The final patient has completed dosing in the multicenter phase 1 clinical trial (NCT04925206) of EdiGene’s ET-01, an investigational autologous CRISPR-Cas9 Modified CD34+ human hematopoietic stem and progenitor cell product intended to treat transfusion dependent 

ET-01 features a CRISPR/Cas9-modified erythroid-specific enhancer of the 

 gene. The investigational new drug (IND) application for the trial was cleared by the China National Medical Products Administration’s Center for Drug Evaluation in January of 2021 and the first patient was enrolled in September of the same year.

 The study has now dosed 8 patients in total.

“The dosing of the 8th and last patient in our multi-center phase 1 study is another important milestone in our efforts to bring a potentially 1-time cure for patients with TDT,” Dong Wei, PhD, chief executive officer, EdiGene, said in a statement regarding the news.

 “We are deeply grateful for the patients and their families, as well as investigators whose participation and dedication have played a critical role in advancing the phase 1 study. The study outcome will shed important insight on the safety and efficacy profile of ET-01 in this particular patient population, and when at an appropriate time in 2023, we plan to discuss with regulators on phase 2 clinical study strategy and design, bringing ET-01 1 step closer to patients with TDT in China.”

The open-label, single-arm clinical trial was open to patients aged 12 years to 35 years who had been diagnosed with 

. Participants were required to have a Lansky/Karnofsky score of at least 70% and to be eligible for hematopoietic stem cell transplantation and conditioning with busulfan in the investigator's judgement. Patients with associated α-thalassemia, any clinically significant acute or uncontrolled infections, a history of uncontrolled epilepsy or other mental disorders, or previous treatment with allogeneic bone marrow transplantation or gene therapy were excluded from participation. It was noted that other inclusion and exclusion criteria may apply.

Patients received intravenous ET-01 infusion after myeloablative conditioning with busulfan. The study’s primary end points are the frequency and severity of adverse events (AEs) and serious AEs, all-cause mortality, the incidence of transplant-related mortality, total lymphocyte count, and the proportion of patients with abnormal proliferation of blood cells. The trial includes locations in 3 cities in China and has an estimated completion date of June 30, 2024.

An earlier, single-patient clinical trial (NCT04390971) for ET-01 was initiated on August 11, 2020. The company plans to present preliminary data from that patient’s treatment at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition, being held December 10-13, 2022 in New Orleans, Louisiana.

 The presentation will include data indicating that ET-01 treatment allowed for timely engraftment and significantly and durably raised production of fetal hemoglobin. EdiGene additionally noted that the patient was transfusion-independent from 3 months after administration of the treatment through 15 months to the May 20, 2022, data cut-off. In terms of safety, ET-01 here demonstrated a profile consistent with autologous hematopoietic stem cell transplantation and myeloablative conditioning.

“I am glad to see that the patient, who needed a transfusion of red blood cells every 2 weeks, has been transfusion free since February 2021,” Jun Shi, director, Regenerative Medicine Clinic at the Institute of Hematology and Blood Diseases Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College, and first presenter of the study, said in a statement earlier this month.

 “We are conducting additional research to further elucidate how gene-edited hematopoietic stem cells engraft and differentiate, hoping to shed light on the implication of gene editing in the short and long term.”

1. Edigene announces completion of last patient dosing in phase I clinical trial of ET-01, its investigational gene-editing hematopoietic stem cell therapy for transfusion dependent β-thalassemia. News release. EdiGene, Inc. November 18, 2022. 

2. Edigene announces approval of its IND application for its CRISPR/cas 9 gene-editing hematopoietic stem cell therapy ET-01 in β-thalassemia by China National Medical Products Administration. News release. EdiGene, Inc. January 18, 2021. 

3. Edigene to present preliminary safety and efficacy results of an investigator initiated trial for ET-01, its investigational gene editing hematopoietic stem cell therapy, at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition. News release. EdiGene, Inc. November 3, 2022. 

Articles

The study has now dosed 8 patients in total. 

Final Patient With TD β-thalassemia Dosed in Gene-edited Cell Therapy Trial 

 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. Omidubicel PDUFA Date Extended to May 2023

Omidubicel’s BLA was originally accepted for priority review in August of this year.

2. Terese Hammond, MD, on Investigating iNKT Cells in COVID-Associated ARDS

The director of the CCU/ICU at Saint John’s Health Center discussed unmet respiratory treatment needs in the beginning of the COVID-19 pandemic.

3. Amod Sarnaik, MD, on New Frontiers in Cell Therapy for Advanced Melanoma

Sarnaik discussed several potential areas of innovation on the horizon.

4. MPS Type IIIA Gene Therapy Trial Fails Primary Endpoint

Statistically significant improvements in cognitive development were only seen in the cohort of patients younger than 30 months.

