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Lysosomal Disorders

Oncology

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The chief of the Division of Rheumatology and professor of medicine and professor of epidemiology at Penn Medicine discussed challenges on the horizon in this rapidly emerging field.

Peter A. Merkel, MD, MPH, on the Challenges of Bringing Cell Therapy to Autoimmune Disease

The chief of the Division of Rheumatology and professor of medicine and professor of epidemiology at Penn Medicine discussed the panel he participated in at the inaugural Cell Therapy for Autoimmune Disease Summit.

Peter A. Merkel, MD, MPH, on Approaching Clinical Trial Design for CAR-T in Autoimmune Disease 

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 

Primary data from a phase 1/2 clinical trial of an investigational dual-vector gene therapy for GM2 gangliosidosis, published in 

 suggest that the approach resulted in measurable enzymatic activity, substrate reduction, and encouraging neurologic outcomes in patients with infantile Tay–Sachs disease (TSD) and Sandhoff disease (SD).

 The therapy, delivered directly to the thalamus and cerebrospinal fluid (CSF), demonstrated dose-responsive target engagement and was generally well tolerated.

These findings mark the first clinical evidence that intraparenchymal gene therapy targeting deep brain structures may be a viable therapeutic strategy for infantile GM2 gangliosidosis, a rare and fatal lysosomal storage disorder that currently lacks approved disease-modifying treatments.

Importantly, patients experienced positive effects on their ability to remain on oral feeding regimens—historicaly, more than 50% of patients with GM2 gangliosidosis need to be fed intravenously—and multiple partial effects related to seizure onset.

"This is encouraging because eating by mouth in an important quality of life outcome for the families of these children,” study investigator Heather Gray-Edwards, DVM, PhD, assistant professor of genetic & cellular medicine at UMass Chan, and a member of the Horae Gene Therapy Center, said in a statement.

“Nonetheless, the partial effects of the therapy indicate the need for continued improvements of the gene therapy."

Enzymatic and Substrate Activity Improvements With AAV Gene Therapy

In total, 9 patients were treated (TSD, n = 7; SD, n = 2), including 6 with infantile and 3 with juvenile forms of GM2 gangliosidosis. The dual-vector approach used separate recombinant adeno-associated virus serotype rh8 (rAAVrh8) constructs to deliver 

 genes, administered via bilateral thalamic infusion and both intra-cisterna magna and lumbar intrathecal injections.

In treated infantile patients, dose-dependent increases in CSF β-hexosaminidase A (HEXA) activity were observed, peaking at 0.59 nmol/h/mL—or 13% of the normal mean—by 12 weeks post treatment. Total serum HEX activity exceeded 40 nmol/h/mL in high-dose recipients, surpassing the lower limit of the reference range.

Biochemical substrate reduction was also observed, with CSF C20:0 GM2 ganglioside levels declining in 4 of 6 infantile patients by up to 52.5% from baseline. These changes suggest that the expressed enzyme reached relevant compartments and was functionally active in degrading stored ganglioside.

Additionally, structural imaging and clinical outcomes aligned with these biochemical improvements. Diffusion tensor imaging (DTI) showed increased fiber tract numbers and fractional anisotropy in white matter regions including the corpus callosum and lentiform nucleus—changes that persisted beyond 12 weeks.

Volumetric MRI scans indicated slower brain volume growth relative to untreated historical controls, with reduced storage burden inferred from lower volumetric expansion. Patients with lower brain volumes showed correspondingly milder clinical severity scores.

Clinically, half of the infantile patients maintained oral feeding ability past 25 months—well beyond the typical window when gastrostomy is required in untreated patients. One high-dose patient retained full oral feeding through 27 months of age.

Delayed seizure onset and improved seizure control were also noted. Two high-dose patients either remained seizure-free or achieved control with a single anti-epileptic drug during the 24-week study period.

Global Clinical Impression (GCI) scores indicated early neurologic stabilization or improvement in several patients, particularly those who received the higher vector doses. One high-dose recipient (Patient 011) maintained neurologic gains through week 24, correlating with the highest post-treatment enzyme activity levels in the cohort.

AAV Gene Therapy Safety Profile and Juvenile Disease Challenges

Across the trial, 171 adverse events (AEs) were reported, 15 of which were considered possibly or definitely related to the gene therapy. Most treatment-related AEs included transient liver enzyme elevations and immune responses to the AAVrh8 capsid. These events responded to corticosteroids and did not result in treatment discontinuation.

Sixteen AEs were associated with the surgical procedure or anesthesia. These were managed with protocol modifications, including extended suture retention to prevent wound dehiscence.

