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Kinnari Patel, PharmD, president and chief operating officer of Rocket Pharmaceuticals, discussed Rocket Pharma’s programs. 

Gene Therapy for Rare Diseases: Latest Updates 

The president and chief operating officer of Rocket Pharmaceuticals discussed the importance of Rare Disease Day. 

Developing Therapies for Rare Diseases: Kinnari Patel, PharmD 

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 

Immix Biopharma and its subsidiary Nexcella's NXC-201, an investigational autologous BCMA-directed chimeric antigen receptor T-cell (CAR-T) therapy, has generated deep hematologic responses in patients with relapsed/refractory (r/r) light chain (AL) amyloidosis who were treated in the phase 1b/2 NEXICART-2 clinical trial (NCT06097832), which is taking place in the United States.

the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting

, held May 30 to June 3, in Chicago, Illinois.

The results reported in the ASCO abstract included 7 patients treated in the trial, whose follow-up ranged from 7 to 209 days (median, 97). Following treatment with NXC-201, all 7 patients (100%) showed normalized pathological disease markers. Furthermore, 6 of the 7 patients showed normalized free light chains (FLCs) at 7 to 14 days posttreatment (median, 7) and a decrease in their dFLC to less than 1 mg/dL. At Day 25 or Day 26 posttreatment, 5 of the 7 patients showed minimal residual disease (MRD) negativity in the bone marrow at a sensitivity of 10

. One patient did not have MRD data available at the data cutoff. First author Heather Landau, MD, the MSKCC Amyloidosis Program director and the NEXICART-2 principal study investigator, and colleagues also noted that at 15 days posttreatment 1 patient achieved a renal organ response along with resolution of the m-spike. It was additionally stated that as of the abstract’s data cut-off, all of the 7 patients were in a state of complete response or very good partial response, and no relapses had occurred. In addition, at 14 days posttreatment 1 patient achieved an improvement in New York Heart Association (NYHA) class from II to I.

With regard to safety, 4 patients experienced grade 1 cases of cytokine release syndrome (CRS) and 1 patient experienced a case of grade 2 CRS. In 3 patients CRS onset began at Day 1 and in 2 patients CRS onset began at Day 3. All cases lasted less than 24 hours after administration of tocilizumab. No neurotoxicity, febrile neutropenia, treatment-related infections, cardiac toxicity, or deaths occurred in the study. Three patients experienced grade 3 cases of neutropenia and 2 patients experienced grade 4 cases of neutropenia. A grade 4 case of acute on chronic kidney injury occurred in a patient who had preexisting stage 4 chronic kidney disease before being enrolled in the study.

“In this first reported US CAR-T clinical trial experience in r/r AL amyloidosis, we demonstrate that NXC-201 can be given safely and resulted in rapid and deep hematologic responses in all patients treated,” Landau and colleagues wrote in the ASCO abstract.

 “Our data suggests that the novel antiBCMA CAR-T NXC-201 may become a valuable treatment option for r/r AL patients.”

The ages of the 7 patients in the trial ranged from 56 to 82 years (median, 66), with 4 women and 3 men included. The patients had received from 2 to 9 previous lines of therapy (median, 4), with 4 of the patients (57%) having previously undergone autologous stem cell transplant. At enrollment, dFLC ranged from 2.4 to 12.1 mg/dL (median, 5.4). Four of the patients (57%) had cardiac involvement, 2 patients had NYHA class II heart failure, and 5 patients had NYHA class I heart failure. Kidney involvement was present in 2 of the 7 patients.

“We are beyond thrilled with the strength of these results,” Ilya Rachman, MD, PhD, the chief executive officer of Immix Biopharma, said in a May 22, 2025, statement.

 “I believe these results could transform the paradigm of relapsed/refractory AL Amyloidosis treatment.”

 regenerative medicine advanced therapy (RMAT) designation from the FDA for r/r AL amyloidosis in February 2025.

 NEXICART-2 is expected to enroll approximately 40 patients in total and is taking place at study sites in California, Michigan, New York, and Ohio.

“Recent NXC-201 FDA RMAT designation and ASCO interim readout demonstrate our progress toward completion of NEXICART-2 enrollment and biologics license application submission,” Gabriel Morris, the chief financial officer of Immix Biopharma, added to the statement.