5. Hemgenix First Gene Therapy Approved for Hemophilia B

A marketing authorization application for etranacogenedezaparvovec is currently under review by the EMA.

Review top news and interview highlights from the week ending November 25, 2022. 

CGTLive’s Weekly Rewind – November 25, 2022 

The neural cell therapy NRTX-1001 was well-tolerated and reduced seizures in the first 2 patients with drug-resistant unilateral 

 (MTLE) treated in a first-in-human phase 1/2 study (NCT05135091).

“The early clinical results with NRTX-1001 in epilepsy are very encouraging, and we look forward to enrolling additional patients in the study,” Cory R. Nicholas, PhD, president and chief executive officer, Neurona Therapeutics, said in a statement.

 “NRTX-1001 is designed to be an off-the-shelf, one-time administration therapy with the potential to durably eliminate seizures and provide a new regenerative cell therapeutic approach in patients for whom anti-seizure medication has failed. It has the potential to be disease-modifying without the tissue-destructive procedural risks associated with lobectomy. Further, there are many who are not currently eligible for lobectomy surgery who may be eligible for NRTX-1001 in the future. We are sincerely grateful to everyone involved in the development of NRTX-1001, including the first participants in this pioneering study, their families, and the respective clinical site teams.”

The patients had up to a 9-year history of seizures and, in the 6 months prior to NRTX-1001 treatment, had averages of 32 and 14 seizures a month while on antiepileptic medications. Both patients received the single dose of NRTX-1001 without any treatment-related serious adverse events (AEs). One patient has had 4 seizures in the first 3 months after treatment and the other has not had any seizures as of the first week after treatment. These data were presented at the ISSCR Boston International Symposium: Translating Pluripotent Stem Cell Discoveries to the Clinic: Preclinical, Manufacturing, and Regulatory Strategies for Success on November 19, 2022, by Nicholas.

Upstaza Approved for AADC Deficiency in UK

NRTX-1001 is designed to repair neural networks by delivering human interneurons that provide long-term secretion of the gamma-aminobutyric acid (GABA) inhibitory neurotransmitter. Participants in the study receive a single stereotactic intracerebral administration of the interneuron cells and remain on a immunosuppressive regimen for 1 year. Evidence of neural cell viability and local inflammation will be assessed using MRI scans for 2 years following the transplant.The single-arm, dose-escalation first stage of the study will enroll up to 10 participants with MTLE and the second will enroll up to 20 to be treated and 10 for a sham comparator arm.

The study is primarily assessing the incidence and severity of AEs over 1 year after NRTX-1001 administration compared to sham treatment. Secondary end points include the change in seizure frequency and the difference in the 75% responder rate between participants who received NRTX-1001 in stage 2 and those who received the sham treatment. The 

“Neurona’s regenerative cell therapy approach has the potential to provide a single-administration, non-destructive alternative for the treatment of drug-resistant focal epilepsy,” Harish Babu, MD, PhD, assistant professor of neurosurgery, SUNY Upstate Medical University and the surgeon who administered the first dose of NRTX-1001, said in an earlier statement.

 “Currently, people with mesial temporal lobe epilepsy who are not responsive to anti-seizure medications have few options, such as an invasive surgery that removes or destroys the affected brain tissue.”

1. Neurona Therapeutics presents encouraging clinical data from first-ever regenerative human cell therapy trial in adults with drug-resistant focal epilepsy and shows supporting manufacturing, delivery, and preclinical data. News release. Neurona Therapeutics. November 21, 2022. 

https://finance.yahoo.com/news/neurona-therapeutics-presents-encouraging-clinical-130000565.html


2. Neurona Therapeutics announces initial subject dosed in first clinical trial of regenerative human cell therapy, NRTX-1001, in adults with drug-resistant focal epilepsy. News release. Neurona Therapeutics. June 29, 2022. https://www.neuronatherapeutics.com/news/press-releases/062922/ 

The first participant has been followed-up for 3 months so far after treatment while the second is only 1 week post-treatment. 

NRTX-1001 Reduces Mesial Temporal Lobe Epilepsy Seizures in 2 Patients 

The cell and gene therapy sectors are growing exponentially, with new players emerging daily and much progress being made both in and out of the lab. 

Around the Helix is your chance to catch up with the latest news in cell and gene therapies, including partnerships, pipeline updates, and more.

1. Hemgenix First Gene Therapy Approved for Hemophilia B

The FDA has approved UniQure and CSL Behring’s etranacogene dezaparvovec (EtranaDez), now marketed as Hemgenix, for treating adults with hemophilia B who currently use Factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.

