I’ll just make a small note here and say that while we may have this very rare and awful disease, it is great to know that there are so many people working on finding treatments and a cure for us ~ Allyson
Enzyme Replacement Therapy
Individuals with Pompe disease are best treated by a team of specialists (such as cardiologist, neurologist, and respiratory therapist) knowledgeable about the disease, who can offer supportive and symptomatic care.
The discovery of the GAA gene has led to rapid progress in understanding the biological mechanisms and properties of the GAA enzyme. As a result, an enzyme replacement therapy has been developed that has shown, in clinical trials with infantile-onset patients, to decrease heart size, maintain normal heart function, improve muscle function, tone, and strength, and reduce glycogen accumulation.
A drug called alglucosidase alfa (Myozyme©), has received FDA approval for the treatment of infants and children with Pompe disease. Another alglucosidase alfa drug, Lumizyme©, has been approved for late-onset (non-infantile) Pompe disease.
Note: In New Zealand, Lumizyme is called Myozyme. In fact, it is only known as Lumizyme in the United States. The rest of the world it is Myozyme.
New Therapies in Development
Next Generation Enzyme Replacement Therapies
There are currently two next-generation ERTs in clinical studies, and two more are being proposed using lower cost platforms.
In February 2021, Amicus announced the initial results from its Phase 3 PROPEL Pivotal Trial for AT-GAA (cipaglucosidase alfa and miglustat) for Pompe—its investigational two-component therapy for the treatment of late-onset Pompe disease (LOPD) that has previously received Breakthrough Therapy Designation from the U.S. FDA and the Promising Innovative Medicine designation from the MHRA in the United Kingdom. As of November 2022, Amicus has not yet received FDA approval in the US due to “the Agency’s inability to complete the manufacturing facility inspection.” “Due to restrictions on travel related to COVID-19, the FDA was unable to conduct the required inspection of the WuXi Biologics manufacturing site in China during the review cycle. As a result, the FDA is deferring action on the application until the manufacturing site inspection is complete. The Company continues to expect the FDA to approve the two components of AT-GAA, including the BLA and New Drug Application (NDA) for miglustat, together.” “In the European Union, where a pre-approval inspection is not required, the regulatory review is on track and the Committee for Medicinal Products for Human Use (CHMP) opinion is expected before year end.” (per 10/28/2022 Amicus Press Release).
Eleva Biologics (previously known as Greenovation)
Eleva continues to work on it’s moss-produced recombinant GAA. According to their website, as of November 2022 they are still in the Pre-Clinical phase. In addition, they claim that their approach shows superior uptake into muscular cells, thanks to the inherent glycan pattern of moss.
According to JCR Pharmaceuticals website, as of November 2022, they are still in Pre-Clinical Development of an ERT that has the potential to cross the blood-brain barrier.
M6P Therapeutics is working on a next generation ERT that is “naturally produced with the highest levels of M6P as compared to other rhGAA ERTs.” As of November 2022, their program is in Pre-Clinical Development. They anticipate applying for Investigational New Drug status (IND) in the second quarter of 2024.
Pharming Group NV
Pharming continues to develop a transgenic ERT for Pompe. According to their website as of November 2022, they are currently studying their alpha-glucosidase therapy in IND-enabling studies.
In July/August 2021, Sanofi received a positive opinion on avalglucosidase alfa, a long-term next-generation enzyme replacement therapy for the treatment of people with Pompe disease, from the U.S. Food and Drug Administration (FDA) and also from the European Medical Authority.The positive opinion is based on data from the Phase 3 COMET study, which found that avalglucosidase alfa showed clinically meaningful improvements in respiratory function and movement endurance measures in people with late-onset Pompe disease. Following those decisions, the treatment became commercially available in the US in third-quarter 2021 for late-onset Pompe. In Europe, the treatment has been approved, but is not yet commercially available as it must be approved on a country-by-country basis. This is the first new treatment for Pompe to be approved since 2006. Substrate Reduction Therapies Substrate reduction therapies (SRTs) seek to affect the disease process by reducing the accumulation of glycogen in the muscles of Pompe patients by reducing the amount of glucose that is turned into glycogen.
Below are listed the two companies who are currently working on Substrate Reduction Therapies for Pompe.
According to their website: “Aro Biotherapeutics is a biotechnology company pioneering the development of tissuetargeted genetic medicines with a platform based on a proprietary protein technology called Centyrins. The company is developing a wholly-owned pipeline of Centyrin-based therapeutic candidates and is working with industry partners to leverage Centyrins for tissue-specific targeting of therapeutics for a diverse set of diseases.” In August 2022, Aro Biotherapeutics was granted Orphan Drug Designation for their Pompe product ABX1100. ABX1100 targets the gene for glycogen synthase 1 (Gys1), an enzyme that is responsible for glycogen synthesis in muscle. Inhibition of Gys1 has been shown to reduce glycogen levels and thus represents a novel treatment approach for Pompe disease. At the TIDES USA 2022 meeting, Aro Biotherapeutics presented data demonstrating that ABX1100 profoundly reduces Gys1 mRNA and GYS1 protein, leading to meaningful reductions in glycogen levels in the skeletal muscle in the Pompe mouse disease model. Aro Biotherapeutics anticipates entering clinical trials with ABX1100 in mid-2023.
