PompeDiseaseNews and the AMDA have just reported that Audentes Therapeutics has begun recruiting Late Onset Pompe Disease (LOPD) patients for a new Phase 1/2 Gene Therapy clinical trial that utilizes the AAV8 vector to deliver a functional copy of the human GAA gene.

This is, of course, very exciting news. In my research, I’ve only found two Gene Therapy clinical trials for Pompe Disease – the initial University of Florida study (2010-2015) and the current Duke University clinical trial of ACTUS-101. In contrast to the on-going Duke study, this therapy delivers a functional copy of the GAA gene directly to the nucleus of muscle cells instead of utilizing the liver to express GAA. Audentes Therapeutics anticipates that this method may be more effective in targeting muscle tissues as it bypasses entirely the use of plasma to transport GAA from the liver to muscles tissues.

The trial goal is to recruit eight LOPD patients between the ages of 18 and 80. Subjects will receive a single IV dose of AT845. Two dose levels are intended to be tested – the second cohort may receive a higher dose if the initial lower dose level is found to be safe. Patients will be evaluated for primary and secondary outcomes at 48 weeks and then followed for five years.

As with most all clinical trials, there are numerous inclusion and exclusion criteria. Trial sites include three US locations (Stanford, UC-Irvine and the University of Utah), one in the UK (Newcastle Upon Tyne Hospitals Foundation Trust Clinical Research Facility) and one in Germany (Ludwig-Maximillians University of Munich). The trial began recruiting today (8/5/2020) with a primary completion date anticipated to occur by December 2022. The overall study is expected to conclude around January 2027.

From the company’s announcement:

Q: How does Audentes’ investigational gene therapy product work?

A: This investigational gene therapy product is comprised of a working copy of the GAA gene, and the new gene is placed inside a vector, which acts as a transportation vehicle and carries the gene to the appropriate cells in the body. A virus is selected as a vector because of its ability to enter the body’s cells. In this case, a very small and simple virus called adeno-associated virus (AAV) is used because it is not known to cause viral illness in people. The vector is administered one time through an intravenous injection and carries the new gene to the control center of the cells, also known as the nucleus. Once inside the muscle cell nucleus, the new gene tells the body’s cells how to make the protein, or GAA, it needs.

Q: How does Audentes’ investigational gene therapy approach differ from other approved treatments and investigational gene therapies?
A: The goal of Audentes’ investigational gene therapy approach is to express GAA preferentially in muscle tissues, including skeletal and cardiac muscle, which are the tissues most affected by the disease.

This approach differs from approved enzyme replacement therapy (ERT) and liver-directed investigational gene therapy candidates that must overcome the challenges of GAA uptake into muscle from plasma, a liquid that makes up about half of the content of blood. The main role of plasma is to take nutrients, hormones, and proteins to the parts of the body that need it. In the case of liver-directed gene therapy products, plasma transports GAA from the liver to the muscle tissue. The ERT and liver-directed approaches leverage a delivery system that may impact the amount and distribution of GAA in the muscle tissue.

Q: What are the objectives of FORTIS?
A: The objectives of the clinical trial are to evaluate the following:

The safety of 2 dose levels of the investigational gene therapy product in trial participants 18 years of age or older with LOPD

Acid alpha-glucosidase (GAA) activity and preliminary efficacy of 2 dose levels of the investigational gene therapy product in participants 18 years of age with LOPD

Q: How many people will take part in this investigative clinical trial?
A: Up to approximately 8 people are expected to be in this trial in North America and Europe. Patients who meet eligibility are not guaranteed enrollment into the trial.For specific clinical trial site information, please visit www.clinicaltrials.gov and enter “Pompe” in the “condition or disease” section and “FORTIS” in the “other terms” section. Click on “Gene Transfer Study in Patients with Late Onset Pompe Disease.”

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.

Methods

We conducted a retrospective study on infantile-onset Pompe disease (IPD) and late-onset Pompe disease (LOPD) patients with onset before age 5 years, ≥12 months of treatment with standard dose ERT, and rhGAA immunogenic tolerance prior to dose escalation. Long-term follow-up of up to 18 years was obtained. We obtained physical therapy, lingual strength, biochemical, and pulmonary assessments as dose was escalated.

