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Lysosomal Disorders

Oncology

1rem

Authors

Patient use of the 2 FDA-approved gene therapy products for sickle cell disease (SCD), Vertex Pharmaceuticals' and CRISPR Therapeutics’ 

 (exa-cel; marketed as Casgevy) and bluebird bio’s 

 (lovo-cel; marketed as Lyfgenia), in the commercial setting has remained low.

Despite the approval of both gene therapy products by the FDA occurring simultaneously on December 8, 2023, only 4 patients have begun treatment with lovo-cel in the commercial setting, while 20 patients are reported to have begun treatment with exa-cel. Alongside the number for lovo-cel, bluebird also pointed out that this year 4 patients have started on elivaldogene autotemcel (Lenti-D, Skysona), its marketed gene therapy for cerebral adrenoleukodystrophy, and 19 patients have started on betibeglogene autotemcel (beti-cel, Zynteglo), its marketed gene therapy for transfusion dependent thalassemia (TDT). As such, bluebird bio has reported 23 total cell collections for SCD/TDT gene therapies lovo-cel and beti-cel. The company expects that patient uptake of the 3 aforementioned therapies will continue to increase, with 85 patient starts expected across the therapies by the end of the year.

“We are seeing clear evidence that our commercial launch is accelerating, with over 20 cell collections completed in SCD and TDT to date in 2024, and more than 40 additional patients already scheduled to initiate the treatment journey for a bluebird gene therapy by the end of this year,” Andrew Obenshain, MBA, the chief executive officer of bluebird bio, said in a statement.

 “We are further encouraged by the commitment to provide patient access across both commercial and government payers, most recently conveyed through multiple positive Medicaid decisions and the growing number of published coverage policies for Lyfgenia, and we expect approximately 85 patient starts across our portfolio this year.”

Notably, unlike lovo-cel, exa-cel is indicated for both SCD and TDT. Since Vertex has not clarified the breakdown of patients treated with exa-cel for each disease, direct comparison is difficult. The approval in TDT came slightly later, with 

“Vertex delivered another strong quarter of revenue growth coupled with outstanding execution across the business, and we are increasing our full year product revenue guidance,” Reshma Kewalramani, MD, the chief executive officer and president of Vertex, said in an August 1, 2024, statement.

 “Our focus for the second half of the year remains on commercial execution in cystic fibrosis and the global launch of Casgevy, readying for the upcoming potential launches of the vanzacaftor triple in cystic fibrosis and suzetrigine in acute pain, while rapidly advancing a robust pipeline that is poised to deliver value for patients and shareholders for the long term.”

Beyond gene therapy for SCD and TDT, uptake of 

hemophilia gene therapies has also been slow

. Although BioMarin’s valoctocogene roxaparvovec (val-rox, marketed as Roctavian) was approved in June 2023, the first patient outside of clinical trials 

 until December 2023, at the Center for Inherited Bleeding Disorders (CIBD) in California.

 Just this month, BioMarin announced that 

 with regard to val-rox, with the company now mainly focusing on distributing the gene therapy in the United States, Germany, and Italy, the 3 countries in which it has been approved for use by relevant regulatory authorities and is reimbursed.

 UniQure and CSL Behring’s hemophilia B gene therapy, etranacogene dezaparvovec (marketed as Hemgenix), which was 

, has also been slow to be embraced by patients.

“We haven't seen a lot of patients dosed yet,” Steven W. Pipe, MD, a professor of pediatric hematology/oncology at CS Mott Children’s Hospital, told 

 regarding Hemegenix earlier in 2024. “And I don't think that’s related to either the enthusiasm of the clinicians or the patients, but really just the mechanics of how to deliver this in the clinical space, as opposed to the research trials... We've seen that a lot of the hemophilia treatment center sites have got their components together, their infrastructure and personnel so that they can actually start delivering this in the commercial setting. And so, I'm really looking forward to seeing this making a difference in patients' lives in a real world setting.”

