Victoria Johnson

The FDA has cleared Sana Biotechnology’s investigational new drug application (IND) for SC291, a CD19-targeted 

 chimeric antigen receptor (CAR) T-cell therapy for the potential treatment of various B-cell malignancies.

“The clearance of our SC291 IND is an important milestone, putting us closer to our goal of making an important medicine for patients with B-cell lymphomas and leukemias,” Steve Harr, President and chief executive officer, Sana Biotech, said in a statement.

 “We look forward to understanding the safety, potency, and persistence of these cells in patients, and we are optimistic that SC291 can become an important medicine for patients with these difficult cancers. Furthermore, this platform forms the backbone for additional development of CAR T cells targeting CD22, BCMA, and beyond. We expect initial clinical data from the SC291 study later this year and believe insights from this study will better inform our opportunities across the broader platform, both for CAR T cells and for programs outside of cancer such as our pancreatic islet cell therapy for patients with type 1 diabetes.”

SC291 is developed with the use of Sana Biotechnology’s hypoimmune platform that is designed to address immunologic rejection of allogeneic cells with the body, and Sana believes the platform could yield longer CAR T persistence and higher, more durable complete response rates in B-cell lymphomas and leukemias. The platform addresses rejection by disrupting major histocompatibility (MHC) class I and MHC class II expression to hide cells from the adaptive antibody and T cell responses. The platform also overexpresses CD47 to inhibit activation of innate immune responses with macrophages and natural killer cells. Preclinical studies of the platform have demonstrated its ability to cloak cells from immune recognition, meanwhile, preclinical studies of SC291 have supported its potential as a therapy for B-cell malignancies.

Alan Trounson, PhD, MSc, on New Frontiers in Allogeneic Cell Therapy

Sana Biotechnology also revealed plans to submit another IND for SC262, a CD22-targeted allogeneic CAR T therapy also developed with the hypoimmune platform for the same potential indications of SC291, B-cell malignancies including non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL). Sana is also developing cell therapies for multiple myeloma, diabetes, central nervous system diseases, and hemoglobinopathies.

“We are making significant progress with our platforms to address two of the fundamental opportunities to enable greater utilization of cell engineering to treat serious diseases – overcoming immune rejection of allogeneic cells and in vivo delivery of gene modification reagents in a cell-specific manner. We look forward to generating human proof of concept starting next year and are positioning the company to invest fully based upon the clinical data,” Harr said in a previous statement.

1. Sana Biotechnology announces FDA clearance of investigational new drug application for SC291, a hypoimmune-modified, CD19-targeted allogeneic CAR T therapy for patients with B-cell malignancies. News release. Sana Biotechnology. January 26, 2023. 

https://www.globenewswire.com/news-release/2023/01/26/2596469/0/en/Sana-Biotechnology-Announces-FDA-Clearance-of-Investigational-New-Drug-Application-for-SC291-a-Hypoimmune-modified-CD19-targeted-Allogeneic-CAR-T-Therapy-for-Patients-with-B-Cell-M.html


2. Sana Biotechnology confirms key program timelines and announces portfolio prioritization. News release. November 29, 2022. https://ir.sana.com/news-releases/news-release-details/sana-biotechnology-confirms-key-program-timelines-and-announces

Articles

Sana Biotechnology also plans to submit another IND for the same indications for a CD22-targeted CAR T later in 2022. 

Allogeneic CAR T Cleared for B-cell Malignancy Trials 

Carina Biotech has received a “Safe to Proceed” letter for its investigational new drug application (IND) for its LGR5-targeted chimeric antigen receptor (CAR) T-cell therapy CNA3103 to be evaluated in a phase 1/2 trial in participants with 

“Our positive engagement with the FDA marks a major step forward for Carina and our continued efforts to develop CNA3103 as a potential treatment for the third most common cancer in the U.S. and worldwide, colorectal cancer,” Deborah Rathjen, chief executive officer, Carina Biotech, said in a statement. “The FDA’s letter provides the pathway for this clinical trial and further validates that a significant unmet need exists for more effective treatment options for colorectal cancer. Preparations, including site selection, are underway as we aim to commence enrolling patients during the first half of 2023.”

Carina is on track to commence patient enrollment in the study in the first half of 2023. The trial has a target enrollment of 44 participants with metastatic, advanced, LGR5-expressing colorectal cancer that has failed prior lines of chemotherapy. The phase 1 portion of the study will enroll 24 patients in select Australian centers, and, in a Bayesian Optimal Interval design will administer ascending CAR-T cell doses to cohorts of 3 patients each. The trial will assess the safety and tolerability of CNA3103 and determine the recommended phase 2 dose. The phase 2 portion of the study will enroll 20 more patients at the optimal dose in both Australia and the US and evaluate antitumor activity, duration of response, and time to disease progression in patients treated with CNA3103.

Diane Simeone, MD, on Addressing Unmet Needs in Colorectal Cancer, NSCLC, and Pancreatic Cancer

CNA3103 targets LGR5, a cancer stem cell gene highly expressed on advanced colorectal cancer and other cancers, with a particularly poor prognosis associated with LGR5-expressing colorectal cancer. Carina hopes that the therapy’s targeting of cancer stem cells will suppress tumor growth and prevent relapses. Preclinical studies of CNA3103 have demonstrated complete tumor regression without recurrence after a single administration, with exceptional tumor access and prolonged survival.

