Guest Column | August 1, 2022

Why Gene Therapy Is Poised To Become A Game-Changer For Treating Rare Diseases With High Unmet Medical Need

By Eric Crombez MD, Chief Medical Officer, Ultragenyx Gene Therapy and Inborn Errors of Metabolism


Our focus at Ultragenyx is to continue to develop novel treatments for serious rare and ultra-rare genetic diseases with no existing therapeutics or with very limited treatment options. Doing so requires the flexibility to work within a high degree of heterogeneity, which is why we’ve taken a unique approach to drug development – investing in platforms for multiple modalities with the potential to target almost any rare disease with high unmet medical need. With multiple approved treatments and a deep pipeline of programs in development, we have established expertise in traditional biologics, small molecules, enzyme replacement therapies, gene therapies and nucleic acid therapies, such as mRNA and ASO. Our approach is grounded in established science, informed by our significant rare disease drug development expertise, and guided by our commitment to listening to and learning from patients and their families.

Among the diverse modalities we employ, gene therapy has the potential to be a one-time, long-term treatment that directly addresses the underlying cause of certain rare diseases, improving the lives of those affected. Our current focus with gene therapy is based on adeno-associated virus vector (AAV)-directed therapy in indications with high unmet medical need that we believe have the highest likelihood of success. In pursuit of this goal, we developed a proprietary producer cell line platform for the efficient production of our AAV gene therapies. We’re also scaling our gene therapy manufacturing capabilities and partnering with other industry leaders who use our scientific and manufacturing advances to deliver their gene therapies at scale

Late-stage Gene Therapy Programs Offer a Glimpse into the Future of Rare Disease Medicine

We selected our lead gene therapy programs because current management and treatments for these indications have significant limitations, and we believe our gene therapy programs have the potential to offer highly effective and durable treatment for these diseases. Longer-term durability data for these programs support our belief that gene therapies can potentially be game changers for patients living with these rare diseases.

Currently, we are advancing the clinical development of several investigational gene therapies for rare diseases. We have traditional pivotal Phase 3 studies underway evaluating DTX401 for the potential treatment of glycogen storage disease Type Ia (GSDIa) and DTX301 for the potential treatment of ornithine transcarbamylase (OTC) deficiency, and seamless Phase 1/2/3 studies underway for both UX701 for the potential treatment of Wilson disease and UX111 for the potential treatment of Mucopolysaccharidosis Type IIIA (MPS IIIA), also known as Sanfilippo syndrome type A. In addition, preclinical studies are underway for investigational gene therapies for the potential treatment of Duchenne muscular dystrophy (DMD) and CDKL5 deficiency disorder (CDD).

GSDIa, a serious genetically inherited glycogen storage disease, is caused by a defective gene that codes for the enzyme G6Pase-α, resulting in the inability to regulate glucose. Hypoglycemia in patients with GSDIa can be life-threatening and the accumulation of the complex sugar glycogen in certain organs and tissues can impair the ability of these tissues to function normally. If chronically untreated, patients can develop severe lactic acidosis, progress to renal failure, and potentially die in infancy or childhood. No pharmacologic therapies are approved for GSDIa, and current treatment is limited to diet and regular doses of uncooked cornstarch, a complex carbohydrate that is slowly digested and therefore maintains glucose levels for a longer period of time than most carbohydrates in food. We are advancing DTX401, an investigational AAV8 gene therapy designed to deliver stable expression and activity of G6Pase-α under control of the native promoter. Administered as a single intravenous (IV) infusion, DTX401 was shown in preclinical studies to improve G6Pase-α activity and reduce hepatic glycogen levels, a well-described biomarker of disease progression.

OTC deficiency, the most common urea cycle disorder, is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia. Patients with OTC deficiency are at risk for periodic metabolic crises with elevated ammonia that results during periods of increased metabolic stress. Ammonia is a potent neurotoxin and elevated levels results in accumulating and irreversible neurocognitive damage. Approved therapies, which must be taken multiple times a day for the patient's entire life, do not eliminate the risk of future metabolic crises and the only potential curative approach is liver transplantation. We are developing DTX301, an investigational AAV8 gene therapy designed to deliver stable expression of OTC following a single IV infusion. In preclinical studies, DTX301 normalized levels of urinary orotic acid, a marker of ammonia metabolism.

To date, we have made considerable progress advancing our DTX401 and DTX301 clinical development programs, as shown by the positive longer-term efficacy and safety data from our ongoing Phase 1/2 studies presented most recently at the American Society of Gene & Cell Therapy Annual Meeting in May 2022. Results showed longer-term durable responses and metabolic stability with these investigational gene therapies, suggesting they could potentially establish normal metabolism and allow patients to live without restrictive or burdensome diets and medications. DTX401 and DTX301 are making a real difference for patients clinically and have the potential to alleviate their signs and symptoms for a very long period of time. Further, both have shown a positive safety profile.

