Therapy Well Tolerated in Solid Tumors

Thorsten Graef, MD, PhD, chief medical officer, Acepodia, discussed data on ACE1702 presented at ESMO 2021. He touched on next steps for the therapy and compared it to other natural killer cell therapies.

2. AlloCAR T Programs Halted Following Chromosomal Abnormality

The FDA has placed all of Allogene Therapeutics’ AlloCAR T trials on clinical hold after a chromosomal abnormality was observed in a patient dosed with ALLO-501A in the ALPHA2 trial (NCT04416984). These programs span tumor types, with phase 1 studies assessing the therapies in hematologic malignancies, solid tumors, and as a lymphodepletion agent.

3. Advantages of mRNA-Based Gene Therapies

Jake Becraft, PhD, chief executive officer and cofounder, Strand Therapeutics, discussed the company’s technology and focus on mRNA therapies. He explained how Strand’s platform works to create these therapies and the ease of manufacturing and delivering such therapies.

4. CAR T-Cell Therapy From CRISPR Therapeutics Efficacious in CD19+ B-Cell Malignancies

CTX110 seems to be well-tolerated and efficacious in patients with relapsed or refractory CD19+ B-cell malignancies, according to updated data from the phase 1 CARBON trial (NCT04035434) announced by CRISPR Therapeutics.

TCR-T Cell Therapy Cleared for Phase 1/2 Study in Acute Myeloid Leukemia

The FDA has accepted Intellia Therapeutics’ investigational new drug application for NTLA-5001, an investigational CRISPR/Cas9 T cell receptor (TCR)-T cell therapy for the potential treatment of acute myeloid leukemia.

Review top news and interview highlights from the week ending October 15, 2021. 

GeneTherapyLive’s Weekly Rewind – October 15, 2021

"ATLAS was created because we understood that you cannot predict yet what is going to be a good target for diverse human subjects. While predictions are quite good for certain subsets of people, it can't work well, in theory, for a whole population... We’re different because we use a biological assay to screen every single possible target to identify what the right target is for a person to be treated with.”

Genocea is creating personalized immunotherapies for patients with solid tumors with the help of their ATLAS platform. The platform uses patient samples to identify the best antigens to target in each patient’s tumors. The company’s 2 lead programs are GEN-009, a neoantigen vaccine, and GEN-011, a neoantigen-specific peripheral T-cell therapy. 

GEN-009 is being investigated in a phase 1/2 trial (NCT03633110) that has demonstrated long term, broad immune responses against neoantigens in data presented at the 

American Society of Clinical Oncology 2021 meeting

 in June. GEN-011 is being investigated in the phase 1/2 TiTAN trial (NCT04596033), which dosed its first patient in July 2021.

 spoke with Jessica Baker Flechtner, PhD, chief scientific officer, Genocea, to learn more about the ATLAS platform and the company’s focus on identifying the right targets for each patient. She also discussed GEN-011 and the TiTan trial.

Genocea provides second quarter 2021 corporate update. News release. Genocea. July 29, 2021. https://ir.genocea.com/news-releases/news-release-details/genocea-provides-second-quarter-2021-corporate-update

Jessica Baker Flechtner, PhD, chief scientific officer, Genocea, discussed the ATLAS platform and the TiTAN trial. 

Identifying Patient-Specific Tumor Targets

Legend Biotech has initiated the phase 1 LB1901-TCL-001 clinical trial (NCT04712864) assessing the anti-CD4 chimeric antigen receptor (CAR) T-cell therapy LB1901 for the potential treatment of relapsed/refractory T-cell 

The open-label, multicenter study is currently recruiting patients with histologically confirmed CD4+ peripheral TCL and cutaneous TCL. It is being led by Dr. Swaminathan P. Iyer, professor, Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center. 

“We are excited by the promise of LB1901, and we look forward to further evaluating the safety and tolerability of LB1901. Determining the optimal dose for subsequent evaluation is one of the key objectives of this trial,” Lida Pacaud, MD, vice president, clinical development, Legend Biotech, said in a statement.

 “The number of patients who relapse or are refractory to current TCL treatments is significant, and this trial will provide important information about the potential of CAR-T therapy to treat this disease.”

The trial aims to enroll 50 participants and has an estimated completion date of December 2025. Its primary outcome is determining the recommended dose for expansion (RDE) and assessing the safety and tolerability of the RDE. Secondary outcomes include efficacy measures such as overall response rate (ORR), time to response, duration of response, disease control rate, progression-free survival (PFS), and overall survival (OS).