“This interaction with the FDA corroborates our ability to gain the agency’s support for our proposed trial of CNA3103 in metastatic colorectal cancer patients,” José Iglesias, MD, chief medical officer, Carina Biotech, added to the statement. “Our approach is doubly innovative, in being one of the of emergent CAR-T treatment protocols in solid tumors and in utilizing a novel, and to our knowledge, unique CAR-T construct against LGR5 – an important cancer stem cell-associated antigen linked to the pathogenesis, dissemination, and treatment resistance of colorectal cancer.”

Carina Biotech receives FDA “Safe to Proceed” letter for IND application for phase 1/2a clinical trial of LGR5-targeted CAR-T cell therapy candidate for treatment of advanced colorectal cancer. News release. Carina Biotech. January 24, 2023. https://www.carinabiotech.com/3324-2/

The phase 1 portion of the trial assessing CNA3103 will start enrollment in Australia in the first half of 2023; the phase 2 portion will expand to the US. 

Advanced Colorectal Cancer CAR T Cleared for Trial

The FDA has granted regenerative medicine advanced therapy (RMAT) designation to DiscGenics’ IDCT (rebonuputemcel) 

, which recently demonstrated safe and durable improvements in low back pain, function, quality of life, and pain medication usage by 12 weeks in patients with lumbar degenerative disc disease (DDD) in 2-year data from the phase 1/2 DGX-A01 study (NCT03347708).

"These clinical results demonstrate the incredible potential of DiscGenics's IDCT to safely treat not only the pain and disability associated with DDD with a single injection, but also to address the underlying cause of the disease—the degenerating disc. This is unlike any treatment I have seen in 30 years of practice and unlike any treatment currently available on the market," Matthew F. Gornet, MD, Board Certified Spine Surgeon, The Orthopedic Center of St. Louis, said in a statement.

 "The improvements we observed in disc volume through MRI image analysis suggest DiscGenics's IDCT produces a regenerative effect within the degenerating disc which indicates the ability to halt and possibly reverse the progression of DDD."

DGX-A01 is evaluating the safety and preliminary efficacy of IDCT allogeneic discogenic progenitor cell therapy in 60 participants with symptomatic lumbar DDD versus vehicle and saline controls. The trial enrolled participants from 13 centers across 12 states. It used measures including 100-mm Visual Analog Scale (VAS), Oswestry Disability Index Questionnaire (ODI), and EQ-5D quality of life index score. At 2 years, overall patient follow-up was 85%.

“This designation represents a critical validation of our novel approach to utilizing a manufactured live progenitor cell population derived from donated adult human intervertebral disc tissue to treat disc degeneration,” Flannagan commented on the RMAT designation.

 “As committed stewards of this technology, we look forward to partnering with the FDA to expedite our drug development program and to ultimately realizing the potential of IDCT to address the unmet medical needs of millions of patients with this painful and debilitating condition.”

Preclinical Research, Genetic Testing, Help Pave Gene Therapy’s Road to Clinic in Parkinson Disease

The new data from DGX-A01 announced by DiscGenics included the announcement that the study had met its primary safety endpoint in the high-dose cohort of 20 participants treated with 9,000,000 cells/mL, with no observed treatment-emergent serious adverse events (AEs).

 The primary efficacy endpoint was previously reported to be reached, with statistically significant improvements in back pain scores by over 30% as measured on a 100mm VAS observed in the high dose IDCT group at 52 weeks (–62.79%, P =.0005). A smaller, significant decrease in VAS was also observed in the vehicle control group.

Clinically meaningful improvements in pain (measured by VAS), function (measured by ODI), and quality of life (measured by EQ-5D)seen in the high-dose group were sustained at 6 months, 1 year, 1.5 years, and 2 years post percutaneous injection. Investigators also observed statistically significant improvements in disc volume, with MRI imaging-derived mean changes in disc volume increasing steadily from baseline and reaching statistical significance at week 52 (249.01 mm3, 

 = .028). In the control group, disc volume decreased although not significantly. This treatment group also showed a decrease in both opioid and nonsteroidal anti-inflammatory drug use.

Participants treated with 3,000,000 cell/mL (n = 20) experienced trends of improvement in the measured clinical outcomes, but these were inconsistent. Ten participants in the vehicle control group also had some pain relief as measured by 100mm VAS, but this was not associated with clinically meaningful improvements in function or quality of life. The 10 participants in the saline placebo control group did not have any significant or meaningful improvements in outcomes.

"We are very encouraged by the final two-year results of this study," Flagg Flanagan, chief executive officer and Chairman of the Board, DiscGenics, added to the statement.

 "The significant and durable improvements we saw in pain, function, quality of life, disc volume, and concomitant pain medication usage are critical indicators of the potential for IDCT to change the paradigm of care for patients with DDD."

1. DiscGenics announces positive two-year clinical data from study of discogenic progenitor cell therapy for degenerative disc disease. News release. DiscGenics. January 23, 2023. 

https://www.prnewswire.com/news-releases/discgenics-announces-positive-two-year-clinical-data-from-study-of-discogenic-progenitor-cell-therapy-for-degenerative-disc-disease-301728259.html


2. DiscGenics announces FDA regenerative medicine advanced therapy (RMAT) designation granted to IDCT for degenerative disc disease. News release. DiscGenics. January 26, 2023. https://www.discgenics.com/news-posts/2023/1/26/discgenics-announces-fda-regenerative-medicine-advanced-therapy-rmat-designation-granted-to-idct-for-degenerative-disc-disease

The DGX-A01 study met its primary safety and efficacy endpoints in its highest dose cohort of IDCT. 

