▎Edited by the WuXi AppTec content team

Recently, the global cell and gene therapy (CGT) field has seen a series of advancements.REGENXBIO Announces Research ProgressGene Therapy RGX-121 Meets Primary Endpoint in Pivotal Clinical Trial for the Treatment of Mucopolysaccharidosis II (MPS II), significantly reducing the levels of biomarkers in the patient's cerebrospinal fluid.These resultsSupport the company in submitting a Biologics License Application to the U.S. FDA via the accelerated approval pathway in 2024.。iRegene announced that the companyUsed foriRegene's NouvNeu001, a Cell Therapy Under Research for Parkinson’s Disease, Completes First Patient Dosing in Phase 1/2 Clinical Trial. This article will provide a brief introduction to some of the key advancements, for readers' reference only.

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◇REGENXBIO Announces RGX-121 Gene Therapy in Pivotal Clinical Trial for the Treatment of Mucopolysaccharidosis IIAchieve the Primary Endpoint, significantly reducing the levels of biomarkers in patients' cerebrospinal fluid. The press release noted that these results support the company's plan to submit a Biologics License Application to the U.S. FDA via the accelerated approval pathway in 2024.

During the pivotal phase of the clinical trial, cerebrospinal fluid D2S6 levels in MPS II patients treated with RGX-121 decreased by an average of 86%, approaching normal levels. D2S6 is one of the key biomarkers of brain disease activity.In addition, long-term follow-up data of patients treated during the dose exploration phase of the clinical trial show that, among patients receiving the recommended dose in the pivotal trial phase,80% of patients did not require standard intravenous enzyme replacement therapy at the most recent follow-up.（ERT）。

RGX-121 is a one-time gene therapy designed to deliver a transgene encoding human iduronate-2-sulfatase (IDS) to the central nervous system (CNS) using an AAV9 vector.RGX-121 has been granted Orphan Drug Designation, Rare Pediatric Disease Designation, Fast Track Designation, and Regenerative Medicine Advanced Therapy (RMAT) Designation by the U.S. FDA.

In addition, REGENXBIO announced positive interim results from the phase 1/2 clinical trial of its investigational gene therapy RGX-202 for the treatment of Duchenne Muscular Dystrophy (DMD). RGX-202 demonstrated good safety in the first five patients treated, with no drug-related serious adverse events reported. Three months after administration,A patient's micro-dystrophin expression level reached 83.4% of the healthy control, and the serum creatine kinase (CK) level decreased by 93% from baseline at 10 weeks.

RGX-202 is an AAV8 vector-based gene therapy designed to deliver a transgene expressing micro-dystrophin into skeletal and cardiac muscle tissues.Currently, patient enrollment for the higher-dose group of this trial has been completed. REGENXBIO is expected to initiate pivotal clinical trials in the second half of 2024.

◇Ultragenyx Pharmaceutical Announces ResearchGene therapy UX111 rapidly and significantly reduced heparan sulfate levels in the cerebrospinal fluid of patients with MPS IIIA in a Phase 1/2 clinical trial.Meanwhile, a sustained reduction in heparan sulfate levels is correlated with the long-term cognitive development of patients.

UX111 aims to use the AAV9 vector for deliverySGSHA functional copy of the gene to the central nervous system and peripheral organs, thereby compensating for the deficiency of SGSH enzyme.The absence of SGSH enzyme leads to the accumulation of heparan sulfate in the brain and other parts of the body, causing progressive cellular damage.

In terms of efficacy,All 12 patients who were using enzyme replacement therapy (ERT) at the start of the study and stopped ERT after receiving treatment remained free of the need for ERT as of September 19, 2023.Among them, the α-galactosidase levels of 11 patients exceeded those of normal individuals, and the level of one patient was similar to that of normal individuals. Among the 13 patients followed up for more than 12 months, renal function remained stable, and the patients reported significant improvements in overall disease severity, quality of life, and gastrointestinal symptoms.

Isaralgagene civaparvovec uses a recombinant AAV2/6 vector to express α-galactosidase.GLAGene delivery to the liver aims to achieve lasting efficacy through a one-time treatment, reducing the burden of ERT infusion.

◇AvenCell Announces First Patient Dosed in Phase 1A Clinical Trial of Allogeneic CAR-T Therapy AVC-201 for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia and Other CD123-Positive Hematologic Cancers

AVC-201 is an allogeneic CAR-T therapy modified through CRISPR gene editing technology, targeting the CD123 antigen. Its uniqueness lies in the combination of two different technologies. The first is AvenCell's UniCAR universal/convertible technology, which consists of two components.Genetically engineered T cells express a "universal" receptor, which is only activated when bound to a targeted biologic molecule. One end of the targeted biologic molecule can bind to tumor antigens, while the other end binds to the receptor expressed on T cells. This design makes the targeting module a switch to activate and deactivate the activity of CAR-T therapy.

