Emerging Treatments

Emerging Treatments

MPS I

Amicus Therapeutics disclosed a preclinical Chaperone-Advanced Replacement Therapy (CHART™) program for MPS I on June 25, 2013. Amicus is developing a proprietary human recombinant IDUA (rhIDUA) enzyme co-formulated with a novel pharmacological chaperone as a next-generation therapy for MPS I. The pharmacological chaperone is designed to improve tissue uptake and reduce the immunogenicity of rhIDUA by stabilizing the enzyme in its properly folded and active form. This next-generation enzyme replacement therapy is in the pre-clinical stage of the development pipeline. For more information visit http://www.amicusrx.com/.

Eloxx Pharmaceuticals is a biopharmaceutical company focused on discovery and development of compounds for the treatment of genetic diseases caused by nonsense mutations. To address the need for drugs capable of suppressing premature termination, Eloxx synthetized and characterized new chemical entities that selectively induces ribosomal readthrough of premature but not normal termination codons. Eloxx Pharmaceuticals’ approach and knowhow allows moving rapidly to clinical trials building a robust pipeline of molecules designed for an array of nonsense genetic diseases, including MPS I.

Immusoft Corporation is a Seattle, Wash.-based gene therapy company. The company’s mission is to treat diseases using its breakthrough technology platform called Immune System Programming (ISP™).

ISP uses a patient’s immune cells to cure disease. Cells that are reprogrammed using the technology become miniature drug factories that are expected to survive in the patient for many years. Immusoft expects its first clinical application to be MPS I.

An important part of Immusoft’s approach is the use of a safe, non-viral vector called the Sleeping Beauty™ Transposon system. In comparison to viruses, Sleeping Beauty is vastly more scalable and much less expensive for programming cells.

Immusoft hopes and expects that cell therapy with ISP will be a breakthrough in treating many diseases and be a marked improvement over biologic drug therapies. The company expects that ISP could replace a lifetime of infusions by instructing cells to constantly secrete therapeutic enzymes, proteins or antibodies; minimize the risk that a patient’s immune system may target a treatment; and, eliminate damage to veins and injection site reactions.

In July 2015, Immusoft completed a pre-IND (Investigational New Drug) hearing with the U.S. Food and Drug Administration for an MPS I clinical trial. The company received feedback from the FDA and is well underway generating the data the agency wants to see before human trials to treat MPS I might begin.

Immusoft is raising its Series B round this year. The round will help finance its anticipated clinical trial to treat MPS I. It will also help advance additional preclinical programs requiring enzyme/protein replacement therapy to IND filing.

For more information visit: www.immusoft.com

Plexcera Therapeutics:

Plexcera Therapeutics: Pentosan polysulfate (PPS) update on the development of therapy for MPS was provided by Dr. Calogera Simonaro and Dr. Edward Schuchman.

Two studies have now been published using the rat model of MPS VI (PLos One, 2013, 2014). These studies compared the effects of daily oral administration of PPS to once weekly subcutaneous (under the skin) injection. Significant improvements were observed in both studies, including a reduction in inflammation, improved mobility, and improved dentition and tracheal deformities. Notably, we also found that once weekly subcutaneous administration significantly reduced GAG levels in tissues and urine of the treated rats.

Based on these findings in the MPS VI rats, a similar comparative study was undertaken in MPS I dogs. This work has recently been submitted for publication, and confirmed the safety and GAG-reducing effects of subcutaneous PPS treatment. It also revealed positive effects on MPS cardiovascular disease. Based on the outcome of these animal studies, it was decided to develop injectable PPS for the treatment of MPS patients.

PPS is approved and marketed as an injected drug in several European countries for various disease indications. To advance the development of PPS for MPS patients, two small investigator-initiated studies were undertaken in Germany and Japan in adult MPS individuals (types I and II, respectively) using subcutaneous PPS administration. The goal for both of these studies was to establish the safety of injectable PPS in adult MPS patients. Several clinical and biochemical endpoints were observed. Both studies have been completed and data will be reported at the 2016 WORLD meeting in San Diego, CA. The findings confirmed the safety of PPS administration, and provided the first clinical evidence of the anti-inflammatory, GAG-reducing, and disease modifying effects.