No treatment-related deaths occurred. Two deaths—1 from disease progression and another from 

 infection—occurred but were not attributed to the therapy.

Notably, all 3 juvenile patients exhibited either worsening dystonia or neurologic decline following treatment. While the cause has been noted as unclear, the investigators elected to exclude juvenile patients from further enrollment and analysis. Imaging findings suggested possible thalamic inflammation, but no clear causal link was established.

Expert Perspective and Future Direction for HEXA / HEXB Gene Therapy

“Biochemically, it worked,” Gray-Edwards said in a statement.

 “We were able to induce production of the appropriate enzyme and that enzyme was functional. Although we didn’t achieve therapeutic levels, our thalamic injections ended up being safe in patients and the transgene vectors work. That’s an important step.”

The investigational gene therapy was developed in collaboration with UMass Chan Medical School and supported by several patient advocacy groups, including the National Tay-Sachs & Allied Diseases Association, Cure Tay-Sachs Foundation, and the Blu Genes Foundation.

“This research is an example of the important work that our faculty is doing in our Translational Institute for Molecular Therapeutics,” Flotte, the Elisabeth Chair for the Dean of Medicine, executive deputy chancellor, provost and dean of the TH Chan School of Medicine, said in a statement.

 “Driven by Dr. Gray-Edwards and Dr. Sena-Esteves, the institute leverages our extensive experience in researching and developing gene therapies for early-stage clinical trials so we can play a key role in moving therapies for rare diseases forward. It is so important to patients and families like those who participated in these trials that our research is providing hope for some help for this devastating disease.”

Given the existing limitations of dual-vector dosing and delivery, the research team is now pursuing a bicistronic vector platform to simplify administration and potentially expand clinical applications. A next-generation construct coexpressing both 

 genes in a single AAV vector is currently in development.

This trial represents a major milestone in the treatment of infantile GM2 gangliosidosis, laying the groundwork for future trials aimed at improving durability, delivery efficiency, and accessibility of gene-based approaches for lysosomal storage disorders.

REFERENCES
1. Eichler F, Cataltepe OI, Daci R, et al. Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial. 

2025. doi:10.1038/s41591-025-03822-4
2. Phase I/II clinical study of gene therapy for GM2 gangliosidosis, including Tay-Sachs and Sandhoff diseases, shows encouraging results. News release. UMass Chan Medical School. August 18, 2025. Accessed August 29, 2025. https://www.eurekalert.org/news-releases/1095058

The rAAVrh8 gene therapy delivers HEXA and HEXB genes, and has posted postive phase 1/2 results in infantile GM2 gangliosidosis, with enhancements in enzymatic activity and neurological outcomes.

Dual-Vector AAV Gene Therapy for GM2 Gangliosidosis Shows Promising Early Outcomes

Ultragenyx has begun the submission of a rolling biologics license application (BLA) to the FDA for DTX401, an investigational adeno-associated virus serotype 8 (AAV8) vector gene therapy expressing the human 

 gene that is intended to treat Glycogen Storage Disease Type Ia (GSDIa).

The company noted that the nonclinical and clinical modules have been submitted, and the chemistry, manufacturing, and controls information will be submitted later. Ultragenyx anticipates that the full BLA will be submitted in the fourth quarter of this year.

The BLA is supported by 96-week data from the randomized, placebo-controlled phase 3 GlucoGene clinical trial (NCT05139316). In comparison to previously reported 48-week data, the 96-week data showed that patients in both the ongoing DTX401 group and the crossover placebo to DTX401 group had greater reductions in their total daily cornstarch at their most recent visit compared to baseline. Specifically, the ongoing DTX401 group showed a 60% reduction from baseline at 96 weeks, and the crossover placebo to DTX401 group showed a 64% reduction from baseline at 96 weeks.

 (CRL) from the FDA for a BLA for one of its other investigational therapies, UX111, in July of this year.

 UX111 is an AAV vector-based gene therapy intended to treat mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome). According to Ultragenyx, the CRL pertained to a need for additional chemistry, manufacturing, and controls (CMC) information and improvements and observations from inspections of manufacturing facilities that were conducted recently. The company noted its perception that the concerns are related to facilities and processes rather than to the quality of the gene therapy product itself, that it plans to work with the agency to address these observations, and that it plans to resubmit the BLA thereafter.

“We have been diligently responding to the recent CMC observations, and our priority is to resolve them so that we can resubmit the BLA as soon as possible,” Emil D. Kakkis, MD, PhD, the chief executive officer and president of Ultragenyx, said in a July 2025 statement.