Another technology platform is a gene editing platform developed by Intellia Therapeutics, which prevents graft-versus-host disease (GvHD) and immune rejection mediated by the patient's innate and adaptive immune systems through CRISPR/Cas9 gene editing.

TAC101-CLDN18.2 is an innovative engineered autologous T-cell therapy. The T-cell antigen coupler (TAC) it expresses targets Claudin 18.2 while leveraging the intrinsic signaling pathways of the natural T-cell receptor complex, which helps prevent overactivation and premature exhaustion of T cells.

This clinical trial will be conducted in Claudin 18.2-positive solid tumor patients who have received at least two prior treatments.

◇iRegene announced that the companyNouvNeu001, an investigational cell therapy for the treatment of Parkinson's disease, has completed the first patient dosing in a Phase 1/2 clinical trial, and the patient has also successfully passed the observation period.

NouvNeu001 is a dopamine neuron precursor cell derived from induced pluripotent stem cells (iPSC) and chemically induced differentiation.Dr. Wei Jun, co-founder and CEO of iRegene, introduced in an earlier interview with the content team of WuXi AppTec: "Adhering to the principle of 'starting from the needs of patients and addressing real clinical needs,' iRegene prioritizes safety and accessibility as its primary principles. Through original innovation, it has ultimately formed...Unique "AI + Chemical Induction" SystemSpecifically, we first utilize knowledge graphs to conduct enrichment analysis of core genes in developmental biology. Then, by integrating omics analysis and calculating the topological structure of interaction networks, we identify specific key developmental pathways and their inducing compounds, thereby determining the most suitable cell and chemical induction processes for treatment. Ultimately, a simple combination of a few appropriate small-molecule chemicals with basal culture medium can achieve efficient and precise conversion of pluripotent stem cells into target cells on an industrial scale. This concept also helps the company’s research products achieve faster and better therapeutic effects."

◇Adverum Biotechnologies Announces Positive Preliminary Results from Phase 2 Clinical Trial of Investigational Gene Therapy Ixoberogene Soroparvovec (Ixo-Vec, Formerly ADVM-022) for the Treatment of Wet Age-Related Macular Degeneration (AMD)In patients treated with ixo-vec at doses of 6E10 and 2E11, the frequency of anti-VEGF therapy injections was reduced by 90% and 94%, respectively, at 26 weeks.The company simultaneously announced the completion of $127.5 million in financing.

Ixo-vec uses the company's proprietary adeno-associated virus vector AAV.7m8 to deliver the transgene encoding the anti-VEGF-A fusion protein aflibercept into the retina via intravitreal injection.This therapy aims to provide long-term efficacy through a single injection, reducing the burden on patients who would otherwise require frequent anti-VEGF therapy injections.

◇Beacon Therapeutics Announces Positive Results from Phase 2 Clinical Trial of Investigational Gene Therapy AGTC-501 for X-linked Retinitis Pigmentosa (XLRP). Follow-up data at 12 months showedAGTC-501 Demonstrates Good Safety and Tolerability While Improving Patients' Visual Function. The Response Rate for Eyes Treated with High-Dose AGTC-501 is 63%.

XLRP is mainly caused by the pigmentary retinal GTPase regulator (RPGR) Gene mutation caused.AGTC-501 expresses the full-length RPGR protein, thus is expected to rescue the function of rod and cone cells., making it highly suitable as a potential treatment to improve the lives of patients with XLRP.

◇Krystal Biotech announced that the research on gene therapy beremagene geperpavec (B-VEC) as eye drops for treating conjunctivitis in patients with dystrophic epidermolysis bullosa (DEB) was published in The New England Journal of Medicine. The press release noted that this isThis gene therapy was used for the first time to treat ophthalmic complications in DEB patients.

B-VEC is a gene therapy that uses type 1 herpes simplex virus (HSV-1) as a vector to deliver the transgene encoding type VII collagen (COL7) to patients' skin cells.By expressing COL7, it can help DEB patients with skin damage caused by COL7 deficiency to heal wounds. 25% of DEB patients will experience ocular complications, including corneal damage, blistering, and scar tissue formation, leading to impaired vision.

After receiving surgical treatment to remove scar tissue, the patient was treated with B-VEC eye drops. The trial results showed that B-VEC exhibited good tolerance, with complete healing of the corneal epithelium after 3 months of use, and a significant improvement in vision close to normal levels after 8 months of treatment.

