The European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) has granted a positive opinion to PTC Therapeutics’ gene therapy eladocagene exuparvovec (PTC-AADC; Upstaza) for treating 

aromatic L-amino acid decarboxylase (AADC) deficiency

"We are thrilled with the positive opinion from the CHMP, and are eager to bring Upstaza to patients living with AADC deficiency," Stuart W. Peltz, PhD, chief executive officer, PTC Therapeutics, said in a statement.

 "Upstaza will be the first marketed gene therapy that is directly administered into the brain, the first gene therapy approved in a major market in several years, the third gene therapy that is on the market now, and only the fourth in vivo gene therapy ever approved. It's important for the biotech community to have gene therapy products achieving approvals at regulatory bodies, as well as it being an important milestone for PTC that will help us build the gene therapy franchise and grow our revenue base."

The positive opinion is based on the findings of studies (NCT01395641; NCT02926066). conducted in Taiwan that demonstrated significant improvements in motor and cognitive function that persisted for up to 9 years of follow-up.

 The gene therapy was well-tolerated, with most adverse events (AEs) related to the disease course and only some mild cases of dyskinesia that resolved within a few months.

Gene Therapy for AADC Deficiency Yields Durable Developmental Improvements

"The difference Upstaza, a one-time gene therapy, can make is life-changing," lead investigator Paul Wuh-Liang Hwu, MD. PhD, National Taiwan University Hospital, added to the statement. "AADC deficiency is a devastating neurological disorder with no effective treatment. Before therapy, affected children couldn't even lift their head, but now many can sit, stand with help, feed themselves and some can walk and talk."

Eladocagene exuparvovec is directly infused in the putamen of the brain of participants with AADC deficiency. The targeted infusion is designed to be safer and more efficacious than systemic treatments. 

 about the investigations into the gene therapy as well as this mode of delivery.

"More aggressive, systemic treatments... can cause liver damage and damage other cells. In comparison, we deliver not very vigorously spreading virus by local injection [to the putamen]. The treatment is just involved in that region and does not spread out too much. That is safer and more effective,” Hwu told 

PTC Therapeutics expects a marketing decision to come from the EMA in about 2 months.

 If authorized, the Upstaza will be the first approved disease-modifying treatment for patients with AADC deficiency of 18 months of age or older as well as the first authorized gene therapy delivered via direct brain infusion.

REFERENCES
1. PTC Therapeutics receives positive CHMP opinion for Upstaza for the treatment of AADC deficiency. News release. PTC Therapeutics. May 20, 2022. 

https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-receives-positive-chmp-opinion-upstazatm


2. Tai CH, Lee, NC, Chien YH, et al. Long-term efficacy and safety of eladocageneexuparvovec in patients with AADC deficiency. 

. 2022;30(2):509-518. doi: 10.1016/j.ymthe.2021.11.005

Articles

The positive opinion was based on findings from studies conducted in Taiwan. 

Gene Therapy for AADC Deficiency Receives Positive CHMP Opinion 

“We expected some gradual improvement and we expected maybe they feel a little bit better. But we didn't really expect people to come out of this completely normal... [in terms of] side effects, they don't even feel like they had a transplant and... they can't remember this disease anymore.”

Patients with pyruvate kinase deficiency (PKD) treated with RP-L301, a gene-edited lentiviral mediated hematopoietic stem and progenitor cell therapy, reached normal levels of hemoglobin production, improved hemolysis and sustained transgene expression with no need for red blood cell transfusions at 1-year post infusion.

These data, from an ongoing phase 1 study (NCT04105166) presented at the 

2022 American Society of Gene and Cell Therapy Annual Meeting, May 16-19, 2022

, in Washington DC, by Ami J. Shah, MD, clinical professor of pediatrics, Division of Hematology/ Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford Medicine.

spoke with Shah to learn more about the efficacy findings of the trial and the positive patient-reported outcomes. She also discussed the progress of the trial and the new pediatric cohort being enrolled.

Shah AJ, López Lorenzo JL, Navarro S, et al. Changing the treatment paradigm for pyruvate kinase deficiency with lentiviral mediated gene therapy: Interim results from an ongoing global phase 1 study. Presented at: ASGCT 25th Annual Meeting, May 16-19, 2022. Abstract #357

Videos

The clinical professor of pediatrics at Stanford Medicine discussed positive interim findings from a phase 1 study of RP-L301. 