We also are pleased to report that several contractual agreements have been put in place to advance the clinical development of PPS for MPS. First, Mount Sinai has licensed relevant patents to Plexcera Therapeutics, a small drug company formed in 2013 based on research from our laboratory and for the advancement of therapies for rare diseases. Plexcera also has established an exclusive supply agreement with bene pharmaChem (Germany), the company who developed PPS and the only company that currently manufactures PPS approved for human use. In addition, orphan drug status for MPS I has been obtained by Plexcera from the European Medical Association (EMA) and FDA. Orphan drug status for MPS VI also has been obtained from FDA.

Based on the outcome from the two adult studies described above, safety studies in MPS children will be undertaken in 2016. The initial pediatric trial will take place in Europe since injectable PPS is an approved drug in Europe, but not the United States. Plexcera Therapeutics has presented it’s plans for the pediatric trial to the EMA and received positive feedback. Based on this feedback a formal study protocol is being prepared.

We are excited to continue with these efforts and the further evaluation of the safety and efficacy of PPS in MPS patients. Our goal remains the development of new treatments that may improve the quality of life for all MPS individuals. PPS is an example of one such therapy. For more information visit http://www.plexcera.com/.

REGENXBIO Inc. is a leading biotechnology company focused on the development, commercialization and licensing of recombinant adeno-associated virus (AAV) gene therapy.  The company’s mission is to transform the lives of patients suffering from severe diseases with significant unmet medical needs by developing and commercializing in vivo gene therapy products based on our NAV Technology Platform.  RGX-111 is REGENXBIO Inc.’s product candidate for the treatment of Mucopolysaccharidosis Type I (MPS I).  Individuals with MPS I have a deficiency of alpha-l-iduronidase (IDUA), an enzyme found throughout the body, including in cells in the central nervous system (CNS) that is responsible for the breakdown of polysaccharides.  RGX-111 uses the AAV9 vector to deliver the IDUA gene to the CNS creating the potential that normal IDUA enzyme can be produced.  Delivery of the gene encoding the enzyme could provide a permanent source of secreted IDUA beyond the blood-brain barrier, allowing for long term cross-correction of cells throughout the CNS.  This strategy could also provide rapid IDUA delivery to the brain, potentially preventing the progression of cognitive deficits that otherwise occurs in MPS I patients.  The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation and Rare Pediatric Disease Designation to RGX-111 for the treatment of MPS I.   Initiation of a Phase I/II clinical trial is planned for mid-2016.  For more information, visit http://www.regenxbio.com/.

Sangamo BioSciences is developing a genome editing approach (a type of gene therapy) to lysosomal storage disorders (LSDs) beginning with MPS I and MPS II, which are caused by defects in the enzymes alpha-L-iduronidase (IDUA) and iduronate-2-sulfatase (IDS), respectively. Sangamo’s ZFP Therapeutics® for MPS I and MPS II are designed to provide life-long production of sufficient quantities of corrective enzyme from the patient’s own liver to eliminate the need for chronic enzyme replacement therapy (ERT).

The approach uses Sangamo’s proprietary In Vivo Protein Replacement Platform™ (IVPRP) which is based on its zinc finger nuclease (ZFN) genome editing technology. ZFNs can best be described as genetic “scissors” that are designed to “edit” the patient’s genome in a highly specific manner. In the IVPRP, ZFNs are used to insert a functioning copy of the gene that is defective in the LSD into what is known as a “safe harbor site” in the DNA of a patient’s liver cells. The safe harbor site used in the IVPRP is the Albumin gene because this gene’s expression machinery normally makes very large quantities of albumin protein which is secreted into the bloodstream. Using ZFNs, liver cells can be engineered to make IDUA, IDS or any other secreted protein from that site instead of albumin. Because the albumin production machinery in each cell is so powerful, it is estimated that less than 0.1% of the liver cells have to be edited by ZFNs in order to make clinically relevant levels of most LSD enzymes. The ZFNs and the functioning gene are delivered to the liver cells using adeno-associated viruses (AAVs) as delivery vehicles, or vectors. AAV is a small virus that infects humans, but is not known to cause disease and has been used safely in many human clinical studies. A single treatment will be administered intravenously (IV), however the effects are expected to last for the patient’s lifetime.