Discogenic Progenitor Cell Therapy Shows Improvements in Lumbar Degenerative Disc Disease, Recognized by FDA 

The phase 1/2 TRANSCEND CLL 004 trial (NCT03331198) of

(Breyanzi; Bristol Myers Squibb) met its primary endpoint of achieving complete responses (CRs) compared to historical control in the prespecified subset of patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) refractory to a BTK inhibitor and pretreated with a BCL-2 inhibitor, according to topline results from the study announced today.

“CLL is an incurable disease with complex biology and immune dysregulation that has made the development of T cell-based therapies that provide deep remission very challenging,” Anne Kerber, senior vice president and head, Cell Therapy Development, Bristol Myers Squibb (BMS), said in a statement.

 “In a population that has limited options, the TRANSCEND CLL 004 study represents the first multicenter trial evaluating a CAR T cell therapy in heavily pre-treated patients with relapsed or refractory CLL or SLL, with results showing the potential of Breyanzi as a personalized one-time treatment approach for patients with this difficult-to-treat disease.”

The multicenter, open-label, single-arm TRANSCEND CLL 004 study is evaluating Breyanzi, a CD19-targted chimeric antigen receptor (CAR) T-cell therapy, in patients with R/R CLL or small lymphocytic lymphoma. The trial started off with a phase 1 portion which evaluated safety and determined the phase 2 recommended dose while the phase 2 portion is currently evaluating efficacy of this dose. The phase 2 portion met its primary endpoint of CR rate including CR with incomplete bone marrow recovery, based on independent review committee according to the International Workshop on Chronic Lymphocytic Leukemia 2018 guidelines. More detailed data from TRANSCENNE CLL 004 will be presented at an upcoming medical meeting and BMS will discuss these results with regulatory agencies.

 for patients with large B-cell lymphomas (LBCL) that relapsed or were refractory within 12 months of first-line treatment who are not eligible for hematopoietic stem cell transplant in June 2022.The therapy was original approved in February 2021 for adults with relapsed or refractory diffuse LBCL who have not responded to at least 2 other treatments based off data from the pivotal phase 3 TRANSFORM (NCT03575351) trial.

 It is also approved in Europe, Switzerland, Canada and Japan for R/R LBCL 2 or more lines of systemic therapy and is currently being evaluated in earlier lines of treatment of LBCL and other types of lymphoma and leukemias.

Advocating for Patients With Chronic Lymphocytic Leukemia

BMS also recently announced results from the phase 3 TRANSFORM study (NCT03575351) that demonstrated 

 (SOC) chemotherapy induction and autologous stem cell transplant (ASCT) in second-line treatment of high-risk, R/R LBCL. Second-line liso-cel was found to reduce the risk of an event occurring by 64.4% compared with SOC chemoimmunotherapy induction and ASCT.

 The median event-free survival (EFS) was not yet reached with liso-cel compared with 2.4 months for SOC (HR, 0.356; 95% CI, 0.243-0.522) after a median follow-up of 17.5 months in the open-label study. The 18-month EFS rate was 52.6% with liso-cel (95% CI, 42.3%-62.9%) vs 20.8% with SOC (95% CI, 12.2%-29.5%).

“The primary analysis of the TRANSFORM study confirms the superiority of liso-cel over SOC. Liso-cel resulted in significant improvements in event-free survival, complete response rates, and progression-free survival, with 18-month event-free and progression-free survival rates for liso-cel more than double those of standard of care,” lead study author Jeremy S. Abramson, MD, from the Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, said in a statement.

 “Despite allowing for crossover, overall survival numerically favored liso-cel and a supportive overall survival adjusting for crossover showed an overall survival benefit in favor of liso-cel."


1. Bristol Myers Squibb announces TRANSCEND CLL 004 trial of Breyanzi® (lisocabtagenemaraleucel) met primary endpoint of complete response rate in patients with relapsed or refractory chronic lymphocytic leukemia. News release. Bristol Myers Squibb. January 25, 2023. 

https://www.businesswire.com/news/home/20230125005878/en/Bristol-Myers-Squibb-Announces-TRANSCEND-CLL-004-Trial-of-Breyanzi%C2%AE-lisocabtagene-maraleucel-Met-Primary-Endpoint-of-Complete-Response-Rate-in-Patients-with-Relapsed-or-Refractory-Chronic-Lymphocytic-Leukemia


2. U.S. FDA Approves Bristol Myers Squibb’s CAR T Cell Therapy Breyanzi® for Relapsed or Refractory Large B-cell Lymphoma After One Prior Therapy. News release. Bristol Myers Squibb. June 24, 2022. 

https://news.bms.com/news/details/2022/U.S.-FDA-Approves-Bristol-Myers-Squibbs-CAR-T-Cell-Therapy-Breyanzifor-Relapsed-or-Refractory-Large-B-cell-Lymphoma-After-One-Prior-Therapy/default.aspx


3. FDA Approves New Treatment For Adults With Relapsed Or Refractory Large-B-Cell Lymphoma. News release. FDA. February 5, 2021. 

https://www.prnewswire.com/news-releases/fda-approves-new-treatment-for-adults-with-relapsed-or-refractory-large-b-cell-lymphoma-301223275.html


4. Abramson JS, Solomon SR, Arnason JE, et al. Lisocabtagenemaraleucel (liso-cel) versus standard of care (soc) with salvage chemotherapy followed by autologous stem cell transplantation (asct) as second-line (2L) treatment in patients with relapsed or refractory large B-cell lymphoma (LBCL): primary analysis of the randomized, phase 3 Transform study. 