 “We believe the CMC observations are readily addressable, and many have already been addressed. While the CRL will delay the potential approval of UX111 to 2026, we are working with urgency to respond and resubmit.”

With this in mind, Ultragenyx noted that it is incorporating learnings from the experience with UX111 into its BLA submission for DTX401.

 Specifically, the company pointed out that the BLA will contain updates meant to “proactively respond” to the FDA’s observations in the UX111 CRL and at Ultragenyx’s manufacturing facilities for its gene therapy products.

“Initiating the BLA for DTX401, for the potential treatment of GSDIa, is an important milestone for this much-needed treatment option for individuals and families affected by this disorder,” Eric Crombez, MD, the chief medical officer at Ultragenyx, said in the press release announcing DTX401’s rolling BLA submission.

 “Currently, patients are required to take large and frequent doses of cornstarch to protect themselves from the risk of potentially life-threatening hypoglycemia. By granting a rolling review, the FDA can begin reviewing the nonclinical and clinical sections of the BLA, where we demonstrate the clinically significant reduction in cornstarch burden and improved clinical outcomes, while we proactively resolve any relevant CMC and facility questions that were learned in our UX111 program. Over the next few months, we expect to resolve the FDA’s observations and then complete our DTX401 BLA submission in the fourth quarter of this year.”

REFERENCES
1. Ultragenyx initiates rolling submission of biologics license application (BLA) to U.S. FDA for DTX401 AAV gene therapy for the treatment of glycogen storage disease type Ia (GSDIa). News release. Ultragenyx Pharmaceutical Inc. August 18, 2025. Accessed August 26, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-initiates-rolling-submission-biologics-license
2. Ultragenyx receives complete response letter from FDA for UX111 AAV gene therapy to treat sanfilippo syndrome type A (MPS IIIA). News release. Ultragenyx Pharmaceutical Inc. July 11, 2025. Accessed August 26, 2025. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-receives-complete-response-letter-fda-ux111-aav-gene

Ultragenyx anticipates that the full BLA will have been submitted in the fourth quarter of this year.

Ultragenyx Puts Rolling BLA for Glycogen Storage Disease Gene Therapy DTX401 in Front of FDA

This video originally appeared on our sister site,

The medical director of Apheresis and a hematologist-oncologist in the Division of Hematology and Cellular Therapy at Allegheny Health Network spoke about unmet needs in patients who receive early-line CAR-T for R/R MM.

Prerna Mewawalla, MD, on Unmet Needs Following Early-Line CAR-T for R/R Multiple Myeloma

“Our current salvage options and sequencing after using early CAR T-cell therapy are not clearly defined. Do we go to bispecific [antibodies] later? Do we go to our traditional regimens after? This truly needs to be defined after early CAR T-cell therapy.”

 the chimeric antigen receptor T-cell (CAR T) therapy ciltacabtagene-autoleucel (marketed as Carvykti) in April 2024 for patients with relapsed/refractory (R/R) multiple myeloma (MM) who have previously received at least 1 line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and who are refractory to lenalidomide (Revlimid). Notably, the FDA simultaneously approved another CAR T product, idecabtagene vicleucel (marketed as Abecma), for the treatment of patients with R/R MM who have been treated with at least 2 prior lines of therapies, including a PI, an IMiD, and an anti-CD38 monoclonal antibody.

, Prerna Mewawalla, MD, the medical director of Apheresis and a hematologist-oncologist in the Division of Hematology and Cellular Therapy at Allegheny Health Network, as well as an associate professor at the Drexel University College of Medicine, spoke about unmet needs and emergent questions that come up after CAR T therapy is used to treat patients for R/R MM in earlier-line settings.

Mewawalla pointed out that several questions have yet to be addressed regarding further disease management after earlier lines of CAR T-cell therapy in patients with R/R MM. She noted that current salvage options and sequencing strategies after early CAR T-cell therapy remain undefined. She added that questions include whether bispecific antibodies and traditional regimens should be used following early CAR T-cell therapy.

Furthermore, trials are evaluating whether maintenance therapy is required after CAR T-cell therapies, and whether this could affect patients’ chances of achieving durable responses is another currently unanswered question, Mewawalla stated. The scaling up of CAR T-cell therapy access to meet the growing demand is another unmet need, she explained. CAR T-cell therapies are intensive treatments, and infusion center infrastructure may further limit how many patients can receive these treatments, revealing another disparity, particularly for patients who are eligible but live far away from academic centers or transplant sites, she concluded.