Maze Therapeutics is working on a substrate reduction therapy (SRT) that has potential therapeutic benefits for Pompe. Their approach to treating Pompe disease is achieved by halting skeletal and respiratory muscle glycogen synthesis and its subsequent accumulation by inhibiting the action of the gene GYS1 through SRT. Maze has completed a Phase 1 study in healthy individuals, and hopes to announce these results by the end of 2022. They also hope to start a Phase 2 trial in Pompe patients in the first half of 2023. Cell and Gene Therapies (Regenerative medicine) Regenerative medicine across rare disease has continued to gain interest.
Below we have listed a number of different approaches that may each provide a solution for Pompe. Amicus Therapeutics. Amicus is working with the Gene Therapy Program in the Perelman School of Medicine at the University of Pennsylvania (Penn) to pursue research and development of novel gene therapies for Pompe disease. This program remains at the Preclinical development stage as of November 2022.
Astellas Gene Therapies (previously known as Audentes Therapeutics)
According to their website, Astellas Gene Therapies is developing AT845, a novel gene replacement investigational therapy to address the recognized limitations of ERT by targeting the muscle tissues, the primary tissue affected in Pompe disease. AT845 utilizes a muscle-directed approach with an AAV8 capsid serotype that is being investigated to determine whether it can deliver a functional GAA gene that is efficiently transduced to express GAA directly in tissues affected by the disease, including skeletal and cardiac muscle. At WORLD 2022, Astellas presented their initial results from the FORTIS clinical trial. However, in June 2022, Astellas announced “that the US Food and Drug Administration (FDA) has placed a clinical hold on the FORTIS Phase 1/2 trial following the occurrence of a serious adverse event (SAE) of peripheral sensory neuropathy in one of the trial participants. FORTIS is a clinical trial evaluating AT845, an investigational adeno-associated virus (AAV) gene replacement therapy in adults with Late-Onset Pompe Disease.” As of November 2022, the clinical trial is still on hold and we are waiting to see how things progress with the FDA.
AVR-RD-03, the Lentiviral gene therapy platform used by AvroBio modifies the patient’s own stem cells taken from the bone marrow. As of November 2022, this program is still in pre-clinical research.
According to their website: “AVROBIO has a preclinical research program for a gene therapy for Pompe disease. We have shown a favourable preclinical safety and efficacy profile in a mouse model of Pompe disease.”
In October 2020, Bayer acquired AskBio, and its gene therapy platform. The intent is to help to bring their therapies to commercial market. In regards to Pompe disease, AskBio continues to enrol patients with Late-Onset Pompe Disease (LOPD) to assess multiple doses of its gene therapy ACT-101 (also known as ACTUS-101). ACT-101 is infused intravenously and designed to deliver a functioning copy of the GAA gene (malfunctioning in Pompe disease) to the liver. The goal is to restore GAA production to a level sufficient to no longer require ERT. The primary objective of this study is to assess the safety of ACT-101 for the treatment of LOPD in adults, as well as assess the impact of this treatment on patient health as measured by changes in exercise capacity (6-minute walk), pulmonary function, and other factors including quality of life. The first patient was dosed in January 2019, and trial is on-going.
Through a partnership between CODEXIS and Takeda, early research into a potential gene therapy for Pompe disease is taking place. As of November 2022, their website states that this Program is in the research development phase, so not much is known yet about this approach.
Pim Pijnappel, Associate Professor Molecular Stem Cell Biology Research continues at the Erasmus MC to study several regenerative therapies for Pompe, including stem cell regenerative therapies and RNA Oligonucleotides, as well as lentiviral gene therapy.
GeneCradle is working on an AAV-mediated gene therapy for Infantile-Onset Pompe. According to ClinicalTrials.gov, there is trial based out of China that is currently recruiting. It will include 6 patients with IOPD who are younger than 6 months of age. This study was first posted on October 5, 2022, so we are still waiting for more information to be released.
LogicBio Therapeutics/CANbridge Care
LogicBio’sGeneRide technology is a program to watch as a second-generation gene therapy. They claim that their technology will be suitable for infants and will not require re-dosing. They are looking across the range of LSDs and GSDs, but say that applying their technology to Pompe disease is more challenging. As of November 2022, this program remains in the Research Phase of development.
According to the June 2022 Annual Shareholder Meeting Report, Regeneron has a Pre-Ind research program for Pompe in their pipeline that is exploring CRISPR/Cas9 + AAV Transgene Insertion. This Program is in a very early stage, so we will continue to keep an eye on it as the program develops further.
Sarepta Therapeutics/Lacerta Therapeutics
Sarepta has an agreement with Lacerta Therapeutics to develop AAV-9 gene therapy for Pompe disease. As of November 2022, this approach remains in the Research Phase of Development.
Spark Therapeutics is developing SPK-3006, an investigational gene therapy for treatment of Pompe disease. Their Phase II trial, Resolute, is still ongoing. The purpose of the RESOLUTE clinical trial is to study the effects of gene therapy SPK-3006 (investigational study drug). Spark announced in February 2021 that the first patient had been dosed in the Phase 1/2 trial.
Visit https://clinicaltrials.gov/ for further details of clinical studies currently underway.