Results

Eleven patients with IPD (n = 7) or LOPD (n = 4) were treated with higher doses of up to 40 mg/kg weekly. There were improvements in gross motor function measure in 9/10 patients, in lingual strength in 6/6 patients, and in pulmonary function in 4/11. Significant reductions in urinary glucose tetrasaccharide, creatine kinase, aspartate aminotransferase, and alanine aminotransferase were observed at 40 mg/kg weekly compared with lower doses (p < 0.05). No safety or immunogenicity concerns were observed at higher doses.

Conclusion

Higher rhGAA doses are safe, improve gross motor outcomes, lingual strength, pulmonary function measures, and biochemical markers in early-onset Pompe disease, and should be considered in patients with clinical and functional decline.

Aleena A. Khan MBBS, Laura E. Case PT, DPT, Mrudu Herbert MD, MPH, Stephanie DeArmey MHS, PA-C, Harrison Jones PhD, Kelly Crisp CCC-SLP, MA, Kanecia Zimmerman MD, Mai K. ElMallah MD, Sarah P. Young PhD & Priya S. Kishnani MD

Genetics in Medicine volume 22, pages898–907(2020)

Background: Late onset Pompe disease (LOPD) is a lysosomal neuromuscular disorder which can progressively impair the patients’ exercise tolerance, motor and respiratory functions, and quality of life. The available enzyme replacement therapy (ERT) does not completely counteract disease progression. We investigated the effect of exercise training alone, or associated with a high-protein diet, on the exercise tolerance, muscle and pulmonary functions, and quality of life of LOPD patients on long term ERT.

Methods: The patients were asked to participate to a crossover randomized study comprehending a control period (free diet, no exercise) followed by 2 intervention periods: exercise or exercise + diet, each lasting 26 weeks and separated by 13 weeks washout periods. Exercise training included moderate-intensity aerobic exercise on a cycle ergometer, stretching and balance exercises, strength training. The diet was composed by 25-30% protein, 30-35% carbohydrate and 35-40% fat. Before and after each period patients were assessed for: exercise tolerance test on a cycle-ergometer, serum muscle enzymes, pulmonary function tests and SF36 questionnaire for quality of life. Compliance was evaluated by training and dietary diaries. Patients were contacted weekly by researchers to optimize adherence to treatments.

Results: Thirteen LOPD patients, median age 49 ± 11 years, under chronic ERT (median 6.0 ± 4.0 years) were recruited. Peak aerobic power (peak pulmonary O₂ uptake) decreased after control, whereas it increased after exercise, and more markedly after exercise + diet. Serum levels of lactate dehydrogenase (LDH) significantly decreased after exercise + diet; both creatine kinase (CK) and LDH levels were significantly reduced after exercise + diet compared to exercise. Pulmonary function showed no changes after control and exercise, whereas a significant improvement of forced expiratory volume in 1 sec (FEV1) was observed after exercise + diet. SF36 showed a slight improvement in the “mental component” scale after exercise, and a significant improvement in “general health” and “vitality” after exercise + diet. The compliance to prescriptions was higher than 70% for both diet and exercise.

Conclusions: Exercise tolerance (as evaluated by peak aerobic power) showed a tendency to decrease in LOPD patients on long term ERT. Exercise training, particularly if combined with high-protein diet, could reverse this decrease and result in an improvement, which was accompanied by improved quality of life. The association of the two lifestyle interventions resulted also in a reduction of muscle enzyme levels and improved pulmonary function.

• Interview with Dwight Koeberl, MD, PhD at Duke University
• Early results from Actus-101 phase 1/2 study (AAV2/8-LSPhGAA in Late-Onset Pompe Disease)
• First three people enrolled
• Have participated in 24 weeks of the study
• Results from low-dose branch
• No serious adverse events
• All three patients met efficacy goals and have now stopped ERT infusions entirely
• Clinical Trial Website
  • https://clinicaltrials.gov/ct2/show/NCT03533673
• Asklepios BioPharmaceutical
  • http://www.askbio.com

My Take:

This is really great news. The results are very preliminary, but the fact that all three study participants were able to quit ERT infusions at 24 weeks is potentially life-changing for thousands of people with Pompe. At this point in the study, it’s really the best news we could hope for at this early time.