REFERENCES
1. Landau H. Safety and efficacy data from Nexicart-2, the first US trial of CAR-T in R/R light chain (AL) amyloidosis, NXC-201. Presented at the 2025 ASCO Annual Meeting, held May 30 to June 3, in Chicago, Illinois. Abstract #7508
2. Immix Biopharma announces positive results for NXC-201 at ASCO oral presentation, enabling pathway to best-in-class therapy for relapsed/refractory AL amyloidosis. News release. Immix Biopharma, Inc. May 22, 2025. Accessed June 3, 2025. https://immixbio.com/immix-biopharma-announces-positive-results-for-nxc-201-at-asco-oral-presentation-enabling-pathway-to-best-in-class-therapy-for-relapsed-refractory-al-amyloidosis/
3. Immix Biopharma receives FDA regenerative medicine advanced therapy (RMAT) designation for NXC-201, sterically-optimized CAR-T for relapsed/refractory AL amyloidosis. News release. Immix Biopharma, Inc. February 10, 2025. Accessed June 3, 2025. https://immixbio.com/immix-biopharma-receives-fda-regenerative-medicine-advanced-therapy-rmat-designation-for-nxc-201-sterically-optimized-car-t-for-relapsed-refractory-al-amyloidosis/

Following treatment with NXC-201, all 7 patients (100%) showed normalized pathological disease markers.

Immix Biopharma’s CAR-T NXC-201 Effects Deep Hematologic Responses in Light Chain Amyloidosis

In Episode 1 of ImmunoLogic, Stephen J. Schuster, MD, discussed the potential of treating lymphoma without chemotherapy.

ImmunoLogic, Episode 1: "Chemo-Free Lymphoma? Seriously?" With Stephen J. Schuster, MD

an assistant professor of microbiology and the director of the Fraietta Lab at the University of Pennsylvania! Fraietta is joined by cohost 

, a clinical fellow in oncology (MSTR Program) at the University of Pennsylvania. Our hope is that this show will become a critical forum for clinicians, translational researchers, and biotech professionals to explore the evolving landscape of immunotherapy. We're seeking to bridge cutting-edge research with practical applications and delve into how immune-based therapies transition from innovative discoveries to transformative patient care solutions

, the director of the Lymphoma Program at Penn Medicine, about the changing role of chemotherapy in lymphoma treatment, and the potential for its elimination. Schuster covered topics including trials for chimeric antigen receptor T-cell (CAR-T) therapy without lymphodepletion, using AI to predict CAR-T treatment outcomes, the importance of T-cell fitness, and the role of persistence in CAR-T success.

 is tailored for an audience fluent in the language of medicine and biotechnology, offering data-driven insights while maintaining accessibility. This podcast is an essential resource for those driving the future of immunotherapy.

Interested in co-hosting an episode or being a guest? Have feedback to share? 

If you'd like to get in touch to talk about the show, contact our editorial director, Matt Hoffman: 

Videos

In Episode 2 of ImmunoLogic, Bruce Levine, PhD, discussed the current the risk-benefit-ratio for CAR-T therapy.

ImmunoLogic, Episode 2: "Charting New Frontiers in CAR T-Cell Safety" With Bruce Levine, PhD

We're excited to introduce another episode of the 

, a clinical fellow in oncology (MSTR Program) at the University of Pennsylvania. Our hope is that this show will serve as a critical forum for clinicians, translational researchers, and biotech professionals to explore the evolving landscape of immunotherapy. We're seeking to bridge cutting-edge research with practical applications and delve into how immune-based therapies transition from innovative discoveries to transformative patient care solutions

 the Barbara and Edward Netter Professor in Cancer Gene Therapy at the Perelman School of Medicine at the University of Pennsylvania, about the black box warnings for secondary malignancies that were issued by the FDA with regard to the autologous chimeric antigen receptor T-cell (CAR-T) therapies approved by the agency, and the implications of the findings that informed these warnings for the risk-benefit ratio of these therapies. Levine, Fraietta, and Minehart covered topics including risk and informed consent, genetic modification as it relates to safety, epitope spreading and T-cell stimulation, and the importance of the National Institutes of Health (NIH) to CAR T-cell research.

In Episode 3 of ImmunoLogic, Marcela Maus, MD, PhD, discussed her research on CAR-T for treating glioblastoma.

ImmunoLogic, Episode 3: "Breaking the Brain’s Barrier: CAR T Cells Take on Glioblastoma" With Marcela Maus, MD, PhD

 a clinical fellow in oncology (MSTR Program) at the University of Pennsylvania. Our hope is that this show will serve as a critical forum for clinicians, translational researchers, and biotech professionals to explore the evolving landscape of immunotherapy. We're seeking to bridge cutting-edge research with practical applications and delve into how immune-based therapies transition from innovative discoveries to transformative patient care solutions

the director of the Cellular Immunotherapy Program at the Massachusetts General Hospital Cancer Center, about her research into the use of chimeric antigen receptor T-cell (CAR-T) therapy to treat glioblastoma. Maus, Fraietta, and Minehart covered topics including challenges and insights from early clinical trials, innovations and clinical results, antigen expression and the possibility of readministration, as well as the autologous versus allogeneic debate.

Kinnari Patel, PharmD

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