Preclinical studies in mouse models of MPS I and MPS II demonstrated that mice treated with a single dose of Sangamo’s ZFP Therapeutic® produced stable, therapeutic levels of functional human IDUA (hIDUA) or IDS (hIDS) in their livers. The enzymes were efficiently secreted into the bloodstream and taken up by tissues such as the spleen, kidney, lungs, heart and brain where they were shown to be active, as observed by the reduction of glycosaminoglycan (GAG) biomarker levels in these tissues. Tissue samples from these animals were also collected and analyzed under a microscope. The analysis revealed that the size of the lysosomes inside the cells of these tissues had significantly decreased as a result of the reduction in GAG levels. In addition, animals were evaluated in the Barnes Maze, which is used to measure memory and learning. MPS I and MPS II mice treated with the ZFP Therapeutic demonstrated significant preservation of learning ability compared to untreated mice. These exciting preclinical data are very encouraging and demonstrate proof of concept for Sangamo’s IVPRP.

In February and June 2016, the U.S. Food and Drug Administration (FDA) cleared Sangamo’s Investigational New Drug (IND) applications to initiate Phase 1/2 clinical trials to test its IVPRP approach for MPS I and MPS II, respectively. The Company expects to initiate its clinical trial for MPS I in mid-2016, and its clinical trial for MPS II by the end of 2016. Sangamo also has a Phase 1/2 clinical trial to evaluate its IVPRP approach for hemophilia B.

For more information visit: www.sangamo.com

 

 

MPS II

Green Cross Corporation is a biopharmaceutical company is Seoul, South Korea that developed an enzyme replacement therapy, Hunterase®, for MPS II (Hunter syndrome). Green Cross applied for Orphan Drug Designation in the US, and received the designation February 13, 2013. It plans to submit an investigative new drug application to U.S. FDA. There are no plans at the current time for a clinical trial in the US that could potentially lead to FDA approval. For more information visit http://www.greencross.com/eng/aboutus/overview.do.

REGENXBIO Inc. is a leading biotechnology company focused on the development, commercialization and licensing of recombinant adeno-associated virus (AAV) gene therapy.  The company’s mission is to transform the lives of patients suffering from severe diseases with significant unmet medical needs by developing and commercializing in vivo gene therapy products based on our NAV Technology Platform.  RGX-121 is REGENXBIO Inc.’s product candidate for the treatment of Mucopolysaccharidosis Type II (MPS II), also known as Hunter syndrome.  Individuals with MPS II have a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), an enzyme found throughout the body, including in cells in the central nervous system (CNS) that is responsible for the breakdown of polysaccharides.  RGX-121 uses the AAV9 vector to deliver the human IDS gene to the CNS creating the potential that normal IDS enzyme can be produced. Delivery of the gene encoding the enzyme that is deficient within cells in the CNS could provide a permanent source of secreted IDS beyond the blood-brain barrier, allowing for long term cross-correction of cells throughout the CNS.  This strategy could also provide rapid IDS delivery to the brain, potentially preventing the progression of cognitive deficits that otherwise occurs in Hunter syndrome patients.  The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to RGX-121 for the treatment of MPS II.   For more information, visit http://www.regenxbio.com/.

Sangamo BioSciences is developing a genome editing approach (a type of gene therapy) to lysosomal storage disorders (LSDs) beginning with MPS I and MPS II, which are caused by defects in the enzymes alpha-L-iduronidase (IDUA) and iduronate-2-sulfatase (IDS), respectively. Sangamo’s ZFP Therapeutics® for MPS I and MPS II are designed to provide life-long production of sufficient quantities of corrective enzyme from the patient’s own liver to eliminate the need for chronic enzyme replacement therapy (ERT).