◇Neurona Therapeutics Announces Successful Completion of $120 Million Financing. The funds raised will be used to advance the development of the company's off-the-shelf cell therapy pipeline, including its lead investigational candidate product, NRTX-1001.Currently, NRTX-1001 is being evaluated in an open-label, single-arm phase 1/2 clinical trial for the treatment of drug-resistant mesial temporal lobe epilepsy (MTLE).

Trial results published in December last year showed that the first two subjects had 32 and 14 epileptic seizures per month, respectively, during the six-month baseline period. After more than a year of treatment with NRTX-1001, the total number of epileptic seizures decreased by more than 95% compared to the baseline, and the severe focal seizures affecting consciousness disappeared.

NRTX-1001 is a regenerative neuron therapy candidate product derived from human pluripotent stem cells. These fully differentiated interneurons secrete the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).After a single administration, these human interneurons can achieve targeted integration in the epileptic regions of the brain and durably suppress epileptic activity.

◇BioNTech and Autolus Therapeutics recently announced a strategic collaboration aimed at advancing the development and commercialization of their autologous CAR-T cell therapies. Under the agreement, Autolus will receive a $50 million upfront payment, and BioNTech will make a $200 million equity investment in Autolus.

BioNTech to Gain Access to Autolus' Manufacturing Capacity, Clinical Trial Sites, and Commercialization Network in the UK, Accelerating the Development of BioNTech’s Investigational Therapy BNT211 Across More CLDN6-Positive Tumor Types. BioNTech Anticipates Including Over 10 Potential Registrational Clinical Trials in Its Pipeline by the End of 2024.

Autolus will lead the development and commercialization of its investigational therapies AUTO1/22 and AUTO6NG in any oncology indications, with BioNTech having the option to support certain development activities and co-commercialize the two candidate products in specific regions. AUTO1/22 is a dual-target CAR-T therapy that targets CD19 as well as CD22. AUTO6NG is a next-generation GD2-targeted T-cell therapy that incorporates additional cellular programming components to overcome immunosuppressive mechanisms in the tumor microenvironment.

Autolus also granted BioNTech an exclusive license to develop and commercialize therapeutic products utilizing certain proprietary binders from Autolus.

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References:

[1] Adverum Biotechnologies Announces Positive Preliminary Efficacy and Safety Data from LUNA Phase 2 Trial of Ixo-vec in Patients with Wet AMD. Retrieved February 8, 2024, from https://www.globenewswire.com/news-release/2024/02/08/2825871/32452/en/Adverum-Biotechnologies-Announces-Positive-Preliminary-Efficacy-and-Safety-Data-from-LUNA-Phase-2-Trial-of-Ixo-vec-in-Patients-with-Wet-AMD.html

[2] Beacon Therapeutics Announces Positive 12-Month Data from Phase 2 SKYLINE Trial of AGTC-501 in Patients with X-Linked Retinitis Pigmentosa. Retrieved February 8, 2024, from https://www.prnewswire.com/news-releases/beacon-therapeutics-announces-positive-12-month-data-from-phase-2-skyline-trial-of-agtc-501-in-patients-with-x-linked-retinitis-pigmentosa-302056840.html

[3] Krystal Biotech Announces Publication in the New England Journal of Medicine on the Application of B-VEC to Treat Ocular Complications in Patient with Dystrophic Epidermolysis Bullosa. Retrieved February 8, 2024, from https://www.globenewswire.com/news-release/2024/02/08/2825862/0/en/Krystal-Biotech-Announces-Publication-in-the-New-England-Journal-of-Medicine-on-the-Application-of-B-VEC-to-Treat-Ocular-Complications-in-Patient-with-Dystrophic-Epidermolysis-Bull.html

[4] BioNTech and Autolus Announce Strategic CAR-T Cell Therapy Collaboration to Advance Pipeline and Expand Late-Stage Programs. Retrieved February 8, 2024, from https://www.globenewswire.com/news-release/2024/02/08/2825810/0/en/BioNTech-and-Autolus-Announce-Strategic-CAR-T-Cell-Therapy-Collaboration-to-Advance-Pipeline-and-Expand-Late-Stage-Programs.html

[5] Genenta Demonstrated Reprogramming of the Tumor Microenvironment in GBM Patients, Paving the Way for Innovative Treatments of Solid Tumors. Retrieved February 8, 2024, from https://www.globenewswire.com/news-release/2024/02/08/2825783/0/en/Genenta-Demonstrated-Reprogramming-of-the-Tumor-Microenvironment-in-GBM-Patients-Paving-the-Way-for-Innovative-Treatments-of-Solid-Tumors.html

