Glycerol Phenylbutyrate

A baby boy born with a debilitating genetic disease will likely no longer require a liver transplant to stabilize his condition, thanks to a first-of-its-kind genetic medicine he got at 6 months of age. The experimental treatment, developed by Philadelphia-based startup iECURE, uses an enzyme to cut DNA at a safe location, then has a virus slip in a new copy of a vital gene. It’s the first time that regulators have allowed researchers to edit genes directly inside an infant’s body. “The baby is doing well and growing,” CEO Joseph Truitt told Endpoints News in an exclusive interview. The baby was treated about six months ago, and the company plans to present more detailed results at a medical conference in March. The infant was born without a vital enzyme called ornithine transcarbamylase, or OTC. It’s the same disease that, 25 years ago, was at the center of a patient’s death from an experimental treatment. That tragedy set back the field for years and tarnished the reputation of the researcher leading the effort, gene therapy pioneer Jim Wilson — who is iECURE’s founder. OTC deficiency affects roughly 100 newborns in the US and 1,000 babies worldwide each year. It leaves patients unable to fully break down protein, causing ammonia to surge in their blood. Left untreated, those protein surges can cause irreversible brain damage. The only cure is a liver transplant, which can take a year to secure. The goal of the gene therapy was to end all of that. After doctors stabilized the baby boy’s condition with hemodialysis, a strict diet and the ammonia-reducing drug Ravicti, the 6.5-month-old baby got an infusion of iECURE’s gene therapy. Within three months, blood levels of a protein building block called glutamine were reduced, suggesting the therapy was working. The doctors began weaning him off Ravicti — something that’s normally never done unless the patient gets a liver transplant — and began increasing protein in his diet to normal levels for his age. “That was the real eye-opening moment,” Truitt said. “Everybody was nervous.” Now, six months after treatment, his ammonia and glutamine levels are normal and he hasn’t experienced any more metabolic crises. “The response hit the absolute upper level of what we anticipated,” Truitt said. “It checked every box.” “We’re on the precipice of a new approach in medicine,” Truitt said. “We’re going to insert the gene in a newborn baby, avoid all the downstream sequela that you would have, and potentially cure the patient and let them live a normal life.” For Wilson, the apparent cure is a remarkable bookend to what was nearly the end of his career . Wilson was attempting to cure OTC deficiency more than 25 years ago at the University of Pennsylvania when Jesse Gelsinger, a patient with the disease, died after a lethal immune reaction to Wilson’s therapy, made from adenoviruses engineered to shuttle a new copy of the OTC gene into his liver. After Gelsinger’s death, Wilson shifted to working with different DNA delivery vessels called adeno-associated viruses, or AAVs. These viruses are now the workhorses of gene therapy and the basis of several approved products. One company, Ultragenyx, is even using them to treat OTC deficiency in adults. But treating liver-based diseases in children and infants has been unsuccessful. That’s because AAVs don’t usually integrate into a patient’s genome. The therapeutic gene just sits alongside the chromosomes in a circular strand called an episome. As the liver continues to grow throughout childhood, those episomes get diluted as cells divide, causing the benefits of the therapy to wane over time. That limitation spurred Wilson to turn to gene editing. He used a pair of molecular scissors to cut DNA in a safe location, allowing the episome to slip in, ensuring that it would be copied and passed on as the patient’s liver grew. iECURE launched in 2021 to develop drugs based on the technique. Wilson, who recently left the University of Pennsylvania to lead a new startup called GemmaBio , told Endpoints in an email that he was “highly encouraged” by iECURE’s results, which he said was a 35-year journey since receiving his first NIH grant to work on a cure for the disease. “While there is much more that needs be done before this can be declared a true clinical success, this illustrates the amazing power of modern day science and the importance of persistence,” he said. Last year, iECURE got a green light from regulators to begin trials. The results from its first patient, treated in the UK with the lowest planned dose, went better than expected. The company plans to treat three more infants with the same dose in the first half of this year, including one baby in the US later this month. “If the next patient or two respond well, we’re going to go back to the regulators and have a discussion about what an accelerated approval pathway would look like,” Truitt said. “I mean, best case scenario, this could be a commercial product in 2027.” That ambitious timeline could catapult iECURE, a lean operation with 23 employees, ahead of many bigger and better-known gene editing companies. Yet with just one patient treated so far, many questions about the therapy remain. The biggest unknown is its durability. The company hasn’t proven that the treatment’s benefit is due to gene integration, which is essential for a permanent benefit. Truitt said that based on the company’s preclinical studies in monkeys, he is convinced that the benefits after six months are due to gene integration, not merely episomes. “But the definitive answer to this will be a biopsy,” Truitt said. Safety is another unknown. A month after infusion, the infant experienced grade 3 transaminitis, a severe elevation of liver enzymes in the blood often seen with gene therapies, but which can be a sign of trouble. Truitt said that the patient got better within a month of taking immunosuppressants and that they will monitor this more closely in the next three patients. Scientists outside the company are sure to have questions about iECURE’s technical approach too. While most companies in the field are working on CRISPR gene editing, iECURE uses a different editing enzyme called Arcus. The startup’s method requires using two AAVs: one to deliver the Arcus editor and a second to deliver the therapeutic gene. It’s a strategy that hasn’t been employed in humans until now. Truitt said the company’s $115 million Series A funding will last through the second half of 2025. Raising another $50 million should be enough to get data from the first four patients, but the company will need about $150 million to take its first therapy to commercialization, he added. Editor’s note: This story was updated with a comment from Jim Wilson.