. 2022;140(suppl 1):1581-1583. doi:10.1182/blood-2022-159702

Breyanzi is currently approved for the second-line or later treatment of large B-cell lymphomas. 

New Data Supports Breyanzi’s Expansion to Chronic Lymphocytic Leukemia 

Iovance Biotherapeutics’ tumor infiltrating lymphocyte (TIL) therapy 

 is creeping closer to clinic for treating both advanced melanoma and metastatic non-small cell lung cancer, according to a recent update from the company.

After discussions with the FDA in the fourth quarter of 2022, Iovance announced the phase 3, confirmatory, TILVANCE-301 study that will investigate lifileucel in combination with pembrolizumab in 670 randomized patients with frontline advanced melanoma compared to pembrolizumab monotherapy. The study’s primary endpoints of objective response rate (ORR) and progression free survival will be used to support approval of the therapy’s biologics license application (BLA) in both frontline advanced melanoma and post-anti-PD-1 therapy advanced melanoma

After initiating in August 2022, Iovance had previously expected to complete the rolling BLA submission for lifileucel for unresectable or metastatic melanoma that progressed on or after prior anti-PD-1/L1 therapy, and if BRAF mutation positive, also prior BRAF or BRAF/MEK inhibitor therapy, by the end of 2022, however, this was 

, and remains on track for, the first quarter of 2023.

 The delay came after the FDA requested supplemental validation information and comparability data for the therapy.

“We continue to make substantial progress with our ongoing BLA submission and remain close to the finish line. The FDA has provided recent valuable feedback to the IND application and remains supportive during the rolling BLA submission process. Iovance is fully committed to securing FDA approval as soon as possible to deliver the first individualized, 1-time cell therapy for advanced melanoma patients, who have a significant unmet medical need,” Frederick Vogt, PhD, JD, interim president and chief executive officer, Iovance, said in a statement.

Amod Sarnaik, MD, on Lifileucel’s Place in the Treatment Lanscape for Advanced Melanoma

In the frontline advanced melanoma indication, Iovance announced positive data on lifileucel in combination with pembrolizumab from 20 participants treated in cohort 1A of the IOV-COM-202 phase 2 trial (NCT03645928).

 The data were consistent with that previously reported, with robust and durable ORRS. More detailed data will be shared later in 2023. 

Iovance also shared data from cohort 3A of patients with non-small cell lung cancer (NSCLC) of the IOV-COM-202 trial, including an ORR of 47% (n =8) in treated patients, with responses observed regardless of PD-L1 status. The study is continuing to enroll,and safety findings have been consistent with  findings of Iovance’s other TIL therapy/pembrolizumab combinations.

In this cohort, response rates were highest in patients who had treatment-naïve disease (80% ORR; n = 4) or post-chemotherapy anti-PD-1-naïve disease (43% ORR; n = 3) and lower in patients with EGFR-mutant disease after prior treatment with tyrosine kinase inhibitors (TKI; 20% ORR; n = 1). Two patients, 1 with post-chemotherapy anti-PD-1 naïve disease and 1 with EGFR-mutant disease after prior treatment with TKI, achieved complete responses and remain in the study. More data will be presented at future medical meetings.

The results and sub analyses will inform a future registration trial of lifileucelin patients with NSCLC, which Iovance plans to meet with the FDA about in 2023. Iovance plans to propose a registration trial in patients with frontline, advanced, EGFR wild-type NSCLC that will be a frontline maintenance study of standard-of-care pembrolizumab and limited duration chemotherapy followed by lifileucel and pembrolizumab combination therapy compared with pembrolizumab monotherapy in responding patients.

1. Iovance Biotherapeutics provides corporate, clinical, and regulatory updates.News release. Iovance Biotherapeutics. January 23, 2023. 

https://finance.yahoo.com/news/iovance-biotherapeutics-provides-corporate-clinical-130000862.html


2. Iovance Biotherapeutics provides update on biologics license application submission for lifileucel in advanced melanoma. News release. Iovance Biotherapeutics. November 18, 2022. https://finance.yahoo.com/news/iovance-biotherapeutics-provides-biologics-license-113000414.html


Iovance is on track to complete its rolling BLA submission for lifileucel in the post-anti-PD1 melanoma indication in the first quarter of 2023. 

Lifileucel Creeps Closer to Clinic for Melanoma, NSCLC 

The FDA has cleared ImmPACT Bio’s investigational new drug application (IND) of its 

chimeric antigen receptor (CAR) T-cell therapy IMPT-314 to be evaluated for safety and preliminary efficacy in a phase 1/2 clinical trial expected to launch in early 2023 in patients with aggressive B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL).

"This IND clearance is a significant milestone for our company," Sumant Ramachandra, MD, PhD, president and chief executive officer, ImmPACT Bio, said in a statement.

 "Results from an investigator-led study evaluating this CAR T-cell therapy demonstrated that 70% of patients achieved a complete response with significant durability of remission. These initial efficacy results combined with the favorable safety profile show that IMPT-314 could potentially be a best-in-class treatment for patients with B-cell lymphomas. We look forward to initiating this phase 1/2 trial to help cancer patients who need new therapies."

IMPT-314 is a CD19/CD20-targeted bispecific "OR-Gate" autologous CAR T-cell therapy based off pioneering work by Yvonne Chen, PhD, associate professor, University of California, Los Angeles (UCLA). The bispecific CAR has demonstrated clinically meaningful results in an ongoing investigator-led phase 1 study at UCLA (NCT04007029) in 10 participants with non-Hodgkin lymphoma (NHL), aggressive B-cell lymphoma, DLBCL, non-indolent or refractory follicular lymphoma (FL), and mantle cell lymphoma (MCL).