Ami J. Shah, MD, on Reaching Normalized Hemoglobin With Gene Therapy in PKD 

Patients treated with an investigational gene therapy to address severe leukocyte adhesion deficiency type 1 (LAD-I) showed impressive survival data and clinically significant reductions in hospitalizations and infections, according to findings presented at the 

2022 American Society of Gene and Cell Therapy Annual Meeting

As of the data cutoff for the phase 1/2 trial (NCT03812263), 7 of 9 patients dosed with the lentiviral gene therapy from Rocket Pharmaceuticals with at least 12 months of follow-up available had a 100% overall survival rate without allogeneic hematopoietic stem cell transplantation based on the Kaplan-Meier estimate post-infusion. In addition, all 9 treated patients have demonstrated statistically significant reductions in all-cause hospitalizations and severe infections, as well as resolution or improvement of all LAD-I-related skin abnormalities, including rashes and wound healing. 

In addition, no treatment-related serious adverse events were recorded, and all patients in the cohort have demonstrated sustained CD18 restoration and expression on more than 10% of neutrophils.

The gene therapy consists of autologous hematopoietic stem cells that are genetically modified with a lentiviral vector that contains a functional copy of the 

 gene, mutations in which cause deficiencies in beta-2 integrin. 

, primary investigator Donald B. Kohn, MD, distinguished professor of microbiology, immunology, molecular genetics, and pediatrics (hem/onc), and director, Human Gene Medicine Program at UCLA, detailed the exciting findings and his hope that the treatment will soon become available. Watch below:

1. Kohn DB, Sevilla J, Rao G, et al. 1188: Interim Results from an Ongoing Phase 1/2 Study of Lentiviral-Mediated Ex-Vivo Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I (LAD-I). Presented at: 2022 American Socienty of Gene and Cell Therapy Annual Meeting. May 16-19, 2022; Washington, DC. 

2. Rocket Pharmaceuticals Presents Positive Top-line Data from Severe Leukocyte Adhesion Deficiency-I Program at the 25th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT). News release. Rocket Pharmaceuticals. May 19, 2022. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-presents-positive-top-line-data-severe 

In an interview with CGTLive, study primary investigator Donald Kohn, MD, discussed the safety and efficacy observed in the phase 2 trial. 

Gene Therapy for LAD-I Posts Impressive Survival Data

Weekly Rewind! We’ve compiled 5 highlights from this week’s coverage of advances in gene and cell therapies, including FDA actions, notable research, and interviews with experts across the field.

1. Final Analysis of Phase 3 HOPE-B Trial: Durability of EtranacogeneDezaparvovec and QoL Improvements

The trial met its primary efficacy end point, and participants reported improvements in quality-of-life factors such as outlook on the future and feelings about having hemophilia.

2. Florian Eichler, MD, on How Novel Gene Therapy Delivery Improved Targeting in GM2 Gangliosidosis

The director of the leukodystrophy service at Mass Gen discussed the phase 1/2 study of AXO-AAV-GM2.

3. At-Risk Genotypes for DMD Gene Therapy Identified

Trial sponsors Pfizer, Sarepta, Genethon, and Solid Biosciences organized a group of experts to investigate shared serious AEs.

4. Homology-Directed Repair-Developed TCR Therapy Shows Potential in Type 1 Diabetes

Investigators from Seattle Children’s Hospital found that engineered T-cell regulatory products demonstrated significant suppression of effector T cells.

5. Yara Abdou, MD, on the Advantages of CAR Macrophages in Solid Tumors

The assistant professor of oncology at UNC School of Medicine discussed the first-in-human study being conducted with CT-0508.

Review top news and interview highlights from the week ending May 20, 2022. 

CGTLive’s Weekly Rewind – May 20, 2022 

“We have a certain window within which we need to treat as soon as these patients are diagnosed and the genetics are clear, but before the disease has advanced too far, because at that point... it is likely these children will not benefit from the kind of gene replacement that we're performing here.”

Bithalamic, intra-cisterna magna (ICM) and intrathecal delivery of AXO-AAV-GM2 (Sio Gene Therapies) gene therapy has been found to be well-tolerated in all 5 participants with GM2 gangliosidosis dosed so far, with MRI evidence of accurate bithalamic targeting.

Updated data from a phase 1/2 trial (NCT04669535) were presented at the

 2022 American Society of Gene and Cell Therapy Annual Meeting, May 16-19, 2022

, in Washington DC, by Florian Eichler, MD, assistant professor of neurology, Harvard Medical School. The study is being conducted at Worcester General Hospital and Massachusetts General Hospital, where Eichler serves as the director of the leukodystrophy service.

spoke with Eichler during the meeting to learn more about the phase 1/2 trial and its current progress with enrollment and dosing. He discussed promising enzyme activity and reduction of gangliosides.