There’s nothing negative about this interview, but there is certainly a lot riding on this trial. Many Pompe Disease patients are hopeful it will offer a “cure” for Pompe and possibly even reduce some symptoms that Myozyme/Lumizyme are typically not able to improve significantly (brain symptoms, for example).

Although many hope this will be something of a “silver bullet”. There are other gene therapy trials in the Pompe Disease treatment pipeline. Audentes Therapeutics in late July 2020 began recruiting patients for their gene therapy trial known as FORTIS.

Video via checkrare.com:

Five patients were cross‐reactive immunologic material (CRIM)‐negative, two in the 20 mg, three in the 40 mg group. We compared (ventilator‐free) survival, motor outcome, infusion associated reactions (IARs), and antibody formation. From 2012 on patients >2 months in the 40 mg group also received immunomodulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) in an enzyme replacement therapy (ERT)‐naïve setting.

Survival was 66% in the 20 mg group and 92% in the 40 mg group. Ventilator‐free survival was 50% and 92%. Both CRIM‐negative patients in the 20 mg group died, whereas all three are alive in the 40 mg group. In the 20 mg group, 67% learned to walk compared with 92% in the 40 mg group. At the age of 3 years, 33% and 92% were able to walk.

Peak antibody titers ranged from 1:1250 to 1:31 250 in the 20 mg group and from 1:250 to 1:800 000 in the 40 mg group. Five patients of the 40 mg group of whom two CRIM‐negative also received immunomodulation. B‐cell recovery was observed between 5.7 and 7.9 months after the last dose of rituximab. After B‐cell recovery titers of patients with and without immunomodulation were similar (ranges 1:6 250‐1:800 000 and 1:250‐1:781 250). This study shows that classic infantile patients treated with 40 mg/kg/week from the start to end have a better (ventilator‐free) survival and motor outcome. Immunomodulation did not prevent antibody formation in our study.

Esther PoelmanJan J. A. van den DorpelMarianne Hoogeveen‐WesterveldJohanna M. P. van den HoutLianne J. van der GiessenNadine A. M. E. van der BeekW. W. M. Pim PijnappelAns T. van der Ploeg

First published: 07 June 2020

https://doi.org/10.1002/jimd.12268

• Data from Pompe Registry
• 396 patients
• All on Enzyme Replacement Therapy (ERT)
• Examined upright FVC
• Median FVC (forced vital capacity) was 66.9%
  • FVC stable at 5 years -> Decline ~ 0.17%/yr
• Baseline FVC lower among some groups
  • Males
  • Older at ERT initiation
  • Longer duration from symptom onset to ERT initiation
  • More advanced disease
• Age of onset NOT associated with baseline degree of dysfunction
• Shorter time from diagnosis to ERT initiation associated with higher FVC after 5 years.
  • Cutoff of 1.7 years used in study
  • Neither short nor long groups’ declines were significantly different from 0.
    • Shorter-Time: − 0.07% predicted/year, p = 0.72;
    • Longer-Time: − 0.25% predicted/ year, p = 0.16

My take:

As a father of a newly diagnosed LOPD infant patient, this is a promising result. As I’m sure is the case with most of you reading, one of my greatest fears is that she (or you or your child) will deteriorate before more effective treatments can be found. The most fascinating finding was that respiratory function (measured with FVC) while on ERT was largely stable over five years. Similarly, although it is potentially better to have begun treatment within 1.7 years of diagnosis, even the group of patients that began ERT later than one year after diagnosis did not have a respiratory function decline significantly different than “no decline”.

With the improved treatments (hopefully) arriving in the not too distant future, a minimal degradation of FVC over five years is encouraging. With the two novel ERT treatments in phase 3 testing and now two current ongoing gene therapy trials [trial 1 and 2], there is certainly hope.