 Investigators found that treated participants had a 90% overall response rate and a 70% durable complete response rate. No patients experienced neurotoxicity and cytokine release syndromewas limited to grade 1. The median progression-free survival is 18.2 months with median follow-up time of over 20 months. The study is continuing to enroll patients.

Marty Giedlin, PhD, on Advantages of Allogeneic NK Cell Therapy Approaches

"Dr. Chen designed this bispecific CAR to address antigen escape, which is a key challenge for current approved CD19 therapies for hematological malignancies," principal investigator of the UCLA study Sarah Larson, MD, associate clinical professor of medicine, UCLA, added to the statement.

 "We tested this anti-CD19/CD20 CAR-T cell therapy in patients with relapsed or refractory NHL and are encouraged about the potential of this therapy for patients."

ImmPACT Bio is also developing 2 other platform logic-gated CAR technologies for solid tumor indications. These are a “not”-gated, iCAR-targeted therapy for lung cancer in IND-enabling studies and another “or”-gated, transforming growth factor beta-targeted therapy for glioblastoma multiforme currently in preclinical studies.

1. ImmPACT Bio announces FDA clearance of IND for novel bispecific CAR to treat aggressive B-cell lymphoma. News release. ImmPACT Bio. January 24, 2023. 

https://www.prnewswire.com/news-releases/immpact-bio-announces-fda-clearance-of-ind-for-novel-bispecific-car-to-treat-aggressive-b-cell-lymphoma-301728582.html


2. Larson SM, Walthers CM, Ji B, et al. CD19/CD20 bispecific chimeric antigen receptor (CAR) in naïve/memory T Cells for the treatment of relapsed or refractory non-Hodgkin lymphoma. 

 Published online November 21, 2022. doi: 10.1158/2159-8290.CD-22-0964

The CD19/CD20 dual-targeted CAR is currently under investigation in an investigator-initiated study in UCLA. 

Logic-gated CAR T Therapy Cleared for Lymphoma Trials 

The FDA has granted investigational new drug application (IND) clearance to 3 of TScan Therapeutics’ T-cell receptor (TCR) T cell therapy (TCR-T) programs, T-Plex, TSC-204-A0201, and TSC-204-C0702 for the potential treatment of

“With the clearance of these three INDs, we believe we are the only company in the cell therapy field to have a clear clinical and regulatory path to develop multiplexed TCR-T cell therapy, which we see as critical for achieving durable responses in patients with solid tumors by overcoming resistance due to target or HLA loss. We will continue to rapidly build out our ImmunoBank, allowing us to deliver customized treatments tailored to each patient’s tumor biology,” Gavin MacBeath, PhD, chief scientific and operations officer, said in a statement. “We are now engaged in study start-up activities and look forward to sharing initial clinical data for the most advanced TCRs in this program by the end of 2023.”

T-Plex is the primary IND in the company’s solid tumor programand includes the IND enables the use of multiple, customized, combinations of TCRs for each patient depending on targets and human leukocyte antigen expression. TCR-Ts are madefrom high-affinity, naturally occurring TCRs in TScan’sImmunoBankand each unique TCR-T will be filed as a secondary IND referencing the primary T-Plex IND.

TSC-204-A0201, and TSC-204-C0702 are 2 of these TCR-T products. They target melanoma-associated antigen 1 (MAGE-A1) on HLA types A*02:01 and C*07:02 and will be evaluated forsafety and tolerability in head and neck, melanoma, cervical, and non-small cell lung cancersin the soon-to-initiate phase 1 trial of singleplex and multiplexed TCR-Ts. TScan noted that, to their knowledge, TSC-204-C0702 is the first clinical program in MAGE-A1 for an HLA type other than A*02:01.

Diane Simeone, MD, on Screening Patients for CAR-T Eligibility Before Solid Tumor Relapse

The trial starts with a screening protocolto pre-identify patients with qualifying tumor targets and HLAs. The 3+3 designed trial will initial evaluate each TCR-T as singleplex therapy at 2 dose levels to establish safety, after which it becomes eligible for combination with other cleared TCR-Ts. The screening protocol is expected to initiate in the second quarter of 2023.

“Today marks the first three IND clearances for our solid tumor program and further validates the use of our proprietary platform to identify therapeutic TCRs suitable for clinical development. With the FDA clearance of T-Plex, along with two MAGE-targeting TCRs, we are now one step closer to bringing bespoke cell therapies to patients. We are continuing to build our ImmunoBank, with four more IND filings anticipated in 2023,” David P. Southwell, president and chief executive officer, TSCan Therapeutics, added to the statement.

TScan Therapeutics announces FDA clearance of three investigational new drug applications for the treatment of solid tumors. News release. TScan Therapeutics. January 23, 2023. https://finance.yahoo.com/news/tscan-therapeutics-announces-fda-clearance-120000100.html

The FAD has granted primary IND clearance to the company’s T-Plex program and 2 initial TCR-T therapies. 

TScan Set to Evaluate Multiplex TCR T Therapies for Solid Tumors 

 (IND) of NGN-401 and the company is planning to initiate a phase 1/2 clinical trial to evaluate intracerebroventricular (ICV) injection of the gene therapy in girls with Rett syndrome in 2023.