REFERENCES
1. bluebird bio reports second quarter 2024 results and highlights operational progress and 2024 guidance. News release. bluebird bio, Inc. August 14, 2024. Accessed August 15, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-reports-second-quarter-2024-results-and-highlights
2. Stock dive for bluebird as sickle cell gene therapy lags behind Vertex rival. News article. Anna Bratulic. FirstWord Pharma. August 14, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5885598
3. Vertex announces US FDA approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia. News release. Vertex Pharmaceuticals Incorporated. January 16, 2024. Accessed August 15, 2024. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene
4. Vertex reports second quarter 2024 financial results. News release. Vertex Pharmaceuticals Incorporated. August 1, 2024. Accessed August 15, 2024. https://investors.vrtx.com/news-releases/news-release-details/vertex-reports-second-quarter-2024-financial-results
5. Center for Inherited Blood Disorders Administers Country's First Gene Therapy Infusion to Treat Hemophilia A. News release. Center for Inherited Blood Disorders. January 11, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5817834?from=article
6. BioMarin Announces Updated Strategy for ROCTAVIAN® to Focus on U.S., Germany and Ital. News release. BioMarin Pharmaceutical Inc. August 5, 2024. Accessed August 15, 2024. https://investors.biomarin.com/news/news-details/2024/BioMarin-Announces-Updated-Strategy-for-ROCTAVIAN-to-Focus-on-U.S.-Germany-and-Italy/default.aspx
7. FDA approves first gene therapy to treat adults with hemophilia B. News release. FDA. November 22, 2022. Accessed August 15, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b

bluebird bio has reported 23 total cell collections for SCD and TDT gene therapies lovo-cel and beti-cel and Vertex Pharmaceuticals has reported approximately 20 cell collections for SCD/TDT gene therapy exa-cel.

Topic

Uptake of Nononcology Gene Therapy Remains Slow in Hematology

(arsa-cel, OTL-200; Orchard Therapeutics) is a gene-edited cell therapy designed to restore arylsulfatase A (ARSA) enzyme activity in children with presymptomatic (PS) late infantile (LI), PS early juvenile (EJ), or early symptomatic (ES) early juvenile (EJ) metachromatic leukodystrophy (MLD).

 arsa-cel under the name Lenmeldy to become the first gene therapy for children with MLD to be approved in the United States, following its approval in the European Union, UK, Iceland, Switzerland, Liechtenstein and Norway under the name Libmeldy.1 Orchard Therapeutics previously announced that the FDA had accepted the biologics license application with 

The FDA’s decision was based on data from patients treated with arsa-cel across 2 clinical trials (NCT01560182; NCT03392987) and additional patients treated in expanded access frameworks. These patients had follow-up times ranging from 0.64 years to 12.19 years (median, 6.76).

“Metachromatic leukodystrophy, is a really important unmet need in the pediatric community. So, this is a disease that's rare, it affects about one in 40,000 children. And up until recently, we have had no curative treatment option for this,” Madeleine Powys, MBBS, Staff Specialist, Blood Transplant and Cell Therapies, The Children's Hospital at Westmead, told 

. "Autologous hematopoietic stem cell gene therapy has offered really promising new hope for these patients.”

Madeleine Powys, MBBS, on Lessons Learned With Libmeldy

Arsa-cel is currently being evaluated in 6 participants enrolled in a phase 3 clinical trial (NCT04283227). The trial enrolled participants with documented biochemical and molecular diagnosis of MLD, including low ARSA activity and identification of 2 disease-causing ARSA alleles, with novel mutations analyzed and excluded as common polymorphisms, alongside specific genotype criteria. Symptomatic individuals must have onset between 7 and 17 years of age, or pre-symptomatic participants must be less than 17 years at treatment initiation and have a sibling with late-juvenile MLD variant, along with normal cognitive and motor function, with seizures or disease signs revealed by instrumental evaluations not being exclusionary if present alone, and compliance with contraceptive use requirements if applicable, with signed informed consent or assent provided by the participant or guardian.

The exclusion criteria for the study include documented HIV infection, malignant neoplasia except localized skin cancer or hereditary cancer syndrome unless successfully treated with no recurrence, myelodysplasia, acute myeloid leukemia, or serious hematological disorders, current enrollment in other interventional trials, prior allogeneic HSPC gene therapy or gene therapy, symptomatic herpes zoster unresponsive to treatment, active tuberculosis unless on antibiotic prophylaxis, acute or chronic stable Hepatitis B or positive Hepatitis C RNA test result unless specific conditions are met, end-organ dysfunction, severe infection not responsive to treatment, or other severe diseases deemed inappropriate for the study by the investigator. Additionally, testing for other transmissible infectious agents may be considered, and participants with elevated liver enzymes or bilirubin may be included after discussion and agreement with the medical monitor.

