Pompe Disease: Causes, Symptoms, Diagnosis, Pathology, Current Marketed and Emerging Drugs in the Pipeline

Pompe disease is an inherited disorder caused by the buildup of a complex sugar called glycogen in the body’s cells. The accumulation of glycogen in certain organs and tissues, especially muscles, impairs their ability to function normally. There are three types of Pompe disease, which differ in severity and the age at which they appear. These types are known as classic infantile-onset, non-classic infantile-onset, and late-onset Pompe disease.

Pompe disease is caused due to mutations in the GAA gene. The GAA gene provides instructions for producing an enzyme called acid alpha-glucosidase (also known as acid maltase). This enzyme is active in lysosomes which are structures that serve as recycling centers within cells. The enzyme normally breaks down glycogen into a simpler sugar called glucose, which is the main energy source for most cells. Mutations in the GAA gene prevent acid alpha-glucosidase from breaking down glycogen effectively, which allows this sugar to build up to toxic levels in lysosomes. This buildup damages organs and tissues throughout the body, particularly the muscles, leading to the progressive signs and symptoms of Pompe disease. Pompe disease is inherited in an autosomal recessive pattern which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. There are many different and more scientific terms for Pompe Disease including Acid maltase deficiency, Alpha-1,4-glucosidase deficiency, GAA deficiency, Glycogenosis type II, and a few others.

Pompe disease symptoms begin in the first months of life, with feeding problems, poor weight gain, muscle weakness, floppiness, and head lag. Respiratory difficulties are often complicated by lung infections. The heart is grossly enlarged. Many infants with Pompe disease also have enlarged tongues. Pompe disease affects about 1 in 40,000 people in the United States. The incidence of this disorder varies among different ethnic groups. Patients with the ‘classic infantile’ form of Pompe disease are the most severely affected. Although hardly any symptoms may be apparent at birth, the disease usually presents within the first three months of life with rapidly progressive muscle weakness (‘floppy infants’), diminished muscle tone (hypotonia), respiratory deficiency, and a type of heart disease known as hypertrophic cardiomyopathy, resulting in diminished cardiac function. These problems together culminate in cardio-respiratory failure within the first 2 years of life. Many infants have a large, protruding, tongue and moderate enlargement of the liver. The legs often rest in a frog position and feel firm on palpation.

The diagnosis of Pompe disease is based on a thorough clinical evaluation, a detailed patient and family history, and a variety of biochemical tests with first of all the measuring of GAA activity. In individuals suspected of having Pompe disease, blood can be drawn and the function/activity of GAA (the ‘enzymatic activity’) can be measured in white blood cells (leukocytes), but only if the proper assay conditions are being used and acarbose is added to the reaction mixture to inhibit the activity of glucoamylase. Alternatively, the GAA activity/functional assay can also be performed on dried blood spots, but this method is not any quicker, less reliable, and also requires the use of acarbose to inhibit the glucoamylase activity. A variety of other tests can be performed to detect or assess symptoms potentially associated with Pompe disease such as sleep studies, tests that measure lung function, and tests that measure muscle function. Muscle MRI (imaging by magnetic resonance) is used to visualize the degree of muscle damage.

As per DelveInsight estimates, the total prevalent population of Pompe Disease in the United States shall grow at a CAGR of 0.48% for the study period of 2017 to 2028.  Overall, the increasing awareness of the disease assisted by organizational support along with the high prices of Enzyme Replacement therapies (and expanded approvals) is expected to fuel the Pompe disease market size in the coming years. Delveinsight analysis also indicates that a total of 2,556 Pompe disease cases were reported in 2017.

Many key pharmaceuticals are proactively involved in producing Pompe Disease treatment therapies including companies like Genzyme, Sanofi, Amicus Therapeutics, Actus Therapeutics, Valerion Therapeutics, Astellas Therapeutics, Roche, Immusoft, Asklepios Biopharmaceutical, Audentes Therapeutics, Genzyme, Lacerta Therapeutics, Selecta Biosciences, Greenovation Biotech, BioMarin Pharmaceutical, Oxyrane, and many others

Currently, there is no permanent cure for Pompe disease. But different treatment options can help ease Pompe disease symptoms. Most patients require supportive therapy to address the symptoms which include respiratory and cardiac problems, physical disability, and difficulty swallowing. Some patients may require a mechanical ventilator during respiratory infections or at night. Physical and occupational therapy can improve patients’ muscle strength and help them to learn to use canes or walkers if necessary. Speech therapy and the usage of feeding tubes are some of the other components.

Pompe Disease Current Treatment Landscape

Pompe disease treatment is disease-specific, symptomatic, and supportive. Treatment requires the coordinated efforts of a team of specialists with expertise in treating neuromuscular disorders. Pediatricians or internists, neurologists, orthopedists, cardiologists, dieticians, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Enzyme replacement therapy is an approved treatment for all patients with Pompe disease. It involves the intravenous administration of recombinant human acid α-glucosidase.

In April 2006, under priority review, the US Food and Drug Administration (FDA) approved a Biologic License Application for the orphan drug Myozyme (alglucosidase alfa, recombinant human [rh] GAA) for patients with Pompe disease. Being the only FDA-approved curative treatment option for the disease it occupied a major market share despite its inherent adverse reactions including pneumonia, respiratory failure and distress, infections, and fever. This was the first disease-specific treatment for an inherited muscular disorder consisting of the intravenous administration of recombinant human GAA (Myozyme / Lumizyme). Prior to the arrival of Enzyme replacement therapy (ERT) in 2006, patients were primarily dependent on Supportive Treatment comprising of respiratory support, ambulatory support, physiotherapy and/or dietary treatment. Although historically, Supportive Care had been the mainstay of treatment (thereby generating a huge amount of revenue), but the approval and subsequent launch of ERT in 2006 after decades of research, helped turn the treatment landscape upside down, prompting a new era in the treatment of this disease.