“Rett syndrome is a particularly challenging disorder for gene therapy because of the requirement to deliver therapeutic levels of MECP2, without also triggering significant side effects associated with too much gene expression,” Rachel McMinn, PhD, chief executive officer and founder, Neurogene, said in a statement. “We believe the preclinical profile for NGN-401 is highly compelling, with the strongest results generated to date across multiple animal models. FDA clearance of NGN-401 represents a significant milestone for Neurogene and the Rett syndrome community and underscores our commitment to turn devastating neurological diseases into treatable conditions, and to improve the lives of patients and families impacted by these rare diseases.”

NGN-401 is an adeno-associated virus (AAV) gene therapy that uses Neurogene’s proprietary gene regulation platform technology Expression Attenuation via Construct Tuning (EXACT) that was developed in collaboration with the University of Edinburgh. EXACT is meant to address toxicities and limitations with conventional gene therapy and is compatible with both viral and non-viral delivery methods. The therapy delivers the full-length human MECP2 gene, expression of which is regulated by EXACT to avoid overexpression-related toxicities.

Preclinical data has shown ICV delivery of NGN-401 was well-tolerated and produced robust efficacy in mouse models of Rett syndrome, including a significant survival benefit and improvements in phenotypes compared to control animals. Expression data showed well-controlled MeCP2 protein levels in key affected brain regions.Conventional MECP2 gene therapy without EXACT regulation showed severe toxicity in mice and early signs of toxicity in non-human primates.

“Rett syndrome is a debilitating disease with a devastating impact on children and their families, with no disease-modifying treatments available,” Bernhard Suter, MD, Assistant Professor of Pediatrics and Neurology, Baylor College of Medicine and neurologist, Texas Children’s Hospital, added to the statement. “The upcoming clinical study of NGN-401, which has a mechanism of action aimed at addressing the root cause of disease, offers hope for improving the lives of those suffering from Rett syndrome.”

NGN-401 is Neurogene’s second investigational gene therapy to enter clinical trials, following NGN-101, which is currently being evaluated in a phase 1/2 clinical trial (NCT05228145) in children with CLN5 Batten disease. NGN-101 is a conventional gene therapy that does not use the EXACT platform. The company also has another conventional gene therapy in IND-enabling studies, NGN-201, for the potential treatment of Krabbe disease.

REFERENCE
Neurogene announces FDA clearance of IND for NGN-401 gene therapy for children with Rett syndrome. News release. Neurogene. January 23, 2023. https://www.businesswire.com/news/home/20230123005045/en/Neurogene-Announces-FDA-Clearance-of-IND-for-NGN-401-Gene-Therapy-for-Children-with-Rett-Syndrome

NGN-401 is Neurogene’s second investigational gene therapy to enter clinical trials. 

Rett Syndrome Gene Therapy Cleared for Clinical Trial 

2022 was nothing short of a roller coaster ride for the biotech space, particularly for those developing novel cell and gene therapies. Waves of layoffs and restructurings were met with a record-setting number of new gene therapy approvals, as well as a novel cell therapy approval for multiple myeloma and several new indications approved for existing cell therapies.

As more therapies are approved, the conversation is rightfully shifting from preclinical pipelines to that of actual treatments and the patients who will receive them, with 2023 shaping up to be an impressive year.

In line with bringing even more life-changing treatments to fruition, 

 chose to focus this year’s roundup on therapies that are within reach of the clinic. With several Prescription Drug User Fee Act (PDUFA) dates already on the calendar and a host of biologics license applications (BLAs) on the horizon, let’s look at 10 therapies we’ll have our eyes on in 2023.

1. Beremagene geperpavec (B-VEC); Krystal Biotech

A topical, redosable gene therapy, B-VEC is currently under FDA review for the treatment of dystrophic epidermolysis bullosa, a rare skin blistering disorder with currently no targeted approved treatment. The result of mutations in the 

 gene that produce a protein that binds the different layers of skin together, B-VEC restores type VII collagen production by delivering functional copies of 

 directly through patients’ open wounds. Current treatment is limited to supportive wound care and infection prevention. 

In a phase 3 trial, treatment with B-VEC was associated with 50% more wounds being completely healed at 3 months than with placebo, with patients having meaningful improvements in pain severity, as well.

Dermatology approvals are having their day in front of the FDA, with 5 novel product approvals in 2022. The approval of B-VEC, which was recently pushed back to a PDUFA date of May 19, 2023 due to an amendment to the application, could help open the floodgates for other investigational gene therapies in conditions like ichthyosis, melanoma, and wound healing.

2. Afamitresgene autoleucel (afami-cel); Adaptimmune Therapeutics

Adaptimmune’s T-cell receptor (TCR) T-cell therapy, afami-cel, is the subject of a rolling BLA submission that, if accepted, may put one of the first engineered TCR cell therapies for a solid tumor in front of the FDA for approval. Indicated for the treatment of synovial sarcoma, the cell therapy targets the MAGE-A4 antigen using Adaptimmune’s SPEAR affinity-enhanced TCR T-cells.

Additional data from the phase 2 SPEARHEAD-1 trial in 52 participants were reported in Q4 2022, with 19 partial respondents, 27 cases of stable disease (51.9%), and 6 cases of progressive disease (11.5%), for a total objective response rate of 36.5% (95% CI, 23.62-51.04). Median duration of response was 50.3 weeks (range, 11.7-122.0+) in patients with synovial sarcoma, and the therapy had an acceptable safety profile overall.

TCR-based cell therapies are a growing subset of T-cell immunotherapy that are garnering the attention of industry and investors alike. Adaptimmune is on track to potentially contribute to a cell therapy breakthrough in solid tumors that the industry has long-awaited.