The medical director of Apheresis and a hematologist-oncologist in the Division of Hematology and Cellular Therapy at Allegheny Health Network spoke about unmet needs in patients who receive early-line CAR T for R/R MM.

Videos

Canonical

Prerna Mewawalla, MD, on Unmet Needs Following Early-Line CAR T for R/R Multiple Myeloma

The FDA has approved Precigen’s zopapogene imadenovec-drba (PRGN-2012), a nonreplicating adenoviral vector-based immunotherapy, for treating adults with recurrent respiratory papillomatosis (RRP).

 The therapy will be marketed under the name Papzimeos.

Papzimeos, which is administered over a 12-week timeframe through 4 subcutaneous injections, is based on the company’s AdenoVerse platform and is intended to trigger an immune response targeted at cells infected by human papillomavirus (HPV) 6 or HPV 11, providing an alternative to the current standard of care for RRP, which typically involves repeated surgical interventions. The therapy was approved based on the results of a pivotal, open-label phase 1/2 clinical trial (NCT04724980). Notably, the FDA granted Papzimeosa full approval, without a requirement for a confirmatory trial to be conducted, even though Precigen had submitted the biologics license application (BLA) for the therapy via an accelerated approval pathway.

"For more than a century, since RRP was first recognized as a distinct disease, patients have had to rely on repeated surgeries to manage this relentless condition,” Helen Sabzevari, PhD, the president and CEO of Precigen, said in a statement.

 “Today marks a historic turning point. With the landmark FDA approval of Papzimeos and broad label, all adult RRP patients are now eligible for access to the first and only approved therapy that targets the root cause of the disease. This milestone affirms the power of our AdenoVerse platform and the exceptional capabilities of our team to rapidly advance a wholly novel therapy from discovery to approval considerably faster than industry benchmarks. We are profoundly grateful to the NIH clinicians, the FDA, and—most importantly—the patients and families who made this breakthrough possible. We look forward to swiftly delivering Papzimeos to the RRP community and ushering in a new era of treatment that targets the underlying cause of the disease rather than just managing its symptoms."

Data from the phase 1/2 trial presented at the 

2024 American Society of Clinical Oncology (ASCO) Annual Meeting

, held May 31 to June 4, in Chicago, Illinois, showed that over 50% of patients (18 of 35) treated in the trial attained a complete response (CR) and over 85% of patients had a decrease in surgical interventions in the year after treatment with the gene therapy, when contrasted with the year before receiving the gene therapy.

 The CR rate (CRR) was defined as the percentage of patients who did not require any RRP surgery during the 12 months after receiving the gene therapy. With regard to safety, it was reported that no dose-limiting toxicities had occurred, nor had any treatment-related adverse events of grade 2 or greater. The therapy was characterized as “well tolerated.”

“Randomized trials are not always needed to approve medical products, and this approval is proof of that philosophy,” Vinay Prasad, MD, MPH, the director of the FDA’s Center for Biologics Evaluation and Research (CBER), said in an FDA news release covering the agency’s decision.

 “The FDA will always demand the correct clinical study for the specific medical product and disease. Our requirements for products given to tens of millions of healthy people will be different than products given to at most hundreds or thousands of patients with unique diseases.”

Precigen noted that it has set up a patient support program for the newly approved therapy, referred to as Papzimeos SUPPORT, which will provide patients with insurance navigation, financial assistance, and other services.

 with priority review in February 2025, following a rolling submission that had been completed in December 2024.

REFERENCES
1. Precigen announces full FDA approval of Papzimeos (zopapogene imadenovec-drba), the first and only approved therapy for the treatment of adults with recurrent respiratory papillomatosis. News release. Precigen, Inc. August 15, 2025. Accessed August 26, 2025. https://investors.precigen.com/news-releases/news-release-details/precigen-announces-full-fda-approval-papzimeos-zopapogene
2. FDA grants priority review to Precigen's BLA for PRGN-2012 for the treatment of adults with recurrent respiratory papillomatosis with PDUFA target action date set for August 27, 2025. News release. Precigen, Inc. February 25, 2025. Accessed August 26, 2025. https://investors.precigen.com/news-releases/news-release-details/fda-grants-priority-review-precigens-bla-prgn-2012-treatment
3. FDA approves first immunotherapy for recurrent respiratory papillomatosis. News release. FDA. August 14, 2025. Accessed August 26, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-immunotherapy-recurrent-respiratory-papillomatosis

Notably, the FDA granted Papzimeos a full approval, without a requirement for a confirmatory trial.

Peter A. Merkel, MD, MPH

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