Although ERT is not a cure, it can slow or halt the progression of Pompe disease. The disease has benefited from the introduction of enzyme replacement therapy (ERT), which is expensive but still is a major therapeutic advancement in preventing the disease progression.

Lumizyme/Myozyme (alglucosidase alfa) produced by Sanofi Genzyme is a hydrolytic lysosomal glycogen-specific enzyme indicated for patients with Pompe disease (GAA deficiency). It is an enzyme replacement therapy produced by recombinant DNA technology. It provides an exogenous source of acid α glucosidase (GAA), an essential lysosomal enzyme that is deficient or absent in patients with Pompe disease, leading to intralysosomal glycogen accumulation. 

Being the only FDA-approved curative treatment option of the disease for a long time, it occupied a significant Pompe disease market share despite its inherent adverse reactions, including pneumonia, respiratory failure and distress, infections, and fever. In May 2010, the FDA approved Lumizyme (alglucosidase alfa), the first treatment for late-onset Pompe disease, which was initially indicated for patients aged ≥8 years. However, although both Myozyme and Lumizyme have the same generic ingredient and work by enzyme replacement, the FDA considers the two treatments as different drugs, with distinct manufacturing processes, as well as some biological differences.

On August 06, 2021, the U.S. Food and Drug Administration approved Nexviazyme (avalglucosidase alfa-ngpt) for intravenous infusion to treat patients 1 year of age and older with late-onset Pompe disease to Genzyme Corporation. Nexviazyme, another Enzyme Replacement Therapy, is an intravenous medication that helps reduce glycogen accumulation. The effectiveness of Nexviazyme for the treatment of Pompe disease was demonstrated in a study of 100 patients who were randomized to take Nexviazyme or another FDA-approved enzyme replacement therapy for Pompe disease. The most common side effects included headache, fatigue, diarrhea, nausea, joint pain, dizziness, muscle pain, itching, vomiting, difficulty breathing, skin redness.

The currently approved rhGAA can significantly improve Pompe disease’s therapeutic effect, in order to provide improved delivery of rhGAA to the lysosome, new technologies have been explored. Small molecule pharmacologic chaperones are currently being evaluated as therapeutic options in several single-gene disorders, including lysosomal storage disorders, where the pathology can be attributed to a misfolded but still functional enzyme, albeit, with reduced activity.

Pompe Disease Emerging Drugs

AT-GAA developed by Amicus Therapeutics is an investigational therapy that consists of ATB200, a unique recombinant human acid alpha-glucosidase (rhGAA) enzyme with optimized carbohydrate structures, particularly mannose-6 phosphate (M6P), to enhance uptake, co-administered with AT2221, a pharmacological chaperone. In Feb 2019, the US Food and Drug Administration (FDA) granted Amicus a Breakthrough Therapy Designation  to AT-GAA for the treatment of late-onset Pompe disease.

SPK-3006 developed by Spark Therapeutics is an investigational Pompe disease gene therapy for the potential treatment of the rare condition. Pompe disease is an oftentimes fatal lysosomal storage disorder and neuromuscular disease, with systemic, multi-organ manifestations resulting from loss of function mutations in the gene encoding acid alpha-glucosidase (GAA). The initial construct for SPK-3006 was in-licensed from Genethon in 2017, and Spark retains global commercialization rights. It is currently in the Phase I/II stage of development.

Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase is being developed by Lacerta Therapeutics, Inc. and is currently in the Phase I stage of development.

Another Pompe disease gene therapy ACTUS-101 currently being developed by Actus Therapeutics is delivered into the blood, specifically targeting the liver to promote the production of the GAA enzyme. However, it is in an early stage of development and recently dosed the first patient for the Phase I/II trial. It would be too soon to predict the impact it will have on the market if and once approved.

VAL-1221 being developed by Valerion Therapeutics is a recombinant fusion protein comprised of rhGAA and a lupus anti-DNA antibody 3E10 with GAA (acid glucosidase), the missing enzyme in GSD Type II (that is believed to utilize the nucleoside transporter ENT2 for cellular uptake of ERT in an M6P-independent manner). The drug candidate is currently in Phase I/II stage of clinical development by Valerion Therapeutics for the treatment of late-onset Pompe disease.

AT845 by Audentes Therapeutics (now a part of Astellas) is a novel Pompe disease product candidate expected to address the recognized limitations of ERT by facilitating the intracellular production of GAA to improve efficacy, reduce immunogenicity, and deliver a durable and transformative clinical benefit from a single intravenous administration. Audentes is now enrolling patients in FORTIS, an open-label, ascending dose, multicenter Phase I/II clinical trial to evaluate its investigational gene therapy product candidate in participants who are 18 years of age or older, ambulatory or non-ambulatory, with late-onset Pompe disease.

The biotech companies Shire and NanoMedSyn launched a new research partnership to evaluate a potential treatment for lysosomal storage disorders including Pompe disease.

What is in Store for Pompe Disease?

There are many key pharmaceutical players in the Pompe Disease therapeutic market landscape such as Sanofi, Actus, Amicus, Roche, and others which are anticipated to develop novel and potential treatment therapies which will enhance treatment outcomes in Pompe patients. In addition to that, investigational gene therapies have the potential to provide a long-term, steady supply of GAA enzymes to the entire body through one-time administration. These kinds of new and innovative researches provide hope for a bright future for the treatment of Pompe Disease.

Also, recently the FDA has been granting many drugs Priority Review,  Fast Track &  Breakthrough Therapy designations which may provide incentives to assist and encourage the development of drugs for rare diseases.

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