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.

1. FDA Blocks 4D’s Gene Therapy Program for Fabry, Clears IND for Diabetic Macular Edema

The clinical hold comes a few weeks after the company announced it was stopping enrollment in the phase 1/2 clinical trial.

2. Raj Mehra, PhD, and Krishna Subramanian, PhD, on Striving For Disease-Modifying Therapies in Parkinson Disease

Mehra and Subramanian discussed preclinical research with the investigational gene therapy SLS-004.

3. Giant Axonal Neuropathy Gene Therapy Needs Double-blind Trial Before BLA Submission

The dosing of additional patients in a double-blind, placebo-controlled design will help support a BLA submission for TSHA-120.

4. Gerhard Ehninger, MD, on Managing Toxicities With Switchable CARs in AML

The professor at University Hospital Dresden discussed the positive safety profile of Unicar-T-CD123.

5. Remestemcel-L Cell Therapy Makes Comeback With Resubmitted BLA for Pediatric GvHD

Mesoblast is resubmitting its BLA with new CMC, survival, and mechanism of action data on the therapy and phase 3 trial.

Articles

Review top news and interview highlights from the week ending February 3, 2023. 

CGTLive’s Weekly Rewind – February 3, 2023 

The FDA has placed a clinical hold on 4D Molecular Therapeutics’ Fabry disease gene therapy program 4D-310 while also clearing the company’s investigational new drug application (IND) for its 

The hold comes weeks after 4D announced it was stopping enrollment in the phase 1/2 clinical trial of 4D-310 (NCT04519749) after 3 instances of treatment-related serious adverse events of atypical hemolytic uremic syndrome (aHUS) that resolved within 2 to 4 weeks.

In 1 participant, a 69-year-old man with underlying kidney dysfunction, the AE was classified as a grade 4 dose-limiting toxicity and required temporary hemodialysis; the other 2 patients did not receive dialysis.

“4D-310 holds promise as a potential first-in-class treatment for Fabry disease-associated cardiomyopathy, the leading cause of death in this patient population, as demonstrated by the cardiac clinical data announced today. Utilizing a novel vector invented at 4DMT with the goal of achieving increased delivery and transduction within the heart in humans, 4D-310 is designed to enable transgene expression and disease correction directly within cardiomyocytes,” principal investigator Eric Adler, MD, professor of medicine and section head for heart failure, University of California, San Diego, said in a statement at that time.

“We look forward to working with the 4D team to design and evaluate potential treatment regimens based on rituximab and sirolimus which in our clinical experience is effective at preventing aHUS following intravenous AAV.”

The company will continue to evaluate the 6 participants with Fabry currently enrolled and will re-evaluate the trial after collecting 12-month clinical data from these participants.

These endpoints include peak VO2 (CPET), Quality-of-life (KCCQ) and left ventricular function by global longitudinal strain (echocardiography). At this time, the company also reported improvements in cardiac endpoints for the 3 participants that had reached 12 months of follow-up as well as a cardiac biopsy positive for widespread genome delivery and transgene expression from the 1 available participant.

Gene Therapy Trial Doses First Patient With Wet AMD in China

In notification of the hold, the FDA directed 4D to continue long-term follow-up of these patients and will provide further feedback within 30 days.1The FDA also permitted the IND for 4D-310 to stay open and active. 4D Molecular Therapeutics will be presenting further detailed safety, cardiac biopsy and cardiac efficacy data at the WORLDSymposium conference later in February.

Concerning the company’s ophthalmologic pipeline, the FDA’s clearance of the IND for 4D-150 allows the company to initiate the phase 2 SPECTRA clinical trial for patients with DME in the third quarter of 2023. 4D-150 is being evaluated in the ongoing phase 1/2 PRISM trial (NCT05197270) for patients with 

(AMD), the phase 2 portion of which is currently enrolling. Initial data from the first 3 cohorts in the PRISM trial, which will be presented at the 2023 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, has supported the use of the R100 intravitreal vectorfor other indications including geographic atrophy.

“This is the sixth US IND submitted by 4DMT, and all 6 have been cleared by the FDA. The robustness and efficiency of our product design and development engine are based on sustained excellence by our manufacturing, preclinical, clinical, and regulatory teams,” David Kirn, MD, cofounder and chief executive officer, 4DMT, said in a statement.

“We are excited to have started enrolling the Phase 2 portion of our PRISM trial in wet AMD, and to evaluate the potential of 4D-150 in patients with DME who also require frequent anti-VEGF injections and have a high treatment burden.”

1. US SEC Form 8K. 4D Molecular Therapeutics. February 3, 2023. 

https://ir.4dmoleculartherapeutics.com/node/7801/html


2. 4D Molecular Therapeutics announces FDA Clearance of IND application for 4D-150 genetic medicine for the treatment of diabetic macular edema. February 2, 2023. 

https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4d-molecular-therapeutics-announces-fda-clearance-ind-2


3. 4D Molecular Therapeutics announces updates on clinical pipeline and additional preclinical programs. 4D Molecular Therapeutics. January 9, 2023. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4d-molecular-therapeutics-announces-updates-clinical-pipeline

The clinical hold comes a few weeks after the company announced it was stopping enrollment in the phase 1/2 clinical trial. 

FDA Blocks 4D’s Gene Therapy Program for Fabry, Clears IND for Diabetic Macular Edema 

“The biggest unmet need for Parkinson's, currently, is there are no disease modifying therapies [DMTs] available; almost all the approved drugs are mostly symptom relief. And now that we have started to understand, at the genomic levels, different mutations that lead to Parkinsonism, we should be focused on the DMTs.”

