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5 Companies Looking Beyond Enzyme Replacement Therapy for Treatment of Pompe Disease

24 Oct 5 Companies Looking Beyond Enzyme Replacement Therapy for Treatment of Pompe Disease

Pompe disease is characterized by the build-up of complex sugars named glycogens in the body’s cell, due to the lack of an enzyme called acid alfa glucosidase (GAA), which is responsible for breaking down the sugars. This results in the breakdown of organs, muscles and tissues. The disease is classified into three type’s namely classic infantile onset, non-classic infantile onset and late-onset, depending on the age at which it manifests in the patients.

The disease is very rare and affects only 1 in 40,000 individuals in the U.S and is marked by the presence of muscle weakness, poor muscle tone, enlarged liver or heart, developmental difficulties, feeding issues, respiratory infections, motor disabilities and hearing impairment to name a few.

Pompe is usually diagnosed through blood and enzyme testing. Other testing tools include sleep tests, electromyography, breathing tests to measure lung capacity. Presently Enzyme replacement therapy is approved for the treatment for patients suffering from Pompe, along with symptom management and supportive care.

One of the limitations of using ERT is that though Cardiac muscle responds well to the treatment, its efficacy is limited in case of motor and respiratory functions. Myopathies persist despite being treated with ERT, therefore there is a pressing need to address these limitations and improve outcomes from the application of this therapy in treatment of Pompe.

We take a look at Companies that are using cutting-edge science and research to find a therapeutic solution for this disease, which has a very large unmet medical need.

Audentes Therapeutics, (NASDAQ: BOLD)

Market Cap: $1.20B; Current Share Price: 26.49 USDChart
Data by YCharts

The Company’s lead candidate for the treatment of Pompe is AT845 that facilitates the intracellular production of GAA, through a single intravenous administration, leading to improved efficiency, reduced immunogenicity and a durable clinical benefit. AT845 uses an AAV8 capsid serotype to introduce GAA directly into tissues and skeletal muscles affected by the disease, including heart and nervous system.

Audentes is planning to submit an investigational new drug (IND) application for pompe disease in the third quarter of 2019, encouraged by the progress in the ongoing preclinical trials. AT485 has demonstrated significant increases in enzyme activity in heart and skeletal muscle, in GAA-deficient mice models as part of preclinical studies. The study has also shown improvements in diaphragm contractile and cardiac function, with both a single systemic injection of AT845 and bi-monthly injections of recombinant human GAA, over three months according to a company statement.

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The Company is focused on creating gene therapy products for potentially life-threatening rare neuromuscular diseases. Its pipeline’s lead candidate is AT132, indicated for the treatment of X-Linked Myotubular Myopathy (XLMTM); in addition it is also working on AT307 for the treatment of the CASQ2 subtype of Catecholaminergic Polymorphic Ventricular Tachycardia (CASQ2-CPVT).

Audentes uses its proprietary technology platform and manufacturing expertise to offer services in three areas with large unmet needs, namely gene replacement, vectorized exon skipping, and vectorized RNA knockdown.


Market Cap: $461.97M; Current Share Price: 14.59 USDChart
Data by YCharts

The Company is using its proprietary gene therapy and lysosomal targeting sequence platform to develop a treatment of pompe. Preclinical studies in mice models have demonstrated favorable safety and efficacy data. Plato is AVROBIO’s proprietary vector system and automated closed cell manufacturing system for CD34+ gene therapy, indicated for the treatment of Central Nervous system and lysosomal storage diseases such as gaucher, fabry disease. The platform offers permanent genomic integration along with durable curative benefits.

The Company’s approach to the treatment of Pompe involves the use of a potent transgene promoter, along with a GILT tagged recombitant human (rh) GAA which can impact levels of stored glycogen; this is followed by the use of PLATO for CNS impact.

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The Company is developing AVR-RD-01, a gene therapy candidate for the treatment of Gaucher Disease, which is expected to undergo Phase 1 / 2 clinical trials in the second half of 2019. It consists of a modified, lentivirus that can deliver a healthy GBA gene to replace the dysfunctional GCase enzyme with a healthy one. Hematopoietic (blood-forming) stem cells are collected and modified to incorporate a functional GCase and transfused back into the patient. The preclinical studies in mice models show a significant reduction in glucocerebrosidase-accumulating cells, reversal of spleen enlargement, restoration of blood values, and lowered infiltration of Gaucher cells in the bone marrow.

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In addition, its pipeline consists of candidates for Fabry Disease (Currently undergoing phase 1 trails) and Cystinosis. The Company has planned a series of clinical trials, beginning with Canada, that is currently enrolling patients, with clinical endpoints such as liver and spleen volumes, hemoglobin, platelet counts, bone pain and bone density measures, along with other blood markers. This will be followed by additional clinical sites in U.S and Australia.