The study’s primary measures involve assessing the OTpbmsL-200 Arylsulfatase A (ARSA) activity levels in cerebrospinal fluid (CSF) and the neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter brain regions, both evaluated at 24 months post-treatment, with changes from baseline being monitored.

Secondary measures involve evaluating changes in ARSA activity levels in CSF and neuronal metabolite ratio in white matter brain regions, assessing ARSA levels in peripheral blood mononuclear cells (PBMCs) and specific subtypes, comparing neuronal metabolite ratios to baseline, siblings, or untreated controls, determining engraftment through lentiviral positivity in bone marrow progenitors and vector copy number in BM cells and PBMCs, assessing severity scale for brain MRI, neurocognitive function, full neurological clinical examination, gross motor function classification, nerve conduction velocity, Vineland Adaptive Behavior Scale, and monitoring conditioning regimen and non-conditioning-related adverse events up to 8 years post gene therapy, along with hematological reconstitution, infusion-related reactions, immune response, abnormal clonal proliferation, replication-competent lentivirus, and integration site analysis findings over time.

, held February 4-9, in San Diego, California, by Vera Gallo, MD, staff pediatrician, San Raffaele Telethon Institute for Gene Therapy. The data were from 5 patients with LJ MLD that had follow-up ranging from 3.2 to 21.3 months (median, 17.3). At the time of treatment, 3 patients had PS MLD and 2 had ES MLD. The group included a 2.7-year-old girl (PS), a 9.9-year-old boy (ES), a 15.2-year-old boy (PS), a 6.6-year-old girl (PS), and 10.9-year-old boy (ES) as of the December 2023 cutoff date.

"This represents of course, the proof of principle that gene therapy with ex- vivo lentiviral gene therapy into stem cells can correct a lysosomal storage disorder (LSD)... and could be applicable to other LSDS. So we're working on new diseases to bring this approach of enzyme correction also to other LSDs," investigator Alessandro Aiuti, MD, PhD, deputy director, clinical research, and head, Clinical Research Unit, San Raffaele Telethon Institute for gene therapy, and Group leader, Pathogenesis and therapy, primary immunodeficiencies unit, and full professor, Università Vita Salute San Raffaele, and chief of clinic, Pediatric Immunohematology Unit, San Raffaele, told 

Data from these participants showed that they all had normal hematological reconstitution and engraftment that was consistent with arsa-cel outcomes seen in patients with early-onset MLD who have been treated in other settings. Time to neutrophil engraftment ranged from 26 to 42 days (median, 33) posttreatment and time to platelet engraftment ranged from 25 to 46 days (median, 26) posttreatment. ARSA activity reached supranormal levels in the PBMCs and in CD15+ cells and increased to normal levels in the CSF in 3 patients for whom central nervous system pharmacodynamic efficacy measures were available.At 90 days after administration of arsa-cel transduced bone marrow progenitors made up between 23.81% to 81.25% of bone marrow progenitors. At this time point, the PBMCs showed a median vector copy number (VCN) of 0.49 copies/cell and the CD15+ cells showed a median VCN of 0.82 copies/cell.

In terms of safety, there were no serious adverse events (SAEs) deemed potentially related to arsa-cel. One nonserious AE deemed potentially related to the therapy, a case of erythematous rash, occurred in 1 patient. No SAEs deemed potentially related to the Busulfan conditioning regimen occurred; although cases of febrile neutropenia, cytopenia, and stomatitis were deemed to have potential relation to the regimen. An SAE of upper respiratory tract infection occurred in 1 patient. One patient with prolonged thrombocytopenia who had previously experienced treatment-failure with allogeneic transplant in the form of autologous reconstitution was administered thrombopoietin receptor agonist therapy for 5 months. No multilineage engraftment of transduced cells or malignancy occurred and there was no indication of clonal expansion or replication competent lentivirus.

1. FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 18, 2024. Accessed March 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystroph
2. Orchard Therapeutics announces acceptance of biologics license application for OTL-200 in MLD and receives priority review. News release. Orchard Therapeutics. September 18, 2023. Accessed September 18, 2023. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-acceptance-biologics-license
3. Fumagalli F, Calbi V, De Mattia F, et al. Long-term clinical outcomes of atidarsageneautotemcel (autologous hematopoietic stem cell gene therapy) preserves cognitive and motor development in early-onset metachromatic leukodystrophy with up to 12 years follow-up. Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #92
4. Gallo V, Calbi V, De Mattia F, et al. Lentiviral hematopoietic stem cell gene therapy (atidarsageneautotemcel) for late juvenile metachromatic leukodystrophy (MLD). Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #96

The gene-edited cell therapy has been approved as Lenmeldy by the FDA. 

Phase 3 Trial Seeks to Continue Supporting Arsa-Cel Gene Therapy for MLD 

Bristol Myers Squibb’s supplemental biologics license application (sBLA) for marketed autologous CD19-directed CAR T-cell therapy lisocabtagene maraleucel (liso-cel, marketed as Breyanzi) for marginal zone lymphoma (MZL) has been accepted by the FDA with priority review.

 The Prescription Drug User Fee Act goal date for the sBLA has been set for December 5, 2025.

Specifically, the sBLA is under review for adults with relapsed/refractory (R/R) MZL who have been treated with 2 or more previous lines of systemic therapy. The sBLA is supported by data from the phase 2 TRANSCEND FL clinical trial (NCT04245839).

“While initial therapy for MZL can be effective, multiple relapses over the course of several years are common, leaving patients in need of a new treatment option that can provide high, lasting response rates,” Rosanna Ricafort, the vice president and head of Late Development Program Leadership, Hematology and Cell Therapy, at BMS, said in a statement.

 “This FDA acceptance brings us one step closer to potentially standardizing CAR T-cell therapy as a treatment option for MZL, while building on our commitment to bring this personalized therapy to as many eligible patients as possible.”

Results from TRANSCEND FL’s MZL cohort were recently presented at the 2025 International Conference on Malignant Lymphoma (ICML), held June 17 to June 21 in Lugano, Switzerland.

 Among the 66 efficacy evaluable patients with R/R MZL who were treated with liso-cel, the overall response rate (ORR) was 95.5% (95% CI: 87.3%-99.1%; one-sided 

 <.0001) and the complete response rate was 62.1% (95% CI: 49.3%-73.8%; one-sided 

 < .0001). The 24-month rate for duration of response was 88.6% (median follow-up, 21.6 months), the 24-month rate for progression-free survival was 85.7% (median follow-up, 23.8 months), and the 24-month rate for overall survival was 90.4% (median follow-up, 24.5 months).

“Liso-cel achieved high, lasting response rates in patients with R/R MZL, underscoring the potential of this one-time therapy to significantly improve patient outcomes,” TRANSCEND FL study investigator M. Lia Palomba, MD, a lymphoma and cell therapy specialist at Memorial Sloan Kettering Cancer Center, said in a June 2025 statement.

 “Currently, the median survival for patients with marginal zone lymphoma with multiple relapses is 3 to 5 years, signifying an urgent need for transformative therapies that can effectively address this hard-to-treat disease.”

With regard to safety, cytokine release syndrome (CRS) was reported in 76% of patients, with 4% of patients experiencing grade 3 CRS cases. There were no cases of grade 4 or 5 CRS reported. Neurologic events occurred in 33% of patients, with 4% of patients experiencing grade 3 NE cases. There were no grade 4 or 5 NE cases reported. ORR and safety analyses were ongoing at the time the data were reported.

“MZL is an indolent disease but remains an area of high unmet need for patients who are relapsing and reaching later lines of treatment,” Ricafort added to Palomba’s statement.

 “We are proud to present for the first time the primary analysis data from the MZL cohort of TRANSCEND FL, underscoring our commitment to unlock the full potential of cell therapy to help patients living with R/R lymphomas. As highlighted by the data at ICML, Breyanzi continues to cover the broadest patient eligibility of any CAR T for B-cell malignancies and demonstrates a safety profile consistent with clinical trials and in the real-world setting for approved indications.”

