Gene Therapy (AT845) for Pompe Disease (FORTIS Trial)
Recruiting in Palo Alto (17 mi)
+8 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Waitlist Available
Sponsor: Audentes Therapeutics
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a phase 1/2 open-label, ascending dose, multicenter clinical study to evaluate the safety and efficacy of AT845 in adult (aged ≥ 18 years) subjects, ambulatory or nonambulatory, with Late Onset Pompe Disease (LOPD).
Is the treatment AT845 a promising treatment for Pompe Disease?
Yes, AT845 is a promising treatment for Pompe Disease. It is a gene therapy that helps increase the activity of a crucial enzyme, GAA, in muscles and the heart, which can improve muscle function and reduce glycogen buildup. This approach could potentially offer a more effective and long-lasting solution compared to current treatments.
14678What safety data is available for AT845 gene therapy in Pompe disease?
The safety data for AT845, a gene therapy for Pompe disease, includes findings from various studies. In a Phase I study (NCT03533673), AAV8-LSPhGAA, a similar gene therapy, showed no treatment-related serious adverse events in patients with late-onset Pompe disease. Prednisone was used as immunoprophylaxis, and no anti-capsid T cell responses were observed. In preclinical studies, AT845 was tolerated in cynomolgus macaques at low doses, but high doses led to immune responses and cardiac issues. Another study with AAV2/8-LSPhGAApA in mice showed no significant short- or long-term toxicity, although there were some immune responses. Overall, these studies suggest that AT845 and similar therapies have shown a favorable safety profile, but high doses may pose risks in non-human primates.
26789What data supports the idea that Gene Therapy (AT845) for Pompe Disease is an effective treatment?
The available research shows that Gene Therapy (AT845) for Pompe Disease is effective because it allows the body to produce the necessary enzyme continuously, reducing the need for frequent treatments. In a study, patients who received the gene therapy showed increased enzyme activity and stable muscle condition over a year, even after stopping their regular treatment. This suggests that the gene therapy could be more convenient and potentially more effective than the current standard treatment, which requires regular infusions.
34568Do I have to stop taking my current medications for the trial?
The trial requires that you have been on a stable dose of enzyme replacement therapy (ERT) with rhGAA for at least 6 months before starting. Other medications for chronic conditions must be stable for at least 30 days before dosing. If you are on immune-modulating agents, you must stop them 90 days before dosing. If you are on drugs for myopathy or neuropathy with immunosuppressive therapy, you must stop them 3 months before starting the study.
Eligibility Criteria
Adults over 18 with Late Onset Pompe Disease (LOPD) who have been on enzyme replacement therapy for at least 2 years are eligible. They must not have certain allergies, be part of another study, or have conditions that could affect safety or results. Participants must agree to not donate blood or reproductive cells for a period after receiving the trial treatment.Inclusion Criteria
My lung function is at least 30% of what is expected for someone healthy.
I have been on a consistent dose of ERT with rhGAA for 6 months.
I have been diagnosed with Pompe disease through genetic testing.
I am 18 years old or older.
I have been on enzyme replacement therapy with rhGAA for at least 2 years.
Exclusion Criteria
I haven't taken immune-modulating drugs in the last 90 days, except for inhaled corticosteroids.
I am allergic or cannot take the study drug or corticosteroids due to health reasons.
I do not have a serious heart condition or an ejection fraction below 40%.
I have taken immunosuppressive drugs for myopathy or neuropathy in the last 3 months.
I am not currently in a clinical trial or have had gene or cell therapy.
I have a high risk of severe allergic reactions to certain enzyme treatments.
My blood test shows I have AAV8 antibodies.
I have been diagnosed with nerve damage in my hands or feet.
I have a bleeding condition due to blood-thinning medications.
Participant Groups
The clinical trial is testing AT845, a gene transfer therapy, in adults with LOPD to assess its safety and effectiveness. This phase 1/2 trial involves multiple centers where participants receive increasing doses of AT845 while their health outcomes are monitored.
3Treatment groups
Experimental Treatment
Group I: Third Dose CohortExperimental Treatment1 Intervention
1x10\^14 vg/kg of AT845 administered via intravenous infusion
Group II: Second Dose CohortExperimental Treatment1 Intervention
6x10\^13 vg/kg of AT845 administered via intravenous infusion
Group III: Initial Dose CohortExperimental Treatment1 Intervention
3x10\^13 vg/kg of AT845 administered via intravenous infusion
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
To be announcedDetroit, MI
To be announcedDallas, TX
To be announcedAtlanta, GA
Central Michigan UniversityDetroit, MI
More Trial Locations
Loading ...