Stockholm, December 27, 2024 – Immedica is pleased to announce that its partner OrphanPacific, Inc has submitted an application to the Ministry of Health, Labour and Welfare in Japan for the approval of Ravicti® (glycerol phenylbutyrate) for the treatment of Urea Cycle Disorders (UCD). The submission follows the approval of the orphan drug designation of Ravicti on December 25. "This submission marks a significant step toward bringing this important treatment addition to patients with UCD in Japan. We are pleased to see this progress together with our partner OrphanPacific, as we continue our commitment to addressing unmet medical needs in rare diseases” says Anders Edvell, CEO of Immedica. An orphan drug designation is handled by the Ministry of Health, Labour and Welfare based on Article 77-2 of the Pharmaceuticals and Medical Devices Act. The designation is given to products that meet conditions such as having fewer than 50,000 patients in Japan and being particularly necessary from a medical standpoint, following an opinion of the Pharmaceutical Affairs and Food Sanitation Council. Orphan Pacific has been a valued partner to Immedica in Japan, holding exclusive rights to Buphenyl® (sodium phenylbutyrate). This collaboration was further strengthened in May 2022 through an exclusive license agreement, adding Ravicti to their portfolio for the Japanese market. About Urea Cycle Disorders (UCD) Urea cycle disorders are a group of metabolic diseases that affect a specific enzyme or transporter in the urea cycle leading to elevated ammonia or glutamine levels in the circulation. Symptoms of the disorder can begin at any age, where more severe defects are seen with an onset of the disease early in life. UCD patients may experience episodes, called hyperammonemic crises, when ammonia levels in the blood become excessively high, which can result in irreversible brain damage, coma, or death. Beyond hyperammonemic crises there are also more subtle symptoms including vomiting, refusal to feed, irritability, muscular hypotonia as well as delayed motor and psychointellectual development. As a group, these disorders occur in 1 in 35,000 newborns. About Ravicti® (glycerol phenylbutyrate) Ravicti is a medicine used to treat patients of all ages with UCDs, including deficiencies of carbamoyl phosphate synthetase I (CPS), ornithine carbamoyltransferase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), arginase I (ARG) and ornithine translocase deficiency hyperornithinaemia-hyperammonaemia homocitrullinuria syndrome (HHH) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Ravicti must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements). The medicine is used to reduce the amount of ammonia in the blood in order to reduce the risk of neurological consequences. About OrphanPacific OrphanPacific is a Japanese pharmaceutical company dedicated to developing, manufacturing, and marketing treatments for rare diseases. Our mission is to "bring smiles and happiness to patients with rare diseases and their families." With a commitment to "Leave No One Behind," we actively engage in the development and provision of treatments for rare diseases with very few patients. https://www.orphanpacific.com/ About Immedica Immedica is a pharmaceutical company, headquartered in Stockholm, Sweden, focused on the commercialization of medicines for rare diseases and specialty care products. Immedica’s capabilities cover marketing and sales, compliance, pharmacovigilance, quality assurance, regulatory, medical affairs and market access, as well as a global distribution network serving patients in more than 50 countries. Immedica is fully dedicated to helping those living with diseases which have a large unmet medical need. Immedica’s therapeutic areas are within genetic & metabolic diseases, hematology & oncology and specialty care. Immedica was founded in 2018 and employs today around 130 people across Europe, the Middle East and the U.S. The main owners are the investment firms KKR and Impilo. For more information visit www.immedica.com Immedica contact: Linda Holmström Head of Communication linda.holmstrom@immedica.com + 46 708 73 40 95 Press release - Application to the Ministry of Health in Japan for Ravicti® (Glycerol Phenylbutyrate) submitted Follow us to stay up to date with what is happening at Immedica. We believe we have an important role to fill in society – bringing new, innovative treatments to patients with rare diseases. Focus areas are within genetic & metabolic diseases, hematology & oncology and specialty care. We operate products from phase 2 and all the way to mature products. ESG is an integrated part of our business model. Stay up to date with our latest news. Telephone: +46 (0) 8 533 39 500 E-mail: info@immedica.com