UniQure is betting on its gene therapy, AMT-130, to be the breakthrough the world has been waiting for in Huntington disease (HD). The company has resumed enrollment and expects to report longer follow-up data from patients dosed in the phase 1/2 trial (NCT04120493) later in 2023 after a voluntary pause in August 2022 due to suspected unexpected severe adverse reactions of localized inflammatory responses and other related symptoms in 3 participants treated with the highest dose of AMT-130.

 AMT-130 is currently the furthest gene therapy in the pipeline for HD, and with waning competition, a lot of hope is resting on its shoulders. Previously, Voyager Therapeutics decided to 

 VY-HTT01 after facing a clinical hold in 2021 in favor of a second-generation AAV approach, and BrainVectis’ BV-101 is 

 for its phase 1/2 trial (NCT05541627) and has not yet reported any data.

Intellia is cornering the rare disease gene therapy market with 2 of its lead CRIPSR/Cas 9 gene editing candidates, NTLA-2001 and NTLA-2002. Early clinical data released in 2022 point to a promising future for the therapies, which are currently being evaluated for the treatment transthyretin (ATTR) amyloidosis with cardiomyopathy and hereditary angioedema, respectively. Demonstrating deep, durable treatment effect, Intellia announced plans to move forward with investigational new drug applications to expand study sites into the US for pivotal studies for both candidates. They also plan to launch a phase 3 study to evaluate NTLA-2001 in ATTR amyloidosis with polyneuropathy, making it the only gene therapy candidate currently in clinical trials for this indication.

 Intellia’s demonstrated success using in vivo gene editing provides real-world proof of concept for the gene therapy approach. Company executives are confident, calling the therapies a “functional cure” for their indications, and competitors, including BioMarin’s BMN331, are still a few large steps behind in the trial process.

5. Delandistrogene moxeparvovec (SRP-9001); Sarepta Therapeutics/Roche

Sarepta is looking forward to hitting a major milestone in May 2023: the 

, the company’s gene therapy for Duchenne muscular dystrophy (DMD), which if approved, would mark the first gene therapy in the indication. Sarepta submitted a BLA under the accelerated approval pathway in September 2022 based off safety and efficacy data in 80 treated participants so far, with up to 4 years of follow-up post-treatment. Its randomized, placebo-controlled, phase 3 EMBARK study is ongoing, which Sarepta has branded as a post-marketing confirmatory trial.

Sarepta nearly has the DMD treatment space cornered, with 3 approved antisense oligonucleotides on the market. The approval of SRP-9001 would mark a new chapter for the company and the disease, as the existing therapies leave something to be desired. Any slip-up in the process opens a door for several competitors, including Capricor and REGENXBIO, both of whom have clinical programs in progress.

6. Exagamglogene autotemcel (exa-cel); CRISPR/Vertex

Hot off the heels of the first of its kind approval of beti-cel (Zynteglo; bluebird bio) in transfusion-dependent beta thalassemia (TDT) is CRISPR/Vertex’s exagamglogene autotemcel (exa-cel), a double-hitter gene-edited therapy being evaluated in phase 2/3 trials for both TDT (CLIMB-THAL-111; NCT03655678) and sickle cell disease (SCD; CLIMB-SCD-121; NCT03745287).

 in TDT and vaso-occlusive events in SCD. Recent data show that 42 patients (95%) reached transfusion independence (follow-up, 0.8-36.2 months), with the remaining 2 patients achieving a 75% and 89% reduction in transfusion volume. All patients (100%) with SCD were free of VOCs (follow-up, 2.0-32.3 months).

With a rolling BLA for both therapies set to be complete by the end of Q1 2023, there’s a good chance that exa-cel could be the very first ex vivo gene-edited therapy approved.

7. Tablecleucel (tab-cel); Atara Biotherapeutics

Tablecleucel (tab-cel) made the news in December 2022 after it became the 

first allogeneic T-cell therapy to be approved 

after the European Commission gave it the green light. The therapy, marketed as Ebvallo, was approved as a monotherapy for the treatment of adult and pediatric patients 2 years of age and older with relapsed or refractory Epstein‑Barr virus positive (EBV+) post‑transplant lymphoproliferative disease (PTLD) who have received at least 1 prior therapy. Atara Biotherapeutics is now pursuing an approval in the US and is planning to meet with the FDA in the first quarter of 2023 to gain 

Tab-cel yielded a 51.2% overall response rate in 43 patients with EBV+PTLD after solid organ transplant (SOT) or hematopoietic cell transplant (HCT) in data presented in December’s Annual Society of Hematology meeting from the phase 3 ALELLE study (NCT03394365). The median time to response was 1 month, median duration of response in 22 responders was 23 months, and overall survival was 18.4 months.

EBV (and Atara) have been a hot topic this year, with the company gaining attention for its EBV-targeted therapy for multiple sclerosis after major epidemiological data made the headlines. Its success with tab-cel lends further credibility to its focus on EBV, making it an especially interesting candidate.

 in its rolling BLA submission, Iovance is on track to submit its investigational tumor infiltrating lymphocyte (TIL) therapy lifileucel by the end of Q1 2023. Its acceptance could mark a significant breakthrough in solid tumors, notably melanoma and cervical cancer.

Data presented at SITC 2022 from its phase 2 trial showed an objective response rate of 31.4% in the 2 cohorts from which data were presented, with 9 complete responses and 39 partial responses. Median duration of response (DOR) was not reached at a median follow up of 36.5 months, and 41.7% of responding patients had a DOR of 24 months or more. Median overall survival (OS) was 13.9 months, and the 12-month OS rate was 54% (95% CI: 45.6%-61.6%).