Who is running the clinical trial?
Audentes TherapeuticsLead Sponsor
Astellas Gene TherapiesLead Sponsor
References
Ability of adeno-associated virus serotype 8-mediated hepatic expression of acid alpha-glucosidase to correct the biochemical and motor function deficits of presymptomatic and symptomatic Pompe mice. [2008]The availability of a murine model of Pompe disease has enabled an evaluation of the relative merits of various therapeutic paradigms, including gene therapy. We report here that administration of a recombinant adeno-associated virus serotype 8 (AAV8) vector (AAV8/DC190-GAA) encoding human acid alpha-glucosidase (GAA) into presymptomatic Pompe mice resulted in nearly complete correction of the lysosomal storage of glycogen in all the affected muscles. A relatively high dose of AAV8/DC190-GAA was necessary to attain a threshold level of GAA for inducing immunotolerance to the expressed enzyme and for correction of muscle function, coordination, and strength. Administration of AAV8/DC190-GAA into older Pompe mice with overt disease manifestations was also effective at correcting the lysosomal storage abnormality. However, these older mice exhibited only marginal improvements in motor function and no improvement in muscle strength. Examination of histologic sections showed evidence of skeletal muscle degeneration and fibrosis in aged Pompe mice whose symptoms were abated or rescued by early but not late treatment with AAV8/DC190-GAA. These results suggest that AAV8-mediated hepatic expression of GAA was effective at addressing the biochemical and functional deficits in Pompe mice. However, early therapeutic intervention is required to maintain significant muscle function and should be an important consideration in the management and treatment of Pompe disease.
Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease. [2020]A preclinical safety study was conducted to evaluate the short- and long-term toxicity of a recombinant adeno-associated virus serotype 8 (AAV2/8) vector that has been developed as an immune-modulatory adjunctive therapy to recombinant human acid α-glucosidase (rhGAA, Myozyme) enzyme replacement treatment (ERT) for patients with Pompe disease (AAV2/8-LSPhGAApA). The AAV2/8-LSPhGAApA vector at 1.6 × 10(13) vector particles/kg, after intravenous injection, did not cause significant short- or long-term toxicity. Recruitment of CD4(+) (but not CD8(+)) lymphocytes to the liver was elevated in the vector-dosed male animals at study day (SD) 15, and in group 8 animals at SD 113, in comparison to their respective control animals. Administration of the vector, either prior to or after the one ERT injection, uniformly prevented the hypersensitivity induced by subsequent ERT in males, but not always in female animals. The vector genome was sustained in all tissues through 16-week postdosing, except for in blood with a similar tissue tropism between males and females. Administration of the vector alone, or combined with the ERT, was effective in producing significantly increased GAA activity and consequently decreased glycogen accumulation in multiple tissues, and the urine biomarker, Glc4, was significantly reduced. The efficacy of the vector (or with ERT) was better in males than in females, as demonstrated both by the number of tissues showing significantly effective responses and the extent of response in a given tissue. Given the lack of toxicity for AAV2/8LSPhGAApA, further consideration of clinical translation is warranted in Pompe disease.
Neuroimaging findings in infantile Pompe patients treated with enzyme replacement therapy. [2022]Recombinant human acid α-glucosidase (rhGAA) enzyme replacement therapy (ERT) has prolonged survival in infantile Pompe disease (IPD), but has unmasked central nervous system (CNS) changes.
Liver depot gene therapy for Pompe disease. [2020]Gene therapy for Pompe disease has advanced to early phase clinical trials, based upon proof-of-concept data indicating that gene therapy could surpass the benefits of the current standard of care, enzyme replacement therapy (ERT). ERT requires frequent infusions of large quantities of recombinant human acid α-glucosidase (GAA), whereas gene therapy involves a single infusion of a vector that stably transduces tissues to continuously produce GAA. Liver-specific expression of GAA with an adeno-associated virus (AAV) vector established stable GAA secretion from the liver accompanied by receptor-mediated uptake of GAA, which corrected the deficiency of GAA and cleared the majority of accumulated glycogen in the heart and skeletal muscle. Liver depot gene therapy was equivalent to ERT at a dose of the AAV vector that could be administered in an early phase clinical trial. Furthermore, high-level expression of GAA has decreased glycogen stored in the brain. A unique advantage of liver-specific expression stems from the induction of immune tolerance to GAA following AAV vector administration, thereby suppressing anti-GAA antibodies that otherwise interfere with efficacy. A Phase I clinical trial of AAV vector-mediated liver depot gene therapy has been initiated based upon promising preclinical data (NCT03533673). Overall, gene therapy promises to address limits of currently available ERT, if clinical translation currently underway is successful.
Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature. [2022]Enzyme replacement therapy (ERT) with recombinant human acid-α glucosidase (rhGAA) at standard dose of 20 mg/kg every other week is insufficient to halt the long-term progression of myopathy in Pompe disease.
Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial. [2022]Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease.
Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity. [2022]Pompe disease is a severe disorder caused by loss of acid α-glucosidase (GAA), leading to glycogen accumulation in tissues and neuromuscular and cardiac dysfunction. Enzyme replacement therapy is the only available treatment. AT845 is an adeno-associated viral vector designed to express human GAA specifically in skeletal muscle and heart. Systemic administration of AT845 in Gaa-/- mice led to a dose-dependent increase in GAA activity, glycogen clearance in muscles and heart, and functional improvement. AT845 was tolerated in cynomolgus macaques at low doses, while high doses caused anti-GAA immune response, inflammation, and cardiac abnormalities resulting in unscheduled euthanasia of two animals. Conversely, a vector expressing the macaque GAA caused no detectable pathology, indicating that the toxicity observed with AT845 was an anti-GAA xenogeneic immune response. Western blot analysis showed abnormal processing of human GAA in cynomolgus muscle, adding to the species-specific effects of enzyme expression. Overall, these studies show that AAV-mediated GAA delivery to muscle is efficacious in Gaa-/- mice and highlight limitations in predicting the toxicity of AAV vectors encoding human proteins in non-human species.
Phase I study of liver depot gene therapy in late-onset Pompe disease. [2023]Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid α-glucosidase (GAA) production. We report initial safety and bioactivity of the first dose (1.6 × 1012 vector genomes/kg) cohort (n = 3) in a 52-week open-label, single-dose, dose-escalation study (NCT03533673) in patients with late-onset Pompe disease (LOPD). Subjects discontinued biweekly ERT after week 26 based on the detection of elevated serum GAA activity and the absence of clinically significant declines per protocol. Prednisone (60 mg/day) was administered as immunoprophylaxis through week 4, followed by an 11-week taper. All subjects demonstrated sustained serum GAA activities from 101% to 235% of baseline trough activity 2 weeks following the preceding ERT dose. There were no treatment-related serious adverse events. No subject had anti-capsid T cell responses that decreased transgene expression. Muscle biopsy at week 24 revealed unchanged muscle glycogen content in two of three subjects. At week 52, muscle GAA activity for the cohort was significantly increased (p < 0.05). 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.
Screening data from 19 patients with late-onset Pompe disease for a phase I clinical trial of AAV8 vector-mediated gene therapy. [2023]Late-onset Pompe disease (LOPD) is a multisystem disorder with significant myopathy. The standard treatment is enzyme replacement therapy (ERT), a therapy that is lifesaving, yet with limitations. Clinical trials have emerged for other potential treatment options, including adeno-associated virus (AAV) gene therapy. We present clinical parameters and AAV antibody titers for 19 individuals with LOPD undergoing screening for a Phase I clinical trial with an AAV serotype 8 vector targeting hepatic transduction (AAV2/8-LSPhGAA). Reported clinical parameters included GAA genotype, assessments of muscle function, upright and supine spirometry, anti-recombinant human GAA antibody titers, and biomarkers. Variability in measured parameters and phenotypes of screened individuals was evident. Eligibility criteria required that all participants have six-minute walk test (6MWT) and upright forced vital capacity (FVC) below the expected range for normal individuals, and were stably treated with ERT for >2 years. All participants had Pompe disease diagnosed by enzyme deficiency, and all had the common c.-32-13T>G LOPD pathogenic variant. Screening identified 14 patients (74%) with no or minimal detectable neutralizing antibodies against AAV8 (titer ≤1:5). 6MWT distance varied significantly (percent of expected distance ranging from 24% to 91% with an average of 60 and standard deviation of 21). Upright FVC percent predicted ranged from 35% predicted to 91% predicted with an average of 66 and standard deviation of 18. None of the participants had significantly elevated alanine transaminase, which has been associated with LOPD and could complicate screening for hepatitis related to AAV gene therapy. We review the parameters considered in screening for eligibility for a clinical trial of AAV8 vector-mediated gene therapy.