REFERENCES
1. Bristol Myers Squibb’s application for Breyanzi (lisocabtagene maraleucel) accepted for priority review by U.S. Food and drug administration (FDA) in fifth cancer type for relapsed or refractory marginal zone lymphoma (MZL). News release. Bristol Myers Squibb. August 4, 2025. Accessed August 4, 2025. https://news.bms.com/news/corporate-financial/2025/Bristol-Myers-Squibbs-Application-for-Breyanzi-lisocabtagene-maraleucel-Accepted-for-Priority-Review-by-U-S--Food-and-Drug-Administration-FDA-in-Fifth-Cancer-Type-for-Relapsed-or-Refractory-Marginal-Zone-Lymphoma-MZL/default.aspx
2. Bristol Myers Squibb presents first data from the marginal zone lymphoma cohort of the TRANSCEND FL trial demonstrating deep and durable responses with Breyanzi (lisocabtagene maraleucel). News release. Bristol Myers Squibb. June 16, 2025. Accessed August 4, 2025. https://news.bms.com/news/corporate-financial/2025/Bristol-Myers-Squibb-Presents-First-Data-from-the-Marginal-Zone-Lymphoma-Cohort-of-the-Transcend-FL-Trial-Demonstrating-Deep-and-Durable-Responses-with-Breyanzi-lisocabtagene-maraleucel/default.aspx

The Prescription Drug User Fee Act goal date for the sBLA has been set for December 5, 2025.

FDA Gives Priority Review to BMS’s Supplemental BLA for Liso-Cel in R/R Marginal Zone Lymphoma

INmune Bio's open-label phase 1/2 CaRe PC clinical trial (NCT06056791), which is evaluating its cell therapy INKmune for the treatment of metastatic castration-resistant prostate cancer (mCRPC), has met its primary and secondary end points. The company additionally noted that the trial is no longer enrolling new patients.

INKmune consists of a pharmaceutical-grade, replication-incompetent human tumor cell line that is intended to conjugate resting natural killer (NK) cells to turn them into memory-like NK cells (mlNK cells) that kill tumor cells, by means of essential priming signals. Notably, conditioning and premedication are not needed before administration of INKmune, which is conducted by intravenous infusion in an outpatient setting.

The primary end point of CaRe PC is the therapy’s safety profile, and INmune Bio reported that INKmune was well-tolerated at the 3 dose levels used in the trial. The company characterized the therapy’s safety profile as “excellent.” INmune also pointed out that the greatest improvement in biomarkers of NK cell activation was observed in patients with low NK cell activation. As a result of this, INmune stated that this will be the population targeted with the therapy in future clinical trials.

“INKmune was safe and effective at activating NK cells in a subset of more than half of these patients with advanced disease,” Mark Lowdell, PhD, the chief scientific officer at INmune Bio, said in a statement.

 “Excitingly we did see, in some patients, individual tumor lesions either reducing in size or completely disappearing during treatment, so we believe this could be evidence of a direct effect on tumor cell killing.”

INmune additionally stated that after CaRe PC, which includes patients with advanced-stage disease, is finished, it intends to design a randomized phase 2b clinical trial that will evaluate INKmune in patients with less severe disease. The company expects that this will allow for INKmune’s potential clinical benefits and effects to be assessed in a more robust manner. According to INmune, INKmune is also tumor agnostic and may be able to be used to treat range of different cancer types that are NK-resistant, with leukemia, lymphoma, myeloma, lung, ovarian, breast, renal, and nasopharyngeal cancer listed as examples. The company also notes that tumor-killing NK cells primed by INKmune have shown the ability to persist in patients for over 100 days.

The dosing of the first patient in CaRe PC 

 The trial’s 3 dose levels for INKmune were 1x10

 cells. The therapy was delivered through infusions on days 1, 8, and 15 of the study, and patients were followed for 6 months posttreatment. Notably, in October 2023, INmune received a favorable patentability opinion on INKmune, also known as INB16, from an examiner from the International Search Authority at the United States Patent & Trademark Office.

“Results of immunotherapy trials for mCRPC have been disappointing,” investigator Matt Rettig, MD, a professor of medicine and urology and medical director of the Prostate Cancer Program at David Geffen School of Medicine, UCLA, and a member of Jonsson Comprehensive Cancer Center, said in a January 2024 statement.

 “After many failures using T-cell focused immunotherapy approaches, targeting natural killer cells—which are abundant in the prostate cancer tumor microenvironment—is a promising and novel strategy. I am optimistic about the therapeutic potential of INKmune, an off-the-shelf innate immune therapy.”