MPS IIIA is a rare and fatal lysosomal storage disease with no approved treatment. Patients with this disorder experience severe central nervous system (CNS) degeneration and systemic manifestations affecting every organ system. Children with MPS IIIA present with progressive language and cognitive decline and behavioral abnormalities and have a median life expectancy of 15 years. MPS IIIA is caused by genetic mutations that lead to a deficiency in the enzyme sulfamidase (SGSH), one of several enzymes involved in the lysosomal degradation of the glycosaminoglycan heparan sulfate. UX111 is designed to address the underlying SGSH enzyme deficiency responsible for abnormal accumulation of glycosaminoglycans in the brain and throughout the body that results in the progressive decline associated with the disorder.

Scaling Manufacturing for the Future

Our approach was to start with liver-directed gene therapy for genetic diseases that impact the liver, specifically GSDIa and OTC deficiency, and then diversify to pursue gene therapies for disorders that affect the CNS and muscle, such as CDD and DMD, respectively. To successfully move into larger indications with a relatively high prevalence, we knew we would need to scale our proprietary gene therapy manufacturing platform, Pinnacle PCL™, which is designed to optimize AAV gene therapy.

The Pinnacle PCL platform enables efficient and scalable production of AAV resulting in increased speed, product quality and yield – with simpler workflows and lower material costs than traditional methods – to help meet the rising demands of today’s gene therapy landscape. At the heart of the platform is our Producer Cell Line (PCL) technology. We have engineered PCLs that stably produce high yields of viable, intact AAV vectors, while maximizing the production of full AAV capsids. The cells currently used in our Pinnacle PCL Platform are engineered from modified HeLa cells.

The Pinnacle PCL platform is designed to support the safety of AAV therapy as it is applied to diseases that may require relatively higher doses, such as those impacting CNS and muscle tissues. This evolution in our manufacturing process has allowed us to take on gene therapies for larger indications, such as Wilson disease, a rare genetic disorder of copper metabolism. Wilson disease is caused by a mutation in the ATP7B gene, which provides instructions for cells to make a protein that carries copper from the liver to other parts of the body and removes copper from tissues and organs. People with Wilson disease can experience liver failure and neurological deterioration. We are evaluating our investigational AAV9 gene therapy UX701 to reduce copper accumulation in tissues and organs. UX701 is designed to deliver a modified form of the ATP7B gene, which is otherwise too large to package in an AAV vector. We are currently enrolling patients with Wilson disease in a seamless single-protocol Phase 1/2/3 study of a single intravenous infusion of UX701. This investigational gene therapy is the first to use our PCL manufacturing platform.

As part of our efforts to scale for the future, we are also completing construction of a 100,000-square-foot manufacturing facility in Bedford, Massachusetts. Our gene therapy manufacturing plan will begin operations in 2023 to provide us with the flexibility and control to advance our pipeline and ensure we can bring gene therapies to patients as soon as they become approved.

Partnering with Other Gene Therapy Leaders

Other companies are using our scientific and manufacturing advances to deliver their gene therapies at scale. Bayer is using our Pinnacle PCL Platform to produce its hemophilia A gene therapy at a 2,000-liter scale. This program is now progressing toward a pivotal clinical trial in the near future. Daiichi Sankyo has selected our proprietary AAV-based gene therapy manufacturing technologies, including the Pinnacle PCL Platform, for its internal gene therapy programs, and Solid Biosciences is partnering with us to advance new AAV-based gene therapies for DMD.

Benefits of Gene Therapy – Now and in the Future

The biopharma industry has made tremendous progress since the early days of gene therapy. To date, the U.S. FDA has approved gene therapies for spinal muscular atrophy and retinal dystrophy as well as a cell-based gene therapy to treat multiple myeloma. These approved gene therapies are improving the lives of real people in the real world – not just in clinical trials. Those in development have the potential to improve the lives of countless more in the future. At Ultragenyx, we believe in the promise of gene therapy as potentially life-changing, one-time treatments for patients with rare genetic diseases. With our robust pipeline of multiple investigational gene therapies and our AAV platform for high-quality, commercial-scale manufacturing, we hope to be part of this game-changing revolution in rare disease medicine.

Dr. Eric Crombez bio

Eric Crombez, M.D., a board-certified clinical geneticist, has extensive experience and expertise in the development and execution of clinical development programs for rare genetic disorders. He currently serves as Chief Medical Officer of Gene Therapy and Inborn Errors of Metabolism at Ultragenyx and has been in this role since the acquisition of Dimension Therapeutics in November 2017. Dr. Crombez joined Dimension Therapeutics, a liver-directed AAV gene therapy company, as Chief Medical Officer in November 2014. During that time, he led the clinical development efforts for clinical-stage gene therapy programs for hemophilia B, hemophilia A (in partnership with Bayer), ornithine transcarbamylase (OTC) deficiency and glycogen storage disorder type Ia (GSDIa). Dr. Crombez serves as an industry representative on the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee. Before joining industry, Dr. Crombez was Assistant Professor, Department of Pediatrics, Division of Medical Genetics at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). Dr. Crombez completed residencies in pediatrics and medical genetics and a fellowship in clinical biochemical genetics at the UCLA School of Medicine.