2. Upstaza Approved for AADC Deficiency in UK

PTC Therapeutics’ Upstaza (eladocagene exuparvovec), a recombinant adeno-associated virus serotype 2 (AAV2)-based gene therapy intended to treat aromatic L–amino acid decarboxylase (AADC) deficiency with a severe phenotype, has received marketing authorization from the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of children aged 18 months or older.

3. Lifileucel BLA Completion Pushed Back to Q1 2023

New FDA feedback has pushed back Iovance Biotherapeutics’ expected 2022 lifileucel biologics license application for treating melanoma to the first quarter of 2023. The FDA has requested supplemental validation information and comparability data for lifileucel, which the company will address “promptly”.

4. Omidubicel PDUFA Date Extended to May 2023

The Prescription Drug User Fee Act (PDUFA) date for Gamida Cell’s omidubicel, an investigational allogeneic hematopoietic stem cell transplant (HSCT) candidate intended for the treatment of patients with hematological cancers, has been extended from its original January 30, 2023, date to May 1, 2023.

5. Thermo Fisher Scientific Unveils Gibco CTS AAV-MAX Helper-Free AAV Production System

The system is intended to provide cost-effective current good manufacturing practice production of adeno-associated virus (AAV) vectors for gene therapies at large scales.

6. Replay Launches Second HSV Gene Therapy Company

Telaria will pursue new gene therapies for rare skin diseases that utilize Replay's herpes simplex virus (HSV) delivery vector.

7.  Sarcura Successfully Closes Round of Financing for Cell Therapy Manufacturing System Prototype

The €7M Seed Plus funding round will enable Sarcura to advance development of its platform, which uses silicon chip technology and microfluidic processing.

8. PerkinElmer Launches New Viral Vector Assays

The 7 Adeno-associated Virus Vectors (AAV) Detection Kits utilize the company's AlphaLISA technology and are intended expand assay range and speed up the research for new gene therapies.

9. Umoja Biopharma, IASO Biotherapeutics to Collaborate on New Cell Therapies for Hematological Cancers

The collaboration will combine Umoja's iCIL platform with IASO's chimeric antigen receptors for the development of new off-the-shelf therapies, and will start with a focus on acute myeloid leukemia.

10. Coeptis Therapeutics Partners With IQVIA To Bring New CAR-T Technology to the Clinic

IQVIA will help determine ideal targets for Coeptis Therapeutics' SNAP-CAR platform, which was licensed the University of Pittsburgh.

11. Fujifilm Announces Details of New Cell Culture Media Manufacturing Facility Plans

The company has invested $188 million in the planned facility, which will be more than  250,000 square feet in area and located in Research Triangle Park, North Carolina.

12. Pan Cancer T, NecstGen Partner to Bring New TCR-T Therapies to the Clinic

NecstGen will provide process and analytical development services for Pan Cancer T's investigational TCR-T therapies, which the company intends to progress towards clinical evaluation for the treatment of solid tumors.

Catch up on the latest news, breakthroughs, and announcements from biotechnology companies making advancements in cell and gene therapies. 

Around the Helix: Cell and Gene Therapy Company Updates – November 23, 2022

“Cellular therapy for metastatic melanoma has been a relatively niche field until recently. This reminds me of the implementation of solid organ transplant. At the onset of this type of complex therapy, the therapy was initially implemented at select centers of excellence. But as the therapy gets developed more and practitioners learn more about this exciting technology, I think the technology will be moved to more and more centers in the future. However, this will require some institutional investment in infrastructure...”

Cell therapy is an emerging area of interest for the treatment of patients with advanced melanoma. Iovance Biotherapeutics’ lifileucel (LN-144), an investigational autologous tumor infiltrating lymphocyte (TIL) therapy, is currently being investigated as a potential new treatment option for these patients.

, MD, FACS, Moffitt Cancer Center and University of South Florida, 

 from the phase 2 C-144-01 (NCT02360579) clinical trial evaluating lifileucel at 

the Society for Immunotherapy of Cancer’s (SITC)

 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts.

, Sarnaik discussed several areas of interest in cell therapy research on the horizon for advanced melanoma. He specifically mentioned investigations into CRISPR/Cas9 genetic manipulation of cellular products, which is already underway. Sarnaik also spoke about biomarker development as an area of unmet need for advanced melanoma patients that could be addressed with the help of patient-derived materials obtained during treatment with lifileucel or other cell therapies. He also briefly discussed combination therapy, another area of ongoing research.

Videos

Sarnaik discussed several potential areas of innovation on the horizon. 