REFERENCES
1. INmune Bio’s CaRe PC trial of INKmune in metastatic castration-resistant prostate cancer meets endpoints and is closed to enrollment. News release. INmune Bio. August 4, 2025. Accessed August 5, 2025. https://www.inmunebio.com/index.php/newsroom/2025-news/muneiosaerialofmuneinetastaticas20250804050503
2. INmune Bio announces first patient dosed in a phase 1/2 study of INKmune in patients with metastatic castration-resistant prostate cancer. News release. INmune Bio. January 2, 2024. Accessed August 5, 2025. https://www.globenewswire.com/news-release/2024/01/02/2802613/0/en/INmune-Bio-Announces-First-Patient-Dosed-in-a-Phase-1-2-Study-of-INKmune-in-Patients-with-Metastatic-Castration-Resistant-Prostate-Cancer.html
3. INmune Bio Inc. patent claims covering INB16 cell line and INKmune therapeutic composition given Favorable Patentability Opinion by International Search Authority. News release. Inmune Bio. October 31, 2023. Accessed August 5, 2025. https://www.inmunebio.com/news-2/2023/543-muneioncatentlaimsovering16ellineand20231031

INmune Bio reported that INKmune was well-tolerated at the 3 dose levels used in the trial.

INmune Bio's INKmune Hits End Points in mCR Prostate Cancer Trial

A patient treated in Allogene Therapeutics’ phase 2 ALPHA3 clinical trial (NCT06500273), which is evaluating investigational CD19-directed allogeneic chimeric antigen receptor (CAR) T-cell therapy cemacabtagene ansegedleucel (cema-cel) as a first-line consolidation treatment for large B-cell lymphoma (LBCL), has died.

Notably, the patient was treated in an arm of the trial evaluating a lymphodepletion regimen consisting of fludarabine and cyclophosphamide and anti-CD52 monoclonal antibody ALLO-647 (FCA), and the patient’s death was attributed to this lymphodepletion regimen rather than to cema-cel itself. Specifically, the patient’s death was attributed to hepatic failure that was thought to have arisen from “disseminated adenovirus infection in the setting of immune suppression”. The patient’s death occurred 54 days after infusion and was attributed to ALLO-647 specifically.

ALPHA3 also includes a separate arm using only a standard fludarabine and cyclophosphamide (FC) lymphodepletion regimen, and Allogene noted that no adenoviral infections or hepatic failures have been reported in patients treated in the FC arm in ALPHA3, nor in any of the company’s other clinical trials utilizing an FC regimen. As such, Allogene stated that it has selected FC as the lymphodepletion regimen to be used going forward in ALPHA3, a decision it made following discussions with the FDA and with the study’s data and safety monitoring board and steering committee.

“The loss of a patient is always deeply saddening, and we extend our heartfelt condolences to the patient’s family,” David Chang, MD, PhD, the president, CEO, and cofounder of Allogene, said in a statement.

 “This event, which prompted an early review of the trial data, compelled us to make a decisive choice—one that may ultimately help bring this potentially lifesaving therapy to patients more quickly. The ability to administer cema-cel following standard FC lymphodepletion in an outpatient setting will simplify study treatment and has the potential to accelerate trial enrollment and streamline regulatory review, ultimately transforming care for patients.”

As a result of the change, ALPHA3 is now a 2-arm trial, in which patients are randomly assigned to receive either cema-cel with FC lymphodepletion or to undergo standard of care observation. The company stated that a futility analysis comparing minimal residual disease conversion for ALPHA3 is planned for the first half of 2026, and that the trial currently has 50 active clinical sites in the United States and Canada. Allogene also pointed out that currently, none of its actively enrolling clinical trials for its therapeutic candidates include the use of ALLO-647.

Among Allogene’s other investigational CAR T therapy products is ALLO-329, an investigational allogeneic CAR T therapy that targets both CD19+ B cells and CD70+ activated T cells, with the intention of eliminating dysfunctional cells of both types in rheumatology indications including active refractory moderate-to-severe systemic lupus erythematous; active severe/refractory idiopathic inflammatory myopathy, specifically including dermatomyositis, immune mediated necrotizing myopathy, and antisynthetase syndrome; and active refractory diffuse systemic sclerosis.

received fast track designation from the FDA

 for the aforementioned indications in April 2025 Furthermore, the CAR T product utilizes the company’s Dagger technology, which is intended to reduce or eliminate the need for lymphodepletion by making the CAR T more resistant to rejection by the patient’s immune system.