Eichelr F, Flotte T, Andonian H, et al. AXO-AAV-GM2 gene therapy for infantile- and juvenile-onset GM2 gangliosidosis: Preliminary results from an ongoing phase 1/2 trial. Presented at: ASGCT 25th Annual Meeting, May 16-19, 2022, Washington DC.

The director of the leukodystrophy service at Mass Gen discussed progress dosing in the phase 1/2 trial. 

Florian Eichler, MD, on Promising Efficacy of AXO-AAV-GM2 in GM2 Gangliosidosis 

The gene therapy SGT-001 (Solid Biosciences) continued to demonstrate durable expression of microdystrophin for up to 24 months in participants with Duchenne muscular dystrophy (DMD) from the phase 1/2 IGNITE DMD study (NCT03368742).

Updated data from the study were presented at the 

American Society of Gene & Cell Therapy (ASGCT) 25th Annual Meeting, May 16-19, 2022

, in Washington, D.C., by Carl A. Morris, PhD, chief scientific officer, Solid Biosciences.

“DMD is a progressive, lethal form of muscular dystrophy caused by the absence of the protein dystrophin, which is responsible formaintaining muscle structure and function through successive bouts of contraction and relaxation,” Morris and colleagues wrote.

The IGNITE DMD study is evaluating SGT-001, which contains a form of dystrophin that fits within the adenovirus-associated vector (AAV) while maintaining critical domains including the neuronal nitric oxide synthase (nNOS) binding domain. Preclinical studies have shown that nNOS localization to the muscle membrane through the binding domain of dystrophin protects against exercise-induced muscle ischemia and preserve muscle function due to increased circulating nitric oxide levels.

At-Risk Genotypes for DMD Gene Therapy Identified

Updated data from participants in the 2E14 vg/kg group demonstrated stabilization or improvement in motor function, pulmonary function, and other outcomes compared to baseline and natural history declines. These outcomes were evaluated by use of theNorth Star Ambulatory Assessment, 6-Minute Walk Test, Forced Vital Capacity % predicted (FVC% predicted), peak expiratory flow (PEF% predicted), and Pediatric Outcomes Data Collection Instrument.

Continued expression of microdystrophin, restored β-sarcoglycan and nNOS membrane localization compared to 90-day biopsy assessments and baseline have been shown with previous biopsy data, with mild active dystrophic pathology.

As of January 2022, 9 total participants have been infused, 6 in the 2E14 vg/kg group. Common treatment-emergent adverse events (AEs) include nausea, vomiting, fever, thrombocytopenia, and headache. Serious AEs associated with complement activation have been experienced by 3 participants in the first few weeks after dosing; these included complement-mediated inflammatory response, thrombocytopenia, and transient increases in hepatic transaminases, and resolved without sequelae.

 The most recent participant was dosed in November 2021 and has not experienced any serious AEs. Long-term follow-up continues and patients are doing well up for to approximately 4 years post-dosing.

“These preliminary data continue to suggest a positive benefit-risk profile for SGT-001 warranting continued evaluation for the treatment of DMD,” Morris and colleagues concluded.

Previous data on pulmonary function improvements were presented at the Child Neurology Society 50th Annual Meeting by Oscar H. Mayer, MD, attending pulmonologist and director, Pulmonary Function Laboratory, Children’s Hospital of Philadelphia.

These data showed that PEF% predicted and forced expiratory volume improved in all evaluable patients treated with the adeno-associated viral gene therapy and declined in all evaluable control cohort patients. Improvements in FVC% predicted were also observed, with a mean difference of +16.0% from natural history at 1.5 years from baseline.

1. Morris CA, DreghiciRD, Redican S, et al. IGNITE DMD Study of SGT-001 Microdystrophin gene therapy for duchenne muscular dystrophy: Long-term outcomes and biomarker update. Presented at ASGCT 25th Annual Meeting, May 16-19, 2022. Abstract #1193
2. Solid Biosciences reports additional pulmonary function results from the ongoing IGNITE DMD phase I/II clinical trial of SGT-001. News release. Solid Biosciences. September 29, 2021. https://www.globenewswire.com/news-release/2021/09/29/2305205/0/en/Solid-Biosciences-Reports-Additional-Pulmonary-Function-Results-from-the-Ongoing-IGNITE-DMD-Phase-I-II-Clinical-Trial-of-SGT-001.html

Motor and pulmonary function have stabilized or improved in participants treated with SGT-001. 