 Success in this category for Iovancewould bolster its advancing pipeline of mono- and combination TIL therapies, as well as the pipelines of competitors like Tilt Biotherapeutics, whose phase 1 trial in melanoma and head and neck squamous cell carcinoma is currently recruiting.

The world of ophthalmic gene therapies is awaiting a major readout in the first half of 2023 from Nanoscope’s MCO-010, an optogenetic gene therapy intended to treat retinitis pigmentosa and Stargardt disease. The Phase 2 study’s primary efficacy end point is the Y-mobility test, which measures patients’ ability to navigate between LEDs lights in a dimly lit room.

With only 1 other approved therapy for an inherited retinal disease, Nanoscope’s success could open a new chapter in this therapeutic space that’s ripe for expansion.

10. Fidanacogene elaparvovec (PF-06838435); Pfizer

Topline results announced at the end of 2022 showed that treatment with a single infusion of fidanacogene elaparvovec, Pfizer’s investigational gene therapy for the treatment of severe hemophilia B, demonstrated non-inferiority and even superiority in annualized bleeding ratescompared with factor IX treatment, according to findings from the 

 (NCT03861273). Pfizer expects to readout additional data in the first half of 2023 and will continue discussions with regulatory agencies.

 Pfizer’s data comes hot on the heels of CSL Behring and UniQure’s 

 (Hemgenix) approval, which is currently the only therapy approved for the hemophilia B indication. Further success in this space could mean a significant change in the treatment landscape and outcomes for patients.

With confidence building, numerous cell and gene therapies will likely go before the FDA and other global regulatory agencies this year, in addition to key data readouts. 

10 Cell and Gene Therapies to Watch in 2023 

 phase 1/2 FORTIS trial (NCT04174105) of AT845 in patients with late-onset Pompe disease (LOPD). Astellas is working to resume dosing in the trial.

"With that same spirit and focus on patient safety, we look forward to resuming the FORTIS clinical trial and the continued development of AT845 as an important potential new treatment for adults living with LOPD," Ha Tran, executive medical director, Astellas, said in a statement.

 "As always, we are grateful to the patients participating in the FORTIS clinical trial and we remain committed to developing novel therapies for those with a high unmet medical need."

The gene therapy AT845 uses the adeno-associated virus vector 8 to deliver a functional copy of the GAA gene under a muscle-specific promoter. The multi-center, dose-ascending, open-label FORTIS study is primarily evaluating the therapy for safety in participants with LOPD. Participants receive a 1-time peripheral intravenous (IV) infusion of AT845 and are followed for 1 year for safety, clinical, and biochemical endpoints and then 4 years of long-term safety monitoring. Follow-up will assess GAA activity and protein level in patients’ muscles. The study is also evaluating efficacy as measured by change in muscle GAA protein expression and enzyme activity from baseline. Secondary endpoints include improvements in respiratory, endurance, and quality of life measures.

 due to the incidence of a serious adverse event (AE) of peripheral sensory neuropathy.2 The AE was classified as grade 1 and mild but was serious due to medical significance. The FDA told Astellas that there is not enough information to assess the risks to study participants and that more information is needed about the incidence of neuropathy.

Pompe Disease mRNA Therapy Receives FDA Orphan Drug Designation

"Patient safety is our top priority, and we are working closely with the FDA to determine appropriate next steps," Weston Miller, MD, senior medical director, clinical development, Astellas Gene Therapies, said in a statement.

 "We remain committed to the safe and effective development of AT845 and will keep the scientific and patient communities informed with updates as we learn more."

FORTIS had enrolled 4 participants as of December 3, 2021, dosed with 3 x 10

“There is significant unmet need for patients with Pompe disease due to the short half-life, inefficient uptake in the key tissues affected by the disease and the immunogenicity of ERT,” Tahseen Mozaffar, MD, professor of neurology, pathology, and orthopedic surgery; and director, Division of Neuromuscular Diseases, Neurology School of Medicine, UC Irvine, said in a previous statement.

 “AT845 has the potential to be a best-in-class approach as a muscle-directed gene therapy using an AAV8 capsid serotype. It is being investigated to determine whether it can deliver a functional GAA gene that is efficiently transduced to express GAA directly in tissues affected by the disease, including skeletal and cardiac muscle.”

1. Astellas Announces Hold Lifted by FDA on FORTIS Clinical Trial of AT845 Investigational Treatment for Adult Patients with Late-Onset Pompe Disease. News release. Astellas Pharma. January 20, 2023. 

https://finance.yahoo.com/news/astellas-announces-hold-lifted-fda-060000239.html


2. Astellas announces FDA update on the FORTIS clinical trial of AT845 in adults with late-onset Pompe disease. News release. Astellas Pharma. June 26, 2022. 

https://www.prnewswire.com/news-releases/astellas-announces-fda-update-on-the-fortis-clinical-trial-of-at845-in-adults-with-late-onset-pompe-disease-301575359.html


3. Astellas announces positive safety data from the FORTIS study of AT845 in adults with late-onset Pompe disease. News release. February 7, 2022. Accessed February 8, 2022. https://www.biospace.com/article/releases/astellas-announces-positive-safety-data-from-the-fortis-study-of-at845-in-adults-with-late-onset-pompe-disease/

The FDA has lifted a clinical hold placed in the summer of 2022 due to a mild but medically significant case of peripheral sensory neuropathy. 