Future Research With Stem Cell Therapies in Hematologic Malignancies

Legend Biotech is also developing another CAR T-cell therapy, ciltacabtagene autolecel (cilta-cel), for the treatment of relapsed/refractory multiple myeloma (RRMM), in collaboration with Janssen. The FDA previously accepted the biologic license application for cilta-cel in May 2021 and has set the PDUFA date for November 29, 2021.

Multiple trials have demonstrated cilta-cel's efficacy in RRMM. Legend recently presented longer term data from the phase 1/2 CARTITUDE-1 trial (NCT03548207) at the 2021 ASCO and EHA Annual meetings. These data, from 97 heavily pretreated patients, demonstrated a 98% ORR, an 80% stringent complete response rate, a 66% PFS rate, and an 81% OS rate at 18 months post-treatment.

Results from the phase 2 CARTITUDE-2 trial (NCT04133636) were also presented at the 2021 ASCO and EHA Annual meetings. The data showed early and deep responses in 20 lenalidomide refractory patients with progressive MM after 1-3 prior lines of therapy. Safety was consistent with other trials in the program. The CARTITUDE development program expanded in July 2021 with the addition of the phase 3 CARTITUDE-5 study (NCT04923893) in patients with newly diagnosed MM.

“We have made exciting progress in advancing our first investigational CAR-T therapy ciltacel in the past few months, with key regulatory, data and manufacturing updates. This includes the acceptance of our applications for cilta-cel by the U.S. FDA and EMA and the presentation of additional efficacy and safety data from the CARTITUDE cilta-cel clinical development program at ASCO and EHA Annual meetings,” Ying Huang, PhD, chief executive officer and chief financial officer, Legend Biotech, said in a cimpany update.

 “We look forward to a momentous second half of the year as we work towards bringing cilta-cel to patients living with multiple myeloma and providing their healthcare providers a new therapeutic option, in collaboration with Janssen.”

1. Legend Biotech begins phase 1 clinical trial in the US to evaluate investigational anti-CD4 CAR-T therapy for relapsed or refractory T-cell lymphoma. News release. Legend Biotech. September 13, 2021. 

https://legendbiotech.com/wp-content/uploads/2021/09/Legend-Biotech-Begins-Phase-1-Clinical-Trial-in-the-US-to-Evaluate-Anti-CD4-CAR-T_FINAL.pdf


2. Legend Biotech reports second quarter 2021 financial results and recent highlights. News release. Legend Biotech. August 23, 2021. https://legendbiotech.com/wp-content/uploads/2021/08/Legend-Biotech-Reports-Second-Quarter-2021-Financial-Results-and-Recent-Highlights-2021-08-23-clean.pdf

The study follows Legend Biotech’s initial success with cilta-cel, whose PDUFA date is set for November 2021. 

Study Investigates New CAR T Therapy for T-Cell Lymphoma

"CD19 is an overcrowded target. So, we have an alternative target, CD22, and this CAR is currently being developed for acute lymphoblastic leukemia. We provided data last year at ASH and will provide some updates on this trial soon, so it's a very exciting CAR. It's a huge unmet medical need because a lot of people that relapse CD19 negative or after CD19 treatment then have no options.”

Cellectis is developing chimeric antigen receptor (CAR) T-cell therapies for both hematologic malignancies, including leukemias and lymphomas, and solid tumors. Their investigative therapies target a number of molecular targets for different indications, including CD19, CD20, CD22, and CD70.

Cellectis’ lead programs are allogeneic CAR T-cell therapies, including UCART22 for the potential treatment of relapsed or refractory B cell acute lymphoblastic leukemia, UCART123 for the potential treatment of relapsed or refractory acute myeloid leukemia, and UCARTCS1 for the potential treatment of relapsed or refractory multiple myeloma.

 spoke with André Choulika, PhD, chief executive officer and cofounder, Cellectis, to learn more about the company’s current focus and hematologic malignancies and expansion into solid tumors. He discussed therapies in development, including UCARTFAP, which is designed to penetrate the protective layer of fibroblasts in solid tumors.

Cellectis provides business update and reports financial results for second quarter and first six months 2021. News release. Cellectis. August 5, 2021. https://www.cellectis.com/en/press/cellectis-provides-business-update-and-reports-financial-results-for-second-quarter-and-first-six-months-2021/

André Choulika, PhD, chief executive officer and cofounder, Cellectis, discussed therapies the company is developing. 