The gene therapy AAV8-LSPhGAA (Asklepios Biopharmaceutical) has demonstrated safety and the potential to eliminate the need for enzyme replacement therapy (ERT) in patients with late-onset 

These results, from a phase 1/2 study (NCT03533673), were presented at the 

American Society of Gene & Cell Therapy 25th Annual Meeting

 (ASGCT), held in Washington, DC, and virtually May 16-19, 2022by Edward C. Smith, MD, pediatric neurologist and professor of pediatrics at Duke University School of Medicine.

“Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for ERT by creating a liver depot for acid-alpha glucosidase (GAA) production,” Smith and colleagues wrote.

Three participants with LOPD have been dosed in the low-dose cohort of the phase 1/2 study so far, which is primarily assessing the incidence and severity of adverse events (AEs) as well as clinical laboratory abnormalities. Secondary outcomes include measures of efficacy such as 6-minute walk test distance (6MWT), forced vital capacity (FVC), serum GAA activity, and muscle GAA activity and glycogen content.

Research Needs in Pompe Disease: Barry Byrne, MD, PhD

Participants had no detectable anti-AAV8 neutralizing antibodies, had received at least 12 months of stable ERT dosing, and were able to walk at least 100 meters on the 6MWT. These participants went through ERT withdrawal at week 26 based on quantifiable serum GAA activity and the absence of clinically significant declines in FVC or 6MWT performance. They then received 60 mg per day of prednisone as immunoprophylaxis through Week 4, followed by an 11-week taper.

Investigators found that 2 weeks after treatment with AAV8-LSPhGAA, all participants demonstrated sustained serum GAA levels from 101% to 235% of baseline trough activity. All participants met criteria for ERT withdrawal at week 24 and continued to meet criteria to remain off ERT at weeks 52 and 104, although 1 participant chose to resume ERT at week 97.

Smith and colleagues evaluated muscle biopsies and found that 1 participant had around a 40% decrease in muscle GAA activity at week 24, although muscle GAA activity significantly increased from baseline in the cohort as a whole at week 52 (

<.05). One participant had a 10-fold increase from 2.8% to 28% of normal, the second increased from 19% to 44%, and the third increased from 56% to 94% of normal.

Thew gene therapy was well-tolerated, with no treatment-related serious AEs. Laboratory assessments supported the safety of AAV8-LSPhGAA, with no evidence of elevated serum alanine aminotransferase or ELISPOT signals. One participant experienced 2 headaches classified as moderate severity treatment-related AEs.

“Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease,” Smith and colleagues concluded.

Smith EC, Hopkins S, Case LE, et al. Phase 1 Study of Gene Therapy in Late-onset Pompe Disease: Initial 104-Week Experience. Presented at: ASGCT 25th Annual Meeting, May 16-19, 2022, Washington DC. Abstract #1211

Articles

All study participants met criteria to remain off enzyme replacement therapy through 104 weeks after treatment. 

Gene Therapy May Eliminate Need for ERT in Late-Onset Pompe Disease 

Ocugen has added the phase 3 cell therapy platform NeoCart to its pipeline following its Regenerative Medicine Advanced Therapy (RMAT) recognition for the repair of 

full-thickness lesions of the knee cartilage

“We’re excited that NeoCart® has received this RMAT designation, an important regulatory milestone, especially as we view this product as an enabling technology in cell and regenerative therapy for orthopedic indications. Our next step will be working with the FDA to construct the Phase 3 program to bring this innovation to this emerging treatment area,” Shankar Musunuri, PhD, Chairman, chief executive officer and co-founder, Ocugen, said in a statement.

Neocart consists of autologous chondrocyte-derived neocartilage and was acquired as part of Ocugen’sreverse merger with Histogenics in 2019. The cell therapy is intended to repair articular cartilage lesions which may limit mobility and lead to osteoarthritis.

“People living with articular cartilage lesions literally have holes in their knees that are extremely difficult to heal, and without proper treatment, they’re at high risk of getting osteoarthritis. We believe that NeoCart® offers the potential for an innovative new option where treatments in this area are still limited and results are not optimal,” Musunuri added to the statement.