The approach uses Sangamo’s proprietary In Vivo Protein Replacement Platform™ (IVPRP) which is based on its zinc finger nuclease (ZFN) genome editing technology. ZFNs can best be described as genetic “scissors” that are designed to “edit” the patient’s genome in a highly specific manner. In the IVPRP, ZFNs are used to insert a functioning copy of the gene that is defective in the LSD into what is known as a “safe harbor site” in the DNA of a patient’s liver cells. The safe harbor site used in the IVPRP is the Albumin gene because this gene’s expression machinery normally makes very large quantities of albumin protein which is secreted into the bloodstream. Using ZFNs, liver cells can be engineered to make IDUA, IDS or any other secreted protein from that site instead of albumin. Because the albumin production machinery in each cell is so powerful, it is estimated that less than 0.1% of the liver cells have to be edited by ZFNs in order to make clinically relevant levels of most LSD enzymes. The ZFNs and the functioning gene are delivered to the liver cells using adeno-associated viruses (AAVs) as delivery vehicles, or vectors. AAV is a small virus that infects humans, but is not known to cause disease and has been used safely in many human clinical studies. A single treatment will be administered intravenously (IV), however the effects are expected to last for the patient’s lifetime.

Preclinical studies in mouse models of MPS I and MPS II demonstrated that mice treated with a single dose of Sangamo’s ZFP Therapeutic® produced stable, therapeutic levels of functional human IDUA (hIDUA) or IDS (hIDS) in their livers. The enzymes were efficiently secreted into the bloodstream and taken up by tissues such as the spleen, kidney, lungs, heart and brain where they were shown to be active, as observed by the reduction of glycosaminoglycan (GAG) biomarker levels in these tissues. Tissue samples from these animals were also collected and analyzed under a microscope. The analysis revealed that the size of the lysosomes inside the cells of these tissues had significantly decreased as a result of the reduction in GAG levels. In addition, animals were evaluated in the Barnes Maze, which is used to measure memory and learning. MPS I and MPS II mice treated with the ZFP Therapeutic demonstrated significant preservation of learning ability compared to untreated mice. These exciting preclinical data are very encouraging and demonstrate proof of concept for Sangamo’s IVPRP.

In February and June 2016, the U.S. Food and Drug Administration (FDA) cleared Sangamo’s Investigational New Drug (IND) applications to initiate Phase 1/2 clinical trials to test its IVPRP approach for MPS I and MPS II, respectively. The Company expects to initiate its clinical trial for MPS I in mid-2016, and its clinical trial for MPS II by the end of 2016. Sangamo also has a Phase 1/2 clinical trial to evaluate its IVPRP approach for hemophilia B.

For more information visit: www.sangamo.com

MPS IIIA

Laboratorios Dr. Esteve is developing a novel gene therapy treatment for the Sanfilippo syndrome type A. Currently there is no cure for the Sanfilippo A syndrome. The treatments available are not stopping the progression of the disease. The objective are to develop an effective and safe gene therapy that can stop the progression and potentially reverse the effects of the disease. Orphan Medicinal Product designation has been granted by the FDA and the EMA. For more information visit http://www.esteve.es/EsteveFront/IDI.do?lng=en.

 

 

MPS VI

The MeuSIX consortium plans to conduct a multicenter phase 1/2 clinical trial to investigate the safety and efficacy of AAV-mediated gene therapy in patients with MPS VI (Maroteaux-Lamy syndrome). An orphan drug designation (ODD) has been obtained from both the European Medicinal Agency and the US Food and Drug Administration for the MPS VI therapeutic AAV vector.

Pre-clinical studies have demonstrated that a single intravascular administration of an adeno-associated virus (AAV) encoding ARSB results in levels of expression of therapeutic ARSB for at least four years post-injection and significant improvement in biochemical, visceral and skeletal features.

The results from this clinical trial proposed by the MeuSIX consortium has the potential to have a tremendous impact on the natural history of MPSVI and to significantly improve the quality of life of the affected patients. Moreover, the approach developed may facilitate the development of similar approaches for other inborn errors of metabolism. For more information visit http://meusix.tigem.it/.