[6] REGENXBIO Announces Pivotal Trial of RGX-121 for the Treatment of MPS II Achieves Primary Endpoint. Retrieved February 8, 2024, from https://www.prnewswire.com/news-releases/regenxbio-announces-pivotal-trial-of-rgx-121-for-the-treatment-of-mps-ii-achieves-primary-endpoint-302056283.html

[7] REGENXBIO Announces Completion of Enrollment in Cohort 2 and Additional Positive Interim Data in AFFINITY DUCHENNE® Trial. Retrieved February 8, 2024, from https://www.prnewswire.com/news-releases/regenxbio-announces-completion-of-enrollment-in-cohort-2-and-additional-positive-interim-data-in-affinity-duchenne-trial-302055713.html

[8] Ultragenyx Announces Data Demonstrating Treatment with UX111 Results in Significant Reduction in Heparan Sulfate Exposure in Cerebrospinal Fluid Correlated with Improved Long-term Cognitive Function in Patients with Sanfilippo Syndrome Type A (MPS IIIA). Retrieved February 8, 2024, from https://www.globenewswire.com/news-release/2024/02/06/2824223/20739/en/Ultragenyx-Announces-Data-Demonstrating-Treatment-with-UX111-Results-in-Significant-Reduction-in-Heparan-Sulfate-Exposure-in-Cerebrospinal-Fluid-Correlated-with-Improved-Long-term-.html

[9] Sangamo Therapeutics Announces Updated Phase 1/2 STAAR Study Data in Fabry Disease Showing Sustained Benefit and Differentiated Safety Profile. Retrieved February 8, 2024, from https://www.businesswire.com/news/home/20240205333085/en

[10] Adverum Biotechnologies Announces $127.5 Million Private Placement Financing. Retrieved February 8, 2024, from https://www.globenewswire.com/news-release/2024/02/05/2823441/32452/en/Adverum-Biotechnologies-Announces-127-5-Million-Private-Placement-Financing.html

[11] Neurona Therapeutics Raises $120M to Advance Groundbreaking Pipeline of Regenerative Cell Therapy Candidates for Chronic Neurological Disorders. Retrieved February 8, 2024, from https://www.globenewswire.com/news-release/2024/02/08/2825959/0/en/Neurona-Therapeutics-Raises-120M-to-Advance-Groundbreaking-Pipeline-of-Regenerative-Cell-Therapy-Candidates-for-Chronic-Neurological-Disorders.html

[12] Coeptis Therapeutics to Pursue Phase 2 Program Using Proprietary First-in-Class Allogeneic NK Cell Therapy for the Treatment of Viral Infections. Retrieved February 8, 2024, from https://www.prnewswire.com/news-releases/coeptis-therapeutics-to-pursue-phase-2-program-using-proprietary-first-in-class-allogeneic-nk-cell-therapy-for-the-treatment-of-viral-infections-302055678.html

[13] AvenCell Announces First Patient Dosed in a Phase IA Study with lead product candidate AVC-201, a Novel Allogeneic CD123-Directed Switchable CAR-T Investigational Therapy for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia and other CD123 Hematological Malignancies. Retrieved February 8, 2024, from https://www.prnewswire.com/news-releases/avencell-announces-first-patient-dosed-in-a-phase-ia-study-with-lead-product-candidate-avc-201-a-novel-allogeneic-cd123-directed-switchable-car-t-investigational-therapy-for-the-treatment-of-relapsedrefractory-acute-myeloid-leuk-302053495.html

[14] Triumvira Immunologics Announces First Patient Dosed in Phase I/II Cell Therapy Trial of TAC101-CLDN18.2 for the Treatment of Claudin 18.2+ Solid Tumors. Retrieved February 8, 2024, from https://www.prnewswire.com/news-releases/triumvira-immunologics-announces-first-patient-dosed-in-phase-iii-cell-therapy-trial-of-tac101-cldn18-2-for-the-treatment-of-claudin-18-2-solid-tumors-302052750.html

[15] NouvNeu001 Achieves Milestone with Successful Dosing of First Patient, Signaling Smooth Progress in iRegene Therapeutics' Multicenter Clinical Trial for Innovative Novel Parkinson's Disease Therapy. Retrieved February 8, 2024, from https://www.prnewswire.com/news-releases/nouvneu001-achieves-milestone-with-successful-dosing-of-first-patient-signaling-smooth-progress-in-iregene-therapeutics-multicenter-clinical-trial-for-innovative-novel-parkinsons-disease-therapy-302053243.html

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