Valerion Therapeutics
The Company’s lead candidate for the treatment of Pompe is VAL-1221, a recombinant fusion of 3E10 with GAA (acid glucosidase), a proprietary delivery antibody. The candidate is currently undergoing phase 1 / 2 clinical trials in the US and Europe. The trial is a randomized international, parallel active control, dose escalation study to evaluate the safety, pharmacokinetics, pharmacodynamics and immunogenicity of VAL-1221 and has enrolled 12 patients with late-onset pompe disease.

Image Source: Company

The study aims to prove that VAL-1221 can deliver GAA to muscle better than Myozyme, which is currently approved for the lyosomal replacement of GAA, but is limited in its ability to address the issue of glycogen buildup in cytoplasm and autophagic vacuoles.

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VAL-1121 can deliver therapeutic enzymes into skeletal and cardiac muscle and can clear glycogen from both the lysosome and the cytoplasm, offering a dual mechanism of action.

The initial clinical results reported by the Company show that the drug is well-tolerated and has a safety profile similar to approved treatments. In addition there were no adverse events or discontinuation reported from the study, with all the 12 patients from the cohort 1 enrolling for the open-label extension phase.

The Company is using a proprietary drug delivery technology that uses a modified / optimized antibody 3E10, which has intracellular-delivery capabilities dependent on membrane expression of the nucleoside transporter (ENT2), to develop a pipeline that includes VAL-0417 for the treatment of Lafora disease, VAL-620 for the treatment of Myotubular Myopathy and other undisclosed research programs.

Pharming Group (OTCPINK: PHGUF)

Market Cap: $810.96; Current Share Price: 1.25 USDChart
Data by YCharts

Pharming’s proprietary patented Transgenic Production Technology Platform (TPTP) offers a highly scalable production GMP validated methodology for the development of recombinant human proteins. The Company has been able to generate complex therapeutic proteins, using its transgenesis method, which does not trigger the body’s immune system to launch a defense against the new protein. The platform is capable of high-quality, large-scale and easy upscale-able production.

Furthermore using its technology platform the Company is evaluating protein replacement products for treatment of Pompe and Fabry disease. The aim is to create a new recombinant treatment with improved better immunogenicity, safety and efficacy that can overcome the limitations of existing treatment options.  Pharming already markets RUCONEST, a recombinant human C1 esterase inhibitor for the treatment of hereditary angioedema (HAE) and is targeting the development of a recombinant human C1 esterase inhibitor (rhC1INH) for the treatment of preeclampsia contrast induced nephropathy (CIN) and other indications.

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In August 2019, the Company entered into a development and licensing collaboration with Novartis for the development and commercialization of CDZ173, a small molecule phosphoinositide 3-kinase delta (PI3Kẟ) inhibitor, indicated for the treatment of patients with Activated Phosphoinositide 3-kinase Delta Syndrome (“APDS”). Pharming has developed its proprietary technology platform in partnership with The Shanghai Institute of Pharmaceutical Industry (SIPI), a Sinopharm Company. It has a robust intellectual property rights portfolio covering the technology for the production of recombinant proteins in the milk of transgenic animals.

Oxyrane uses a proprietary engineered yeast expression technology to develop enhanced enzyme replacement therapies (ERTs) for the treatment of lysosomal storage diseases, especially those concerning the CNS. The technology can produce proteins with defined human phosphoglycosyl structures that facilitate intracellular uptake and localization. OXY2810, its lead candidate for the treatment of Pompe Disease is a recombinant human GAA, which is intended to be used as an enzyme replacement therapy.

The Company’s enzymes are more potent that first generation ERT, as they can phosphorylate glycans on any glycosylation site, resulting in higher levels of mannose-6-phosphate on the enzyme and improved uptake into cells and subsequent targeting to lysosomes.

Image Source: Company

Phosphorylated mannose-6-phosphate (M6P) can increase the internalization of the enzymes and targets the enzyme to the lysosome, eliminating the need for introduction of non-native modifications. The Company’s engineering technology delivers consistent production of enzymes and their sugar structures. The platform has a broad applicability with proven, consistent and reproducible results in producing varied with or without mannose-6-phosphate (M6P) residues.

Oxyrane’s clinical pipeline is focused on advancing its lead program with beta-glucocerebrosidase in neuronopathic Gaucher Disease and Parkinson’s Disease. In future the Company intends to further develop its pipeline to focus on enhanced enzyme therapies for other LSDs and metabolic diseases.

In July 2018, the Company was awarded a grant from the Michael J. Fox Foundation under the Therapeutic Pipeline Program to support the advancement of the Parkinson’s disease program at Oxyrane.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

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