While there are treatments available for Parkinson disease (PD), these treatments generally only ameliorate symptoms, and are not disease modifying. As research brings the genetic factors underlying PD into clearer focus, gene therapy approaches that treat the root cause of the disease are becoming an area of increased interest.

, Raj Mehra, chairman and chief executive officer, Seelos Therapeutics, and Krishna Subramanian, PhD, head of non-clinical and translational science, Seelos Therapeutics, discussed SLS-004, the company’s preclinical gene therapy candidate for the treatment of PD. Mehra spoke about underlying factors in PD disease pathology, and why the gene that codes for α-synuclein was selected as the therapeutic target for SLS-004. He also detailed the encouraging results seen so far in mouse model research with SLS-004.

Image depicting modulation of SNCA with AAV-A53T + SLS-004 vector. 

Subramanian expanded on the specifics of the mouse model used in the research. He emphasized the importance of using a humanized mouse model and humanized vector model in order to obtain data more likely to translate to future clinical research. He also spoke about SLS-004's epigenetic approach to modulating gene expression, which could help avoid some of the safety issues associated with direct changes to genetic material.

Videos

Mehra and Subramanian discussed preclinical research with the investigational gene therapy SLS-004. 

Raj Mehra, PhD, and Krishna Subramanian, PhD, on Striving For Disease-Modifying Therapies in Parkinson Disease 

Shared insight on the benefits and drawbacks of using tumor-infiltrating lymphocyte therapy for treatment of solid tumors, as compared to chimeric antigen receptor (CAR) T-cell therapy.

Considerations for Use of TILs versus CAR T-cell Therapies

Expert perspectives on the mechanism of action behind tumor-infiltrating lymphocyte (TIL) therapy and how it might address existing unmet needs in the treatment of solid tumors, including melanoma and non-small cell lung cancer. 

An Overview on Tumor-Infiltrating Lymphocyte Therapy for Solid Tumors

Frontera Therapeutics has dosed the first patient with wet 

 (AMD) in a phase 1 clinical trial (NCT05611424) evaluating its adeno-associated virus (AAV) vector gene therapy FT-003 at the Ophthalmology Hospital of Tianjin Medical University in Tianjin, China.

“I am excited by the momentum the Frontera team has achieved so far this year with the dosing of the first patients in two gene therapy Phase 1 clinical trials during the month of January for FT-001 and FT-003,” Yong Dai, PhD, founder and chief executive officer, Frontera, said in a statement.

 “FT-003 is designed as a one-time treatment for patients with wet-AMD, a leading cause of blindness globally in people over 60 years old. We remain committed to validating our novel AAV technology platform and to making further breakthroughs in bringing gene therapies to patients with unmet medical needs, and expect to have initial clinical results for both FT-001 and FT-003 later this year.”

The trial will begin with a phase 1, 3x3 dose-escalation scheme in up to 18 enrolled participants of at least 45 years of age. The primary outcome is safety and tolerability of intraocular injection of FT-003 as measured by the severity and incidence of adverse events (AEs) and the secondary outcome is change in best-corrected visual acuity (BCVA) of the studied eye from baseline. FT-003 is designed to provide durable expression of therapeutic levels of intraocular protein to maintain vision and reduce the current treatment burden with frequent anti-vascular endothelial growth factors therapy which often results in undertreatment and vision loss in patients with wet AMD in real-world experience.

2023 has seen Frontera’s foray into clinical trials, with a phase 1 clinical trial of another AAV gene therapy, FT-001, also having dosed its first patient in China with Leber congenital amaurosis-2 (LCA-2) in January.

 The therapy also received investigational new drug (IND) clearance for a US trial in late 2022.

Arshad Khanani, MD, on Restoring Aflibercept Expression in Wet AMD With Gene Therapy

“This is an exciting achievement for Frontera Therapeutics as we begin our first clinical trial and take a significant step forward as a company,” Dai said in a statement at that time.

Also in Frontera’s pipeline are additional gene therapies in IND-enabling studies including FT-002 for “rare” ophthalmic diseases, FT-004 for hemophilia B, and FT-005 for another hematologicalindication. The company is also researching undisclosed gene therapy programs in ophthalmologic, hematologic, central nervous system, cardiovascular, and metabolic diseases. 

“Since Frontera’s founding, we have rapidly progressed a significant number of programs into IND enabling studies,” Dai said in another statement.

 “This year, we have advanced our lead program, FT-001, and have received both US FDA and China CDE IND clearances. Building on our product development momentum, we intend to advance a number of programs into clinical studies in the next 6 to 9 months. We will also leverage our APEX Technology & Manufacturing platform to create new innovative programs targeting large global markets such as cardiovascular, metabolic, and central nervous system diseases.”

1. Frontera Therapeutics doses first patient in a clinical trial of FT-003 gene therapy for the treatment of wet AMD. News release. Frontera Therapeutics. February 2, 2023. 

https://finance.yahoo.com/news/frontera-therapeutics-doses-first-patient-140000649.html


2. Frontera Therapeutics doses first patient in phase 1 clinical trial for gene therapy FT-001 for the treatment of leber congenital amaurosis-2. News release. Frontera Therapeutics. January 6, 2023. https://www.fronteratherapeutics.com/frontera-therapeutics-doses-first-patient-in-phase-1-clinical-trial-for-gene-therapy-ft-001-for-the-treatment-of-leber-congenital-amaurosis-2/
3. Frontera Therapeutics receives additional IND clearance for its lead program FT-001. News release. Frontera Therapeutics. September 21, 2022. https://www.fronteratherapeutics.com/frontera-therapeutics-receives-additional-ind-clearance-for-its-lead-program-ft-001/

The phase 1 clinical trial is the second of Frontera’s trials to begin dosing in 2023. 