Harnessing Gene Therapy for Osteoarthritis

Ocugen also recently announced in April 2022 that they had received a positive Data Safety Monitoring Board (DSMB) recommendation for their phase 1/2 clinical trial (NCT05203939) assessing OCU400, a gene therapy for the potential treatment of retinitis pigmentosa.

The DSMB has recommended that Ocugen continue enrolling participants in the current cohort at the target dose level.

OCU400 targets nuclear hormone receptors that regulate multiple functions in the retina, which may be able to address multiple gene mutations and multiple retinal diseases with 1 therapy. The phase 1/2 study is primarily assessing safety as measured by the incidence and severity of adverse events (AEs). Secondary endpoints include best-corrected visual acuity, low-luminance visual acuity, slit-lamp biomicroscopy, intraocular pressure, indirect ophthalmoscopy, anti-adeno associated virus vector antibodies, anti-hNR2E3 antibodies, and T-cell response. Additional outcomes will assess other measures of vision improvements.

“It’s a positive first step that the DSMB review of the current OCU400-101 study results identified no serious adverse events and recommended that the study proceed with enrollment,”OcugenRetina Scientific Advisory Board member Mark Pennesi, MD, PhD, professor of ophthalmology and chief, Paul H. Casey Ophthalmic Genetics Division, Oregon Health & Science University, said in a previous statement.

 “We’re looking forward to understanding how this modifier gene therapy platform could treat inherited retinal degeneration, potentially bringing an option to people affected with this disease.”

1. Ocugen announces new cell therapy program following FDA Regenerative Medicine Advanced Therapy (RMAT) recognition. News release. Ocugen. May 24, 2022. 

https://www.biospace.com/article/releases/ocugen-announces-new-cell-therapy-program-following-fda-regenerative-medicine-advanced-therapy-rmat-recognition/


2. Ocugen, Inc. announces positive DSMB recommendation for OCU400-101 clinical trial. News release. April 25, 2022. https://ir.ocugen.com/news-releases/news-release-details/ocugen-inc-announces-positive-dsmb-recommendation-ocu400-101

NeoCart was originally developed by the company Histogenics. 

Gene Therapy for Knee Cartilage Lesions Receives RMAT Designation 

"With natural killer T-cells, or NK T cells for short, we have the ability to use a homogeneous population of effector lymphocytes that are able to effectively traffic into the tumor sites better than just conventional T cells... They can recognize cancer supportive tumor associated macrophages... and specifically target them. So that provides a big opportunity for NK T cell-based therapeutics to make a major impact in the treatment of solid tumor patients.”

Chimeric antigen receptor (CAR) natural killer (NK) T-cell therapy is well-tolerated with promising responses in patients with neuroblastoma, according to data from a phase 1 study (NCT03294954) presented by Andras Heczey, MD, Associate Professor, Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine at the 

 (ASGCT), held in Washington, DC, and virtually May 16-19, 2022.

Heczey and colleagues found that antitumor activity was associated with dosage and in vivo rate of expansion after treating 12 patients in 4 dose levels of 3x10

 following lymphodepletion. Of these patients, 5 had progressive disease, 4 had stable disease, 2 had a partial response, and 1 had a complete response. No dose limiting toxicities or serious toxicities related to treatment were observed.

spoke with Heczey to learn more about the phase 1 study and trends observed with antitumor activity. He discussed challenges with treating solid tumors and more research to be done.

Herczey A, Courtney A, Ghatwai N, et al. Anti-GD2 CAR NKT cells are safe and produce antitumor responses in patients with relapsed/refractory neuroblastoma. Presented at ASGCT 25th Annual Meeting May 16-19, 2022, Washington DC. Abstract #54

Videos

The director of the Liver Tumor Program at Texas Children’s Hospital discussed a phase 1 study of CAR NK T-cells in neuroblastoma. 

Andras Heczey, MD, on Antitumor Activity of CAR NKTs in Solid Tumors 

uniQure's biologics license application (BLA) fo

(EtranaDez) has been accepted by the FDA for priority review for the treatment of hemophilia B.

"Etranacogene dezaparvovec has the potential to be the first gene therapy approved in hemophilia B and the acceptance of the BLA marks an important milestone in uniQure’s mission of delivering the promise of gene therapy to people living with rare diseases,” Matt Kapusta, chief executive officer, uniQure, said in a statement.