"Receiving these designations for ALLO-329 underscores the versatility and transformative promise of this next-generation allogeneic CAR-T investigational product in redefining the autoimmune treatment landscape," Zachary Roberts, MD, PhD, the executive vice president of research and development and the chief medical officer at Allogene, said in an April 2025 statement.

 "Leveraging our extensive expertise, we've developed this off-the-shelf CAR T specifically for autoimmune diseases, prioritizing both scalability and the reduction or elimination of lymphodepletion—a key barrier in this patient population."

REFERENCES
1. Allogene Therapeutics moves forward with the standard fludarabine and cyclophosphamide (FC) lymphodepletion regimen in the ALPHA3 trial for cemacabtagene autoleucel (cema-cel) in first-line consolidation for large B-cell lymphoma. News release. Allogene Therapeutics Inc. August 1, 2025. Accessed August 4, 2025. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-moves-forward-standard-fludarabine-and
2. Allogene granted three U.S. FDA fast track designations (FTD) for ALLO-329, a next-generation dual-targeted CD19/CD70 allogeneic CAR T, for the treatment of lupus, myositis and scleroderma. News release. Allogene Therapeutics Inc. April 7, 2025. Accessed August 4, 2025. https://ir.allogene.com/news-releases/news-release-details/allogene-granted-three-us-fda-fast-track-designations-ftd-allo
3. Allogene Therapeutics secures U.S. FDA IND clearance for ALLO-329, advancing its next-generation allogeneic CAR T into autoimmune diseases. News release. Allogene Therapeutics Inc. January 28, 2025. Accessed August 4, 2025. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-secures-us-fda-ind-clearance-allo-329

The patient’s death was attributed to anti-CD52 monoclonal antibody ALLO-647 rather than to cema-cel itself.

Patient Dies After Receiving Monoclonal Antibody Lymphodepletion Regimen in LBCL Trial for Allogene’s Cema-Cel

The vice president of neuroscience at Voyager Therapeutics shared preclinical data on the company’s AAV-delivered RNA interference therapy, VY-1706.

Rajeev Sivasankaran, PhD, on Voyager’s Single-Dose AAV Strategy for Silencing Tau for Alzheimer Disease

“I think we're very excited about the progress the preclinical data that we've generated so far, and we're on track for continuing to our GLP tox studies, and we look forward to an IND filing in 2026.”

 spoke with Rajeev Sivasankaran, PhD, vice president of neuroscience at Voyager Therapeutics, who presented new preclinical data at 

the American Society of Gene & Cell Therapy (ASGCT) 28th Annual Meeting

, held May 13 to 17, 2025, in New Orleans, Louisiana. His presentation focused on VY-1706, an investigational gene therapy intended to treat Alzheimer disease by delivering tau-silencing siRNA through a single intravenous (IV) dose of adeno-associated virus (AAV).

VY-1706 is still in preclinical development and utilizes the AAV platform to deliver a potent, selective siRNA payload directly to affected brain regions. The therapy demonstrated strong pharmacologic activity in the P301S mouse model of tauopathy, which shows early and progressive tau accumulation. A single IV administration of VY-1706 resulted in broad central nervous system biodistribution and significantly reduced tau mRNA and protein expression, including reductions in pathologic tau.

In nonhuman primate studies, VY-1706 achieved dose-dependent delivery and greater than 50% knockdown of tau protein in the cortex, hippocampus, and other brain regions relevant to AD. Notably, the treatment was well-tolerated, with no clinical signs or changes in cardiac or liver enzymes and no elevation of neurofilament light chain, a surrogate marker for AAV-associated neurotoxicity. “We did not see any clinical signs or clinical chemistry changes, including cardiac enzymes and liver enzymes,” Sivasankaran told 

The company expects to initiate GLP toxicology studies later this year and aims to submit an investigational new drug application in 2026. VY-1706 is 1 of 2 tau-targeting programs at Voyager, alongside a monoclonal antibody currently in human trials.

Click here to view more coverage of the 2025 ASGCT Annual Meeting.

Eric J. Small, MD

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