Amod Sarnaik, MD, on New Frontiers in Cell Therapy for Advanced Melanoma 

The FDA has approved UniQure and CSL Behring’s etranacogene dezaparvovec (EtranaDez), now marketed as Hemgenix, for treating adults with 

who currently use Factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” Peter Marks, MD, PhD, director, Center for Biologics Evaluation and Research, FDA, said in the release.

“Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

The FDA accepted the biologics license application (BLA) for Hemgenix for priority review in May 2022.

 The BLA was supported by positive data from 54 participants with hemophilia B in the pivotal phase 3 HOPE-B trial (NCT03569891).

The HOPE-B trial met its primary endpoint of reduction in annualized bleeding rate (ABR) post-treatment compared with baseline FIX prophylactic therapy, with mean FIX activity of 39.0 IU/dL (standard deviation [SD], 18.7; range, 8.2-97.1) at 6 months post-treatment and 36.9 IU/dL (SD, 21.4; range, 4.5-122.9) at 18 months.

The 52-week adjusted ABR for all bleeds was reduced by 64% (

= .0002) from 4.19 during the ≥ 6-month lead-in period to 1.51 during months 7-18 and there was an overall 97% reduction in mean unadjusted annualized FIX consumption.

BioMarin Prepares for PDUFA Delay for Val-Rox Hemophilia Gene Therapy

Hemgenix was well-tolerated, with no serious treatment-related adverse events (AEs), although common AEs include liver enzyme elevations, headache, mild infusion-related reactions and flu-like symptoms. No inhibitors to FIX were reported.

“The HOPE-B trial was the first phase 3 study in hemophilia B and has the largest cohort of gene therapy for hemophilia B to report to date. It is also the only trial to include participants with neutralizing antibodies to AAV and this is really unique," investigator 

, professor and head of coagulation disorders and Comprehensive Care Centre, University Hospital of Frankfurt, Germany, previously told 

Hemgenix is an adeno-associated virus gene therapy that delivers the Padua variant of the FIX gene to liver cells via an intravenous infusion. It was previously granted breakthrough therapy designation by the FDA and Priority Medicine (PRIME) regulatory initiative by the EMA. The EMA is currently reviewing a Marketing Authorization Application for EtranaDez in hemophilia B.

Earlier this year, the Institute for Clinical and Economic Review (ICER) concluded that the price of EtranaDez should be

.4 They also suggested a cap of $1.9 million for valoctocogene roxaparvovec (val-rox; Roctavian; BioMarin) for hemophilia A. CSL Behring announced that Hemgenix would cost $3.5 million, less than the $5 million "shared savings" that ICER estimated the therapy could save for the overall healthcare system.

ICER EtranaDez a B+ score for “moderate certainty” of a small or substantial health benefit and “high certainty” of at least a small net health benefit compared with factor IX prophylaxis.

 Primary concerns were limited long-term follow-up safety and durability data.

“HEMGENIX is unique in its approach to increasing mean factor IX activity and hemostatic protection in those with hemophilia B, and today’s approval could fundamentally transform the treatment paradigm for this life-long condition,” investigator Steven Pipe, MD, professor and the Laurence A. Boxer Research Professor of Pediatrics and Professor of Pathology, University of Michigan, said in a statement.

 “As a clinician, I look forward to being able to provide a new treatment option that may help patients treated with HEMGENIX become free from the regular infusion schedule that many people living with hemophilia B rely on to protect them from the debilitating effects of the condition.”

1. FDA approves first gene therapy to treat adults with hemophilia B. News release. FDA. November 22, 2022. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b


2. uniQure Announces FDA Acceptance of Biologics License Application for EtranacogeneDezaparvovec under Priority Review. News release. uniQure. May 24, 2022. 

https://tools.eurolandir.com/tools/Pressreleases/GetPressRelease/?ID=4109235&lang=en-GB&companycode=nl-qure&v=


3. uniQure and CSL Behring announce primary endpoint achieved in HOPE-B pivotal trial of EtranacogeneDezaparvovec gene therapy in patients with Hemophilia B. News release. UniQure. December 9, 2021. https://www.cslbehring.com/newsroom/2021/hope-b-gene-therapy-for-hemophilia-b-topline-results
4. Institute for Clinical and Economic Review. Gene therapy for hemophilia B and an update on gene therapy for hemophilia A: Effectiveness and value. November 3, 2022. https://icer.org/wp-content/uploads/2022/05/Hemophilia_Revised-Report_Updated_For-Publication_110322.pdf
5. U.S. Food and Drug Administration approves CSL’s HEMGENIX® (etranacogene dezaparvovec-drlb), the first gene therapy for hemophilia B. News release. CSL Behring. November 22, 2022. https://www.cslbehring.com/newsroom/2022/fda-hemgenix


A marketing authorization application for etranacogene dezaparvovec is currently under review by the EMA. 