EtranaDez, which is developed in collaboration with CSL Behring as part of a Commercialization and License Agreement as of June 2020, is designed to restore production of Factor IX (FIX) by using an adeno-associated virus (AAV) vector to deliver the Padua variant of the FIX gene. The gene therapy has been granted breakthrough therapy designation by the US Food and Drug Administration and access to Priority Medicine (PRIME) regulatory initiative by the European Medicines Agency (EMA). The EMA is currently reviewing a Marketing Authorization Application for EtranaDez in hemophilia B.

The BLA is supported by positive data from the pivotal phase 3 HOPE-B trial (NCT03569891), which has enrolled 54 patients with hemophilia B and a baseline FIX of < 2%. Of these participants, 33 had pre-existing AAV5 neutralizing antibodies (NAbs) and 21 did not. All participants underwent a > 6-month lead in period of FIX prophylaxis before being dosed with 2x10

 gc/kg EtranaDez. All but one participant (n = 53) completed at least 18 months of follow-up.

Addressing AAV Antibodies in Hemophilia B Gene Therapy: Wolfgang Miesbach, MD, PhD

 of reduction in annualized bleeding rate (ABR) post-treatment compared with baseline FIX prophylactic therapy.

 Previous data showed that mean FIX activity was 39.0 IU/dL (standard deviation ±18.7; minimum 8.2, maximum 97.1) at 6 months post-treatment and 36.9 IU/dL (±21.4; 4.5, 122.9) at 18 months.

Among participants who received a full dose of EtranaDez, FIX prophylaxis was discontinued by all whose AAV5 NAbs were undetected or who had pre-dosing NAbs up to a titer of 678, constituting an overall 97% reduction in mean unadjusted annualized FIX consumption. The 52-week adjusted ABR for all bleeds was reduced by 64% (

 = .0002) from 4.19 during the ≥ 6-month lead-in period to 1.51 during months 7-18.

Mild AEs occurred in most participants (>80%) but EtranaDez was mostly well-tolerated. One death, deemed unrelated to treatment, occured in a 77-year-old patient at 65-weeks following dosing due to urosepsis and cardiogenic shock. A serious AE of hepatocellular carcinoma was also deemed unrelated to treatment based on molecular characterization and vector integration analysis. No inhibitors to FIX were reported.

A final analysis of the trial presented at the 

 (ASGCT), held in Washington, DC, and virtually May 16-19, 2022 demonstrated 

 and improvements in hemophilia-related quality of life (HRQoL).

Significant improvements were seen across HRQoL domains, resulting in a 21.5% total score percentage improvement (least square means, -5.50; 

 < .0001). Notably, large increases were seen in Feelings (current emotions associated with having hemophilia; 45.7%) and Treatment (burden of hemophilia treatments, 59.0%) after treatment with EtranaDez.

“... if approved, etranacogenedezaparvovec would represent our second gene therapy to complete its journey to patients...” Kapusta added to the statement.

 “We are pleased with the promising results generated from our HOPE-B pivotal study, the largest gene therapy trial in hemophilia B to date and, assuming FDA approval, we look forward to partnering with our colleagues at CSL Behring to bring this life-changing treatment option to people with hemophilia B.”

1. uniQure Announces FDA Acceptance of Biologics License Application for EtranacogeneDezaparvovec under Priority Review. News release. uniQure. May 24, 2022. 

https://tools.eurolandir.com/tools/Pressreleases/GetPressRelease/?ID=4109235&lang=en-GB&companycode=nl-qure&v=


2. uniQure and CSL Behring announce primary endpoint achieved in HOPE-B pivotal trial of EtranacogeneDezaparvovec gene therapy in patients with Hemophilia B. News release. UniQure. December 9, 2021. https://www.cslbehring.com/newsroom/2021/hope-b-gene-therapy-for-hemophilia-b-topline-results
3. Pipe S, Leebeek F, Recht M, et al. Stable hemostatic correction and improved hemophilia-related quality of life: final analysis from the pivotal phase 3 hope-b trial of etranacogene dezaparvovec. Presented at: ASGCT 25th Annual Meeting; May 16-19, 2022; Washington, DC. Accessed May 12, 2022.