On the less positive side, Upright FVC is just one of many aspects of respiratory function. This result isn’t especially surprising, as most literature that I have read seems to suggest the same thing (while other performance measurements may experience more considerable declines). I guess it makes sense, however, as these patients were pulled from the Pompe Registry, it’s likely they were written about other previous studies.

Overall, this paper’s results is encouraging for those Pompe Disease to know that over five years it is likely that their upright breathing will not suffer significantly while on ERT.

Abstract

Objective

To examine respiratory muscle function among late-onset Pompe disease (LOPD) patients in the Pompe Registry (NCT00231400/Sanofi Genzyme) during enzyme replacement therapy (ERT) with alglucosidase alfa by assessing the longitudinal course of forced vital capacity (FVC), prognostic factors for FVC, and impact of time from diagnosis to ERT initiation.

Methods

Longitudinal FVC data from LOPD (symptom onset > 12 months or ≤ 12 months without cardiomyopathy) patients were analyzed. Patients had to have baseline FVC (percent predicted upright) assessments at ERT start and ≥ 2 valid post-baseline assessments. Longitudinal analyses used linear mixed-regression models.

Results

Among 396 eligible patients, median baseline FVC was 66.9% (range 9.3–126.0). FVC remained stable during the 5-year follow-up (slope = − 0.17%, p = 0.21). Baseline FVC was lower among various subgroups, including patients who were male; older at ERT initiation; had a longer duration from symptom onset to ERT initiation; and had more advanced disease at baseline (based on respiratory support use, inability to ambulate, ambulation device use). Age at symptom onset was not associated with baseline degree of respiratory dysfunction. Differences between subgroups observed at baseline remained during follow-up. Shorter time from diagnosis to ERT initiation was associated with higher FVC after 5 years in all patients and the above subgroups using a cut-off of 1.7 years.

Conclusion

FVC stability over 5 years suggests that respiratory function is preserved during long-term ERT in real-world settings. Early initiation of alglucosidase alfa was associated with preservation of FVC in LOPD patients with better respiratory function at the time of treatment initiation.

Mol Ther Methods Clin Dev. 2020 Sep 11; 18: 199–214. Published online 2020 Jun 10.
doi: 10.1016/j.omtm.2020.05.026

PMCID: PMC7334420

PMID:  32671132

Naresh Kumar Meena,¹Evelyn Ralston,²Nina Raben,^1,∗ and  Rosa Puertollano^1,∗∗

²Light Imaging Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA

¹Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA

Pompe disease, a deficiency of glycogen-degrading lysosomal acid alpha-glucosidase (GAA), is a disabling multisystemic illness that invariably affects skeletal muscle in all patients. The patients still carry a heavy burden of the disease, despite the currently available enzyme replacement therapy.

We have previously shown that progressive entrapment of glycogen in the lysosome in muscle sets in motion a whole series of “extra-lysosomal” events including defective autophagy and disruption of a variety of signaling pathways. Here, we report that metabolic abnormalities and energy deficit also contribute to the complexity of the pathogenic cascade. A decrease in the metabolites of the glycolytic pathway and a shift to lipids as the energy source are observed in the diseased muscle.

We now demonstrate in a pre-clinical study that a recently developed replacement enzyme (recombinant human GAA; AT-GAA; Amicus Therapeutics) with much improved lysosome-targeting properties reversed or significantly improved all aspects of the disease pathogenesis, an outcome not observed with the current standard of care. The therapy was initiated in GAA-deficient mice with fully developed muscle pathology but without obvious clinical symptoms; this point deserves consideration.

Keywords: Pompe disease, enzyme replacement therapy, lysosomal targeting, mTORC1/AMPK signaling, metabolome, muscle, autophagy, acid alpha glucosidase, glycogen

Mol Ther Methods Clin Dev. 2020 Sep 11; 18: 199–214. Published online 2020 Jun 10. doi: 10.1016/j.omtm.2020.05.026

PMCID: PMC7334420

PMID: 32671132