A final analysis of the pivotal HOPE-B study was presented at ASGCT 2022. 

EtranaDez Accepted for Priority Review in Hemophilia B 

A gene-edited autologous cell therapy, Temferon, is well-tolerated in participants with unmethylated MGMT glioblastoma (GBM) with a promising ability to modulate the tumor microenvironment (TME).

Bernhard Gentner, MD, PhD, group leader, Translational stem cell and leukemia unit, and staff hematologist, San Raffaele Telethon Institute for Gene Therapy, presented findings from a phase 1/2a study (NCT03866109) at the 

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

“We developed a genetically modified cell-based autologous hematopoietic stem cell platform designed to selectively deliver immunostimulatory cytokines into the TME through Tie-2 expressing monocytes. As a consequence, many tumor-associated macrophages, that are well recognized to foster cancer progression, are reprogrammed toward an immune-stimulating and tumor-suppressive phenotype,” Gentner and colleagues wrote.

Temferon is transduced with a lentiviral vector and expresses interferon-alpha2 to the TME of participants with an unmethylated MGMT promoter. As of January 2022, 15 participants with this disease have received doses of Temferon ranging from 0.5 x10

 cells/kg in 5 cohorts. Investigators observed rapid engraftment and fast recovery from the non-myeloablative conditioning.

 Improving Rare Disease Awareness: Bruce Dezube, MD

No dose-limiting toxicities have been observed and median overall survival was 14 months after surgery with a maximum follow-up of 27 months. Serious adverse events (AEs) did occur, but these were mostly attributed to conditioning chemotherapy or disease progression. Persistent Gamma-Glutamyl Transferase elevation occurred in 1 participant and was classified as a suspected unexpected serious adverse reaction.

Four of the 15 participants have undergone a second surgery and these tumors were analyzed for the presence of bone-marrow (BM) derived transduced cells as well as any immunological changes. Analyzed specimens from 3 of 4 patients demonstratedsignificant homing of transduced cells from BM to tumor site.

Vector copy number analysis revealed Temferon-derived differentiated cells in BM and peripheral blood made up to 30% of these cells at their peak and persisted up to 18 months. Single cells RNA sequencing of the TME in treated participants compared to recurrent tumors in control patients had a clear Temferon signature.

“We believe that our interim results provide initial evidence of Temferon's potential to modulate the TME, as predicted by preclinical studies, which will be confirmed with longer follow up in the higher dose cohorts,” Gentner and colleagues wrote.

Gentner B, Eoli M, Capotondo A, et al. Autologous cell & gene therapy for the therapeutic targeting of immune payloads to the solid tumor microenvironment: Preliminary results of the TEM-GBM study. Presented at ASGCT 2022, May 16-19, Washington DC. Abstract #1190.

The cell therapy was tolerated although there was a SUSAR of GGT elevations. 

Cell Therapy Modulates Tumor Microenvironment in Glioblastoma 

“Only by coming together with all the sponsors and everyone who is in the trials, were we able to quickly compare the genotypes, compare the events, confirm that the events are strikingly similar in that clinical evolution, that the genotypes are really similar as well. And that lead to identification of the likely offending immunological epitope on that transgene.”

Investigators have elucidated at-risk genotypes for anti-transgene serious adverse events (SAEs) shared across studies of Duchenne muscular dystrophy (DMD) gene therapies by 4 sponsors, Pfizer, Sarepta, Genethon, and Solid Biosciences.

The group’s findings were presented at the 

, in Washington, D.C., by Carsten Bonnemann, MD, senior investigator, Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke/National Institutes of Health.

Bönnemann and colleagues hypothesize that patients’ genotypes determine a T-cell mediated immune response to the expressed transgene protein in a cross-reactive immunological material (CRIM)-negative setting. CGTLivespoke with Bönnemann to learn more about the group’s findings as well as their impact on trials investigating DMD gene therapies.

Bönnemann CG, Belluscio BA, Braun S, et al. A collaborative analysis by clinical trial sponsors and academic experts of anti-transgene SAEs in studies of gene therapy for DMD. Presented at: ASGCT 25th Annual Meeting, May 16-19, 2022; Washington DC.

The senior investigator from NINDS discussed findings investigating serious AEs across different trials. 