Date: 2017-02-16
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 13th annual WORLDSymposium
Company: Armagen (USA - CA)
Product: AGT-181 (fusion protein of anti-human insulin receptor monoclonal antibody and alpha-L-iduronidase; HIRMAb-IDUA)
Action
mechanism: enzyme replacement therapy/fusion protein. AGT-181 is a novel, investigational enzyme replacement therapy (ERT) for the treatment of neurological complications in patients with Hurler syndrome. AGT-181 is a fusion protein containing alpha-L-Iduronidase that is intended to deliver the enzyme peripherally and to the brain, when administered intravenously. The most severe form of MPS I, Hurler syndrome is a rare, hereditary lysosomal storage disorder that affects the brain and spinal cord in children, resulting in a wide range of debilitating symptoms. Commercially available treatments for Hurler syndrome do not penetrate the blood-brain barrier (BBB), and therefore do not address the severe and progressive neurological complications of the disease. AGT-181 is designed to utilize the body’s natural system for transporting products non-invasively across the BBB by targeting the receptor that delivers insulin to all cells of the body.The fusion protein binds to insulin receptors located on the surface of the BBB, enabling its passage into the brain.
Disease: mucopolysaccharidosis I (Hurler syndrome)
Therapeutic area: Rare diseases - Genetic diseases
Country: Brazil
Trial
details: The study is a safety and tolerability study to obtain safety and exposure data as well as information on the biological activity of AGT-181. This is a two-stage, sequential, single and multi-dose study of AGT-181 in patients with MPS I. The first stage will be an open-label, single-dose, dose-escalation cohort study and the second stage will be an open-label, multi dose, adaptive dose escalation cohort study. (NCT03053089)
Latest
news: * On February 16, 2017, ArmaGen reported preliminary evidence of cognitive improvement in children treated with AGT-181, the company’s investigational therapy for the treatment of Hurler and Hurler-Scheie syndrome (also known as mucopolysaccharidosis type I, or MPS I). The initial results from an ongoing Phase 2 proof-of-concept (POC) study, presented at the 13th annual WORLDSymposium in San Diego, California, suggest that AGT-181 may improve cognitive function in patients with MPS I, demonstrating the ability of ArmaGen’s proprietary drug delivery technology to transport biopharmaceuticals across the blood-brain barrier. In an oral presentation entitled, “Intravenous infusion of iduronidase-IgG and its impact on the central nervous system in children with Hurler syndrome,” Roberto Giugliani, M.D., Ph.D., of Hospital de Clínicas in Porto Alegre, Brazil, reported improvements in neurological and cognitive function in four of five patients, and stabilization of neurological and cognitive function in the fifth patient. He also noted that AGT-181 was similarly efficacious somatically (related to the rest of the body other than the brain) to currently available enzyme replacement therapy and displayed a favorable safety and tolerability profile. At the WORLDSymposium, Dr. Giugliani presented up to 26 weeks of data from the first five children with MPS I (age 2 years or older) enrolled in the 6-month study. All five patients had previously been treated with standard ERT, and one had received a stem cell transplant which had failed engraftment. Once enrolled, the children received weekly intravenous infusions of AGT-181 at doses of 1.0 or 3.0 mg/kg. Developmental age-appropriate neurocognitive testing was conducted at 13 and 26 weeks of treatment, utilizing either the Bayley Scales of Infant Development III; or the Kaufman Assessment Battery for Children. Together, the two tests (commonly abbreviated as B-K) represent a summation of scores from cognitive, language and motor skills. Four of the five patients demonstrated improvement in their B-K cognitive score domain, and the patient who had failed engraftment after stem cell transplantation showed stabilization in this domain. Somatic disease control under AGT-181 was similar to what is commonly observed under standard ERT, based on stabilization of urinary glycosaminoglycan (GAG) levels and either stabilization or reduction in liver and/or spleen volume. Additionally, a trend towards improvement in shoulder range of motion was observed. Drug-related adverse events (AEs) in the Phase 2 POC trial included two infusion site reactions and two hypoglycemic events that were transient and well controlled by glucose administration. No serious AEs were observed that were likely to be drug-related. * On March 31, 2016, ArmaGen announced that the first patient has been dosed with AGT-181 in a Phase 2 proof-of-concept (POC) clinical trial treating pediatric patients with Hurler syndrome in Brazil. The initiation of this pediatric study follows the successful completion of a Phase 1 study in adult patients in Brazil.
The Phase 2 POC study, led by Dr. Giugliani, will be an open-label, multi-dose, dose-escalation study in children (age two or older) with Hurler or Hurler-Scheie syndrome and central nervous system involvement. The primary objective of this study is to determine the safety and tolerability of weekly infusions of 1.0 or 3.0 mg/kg of AGT-181 in children with Hurler or Hurler-Scheie syndrome.
Ten patients will be enrolled into the study and the period of observation will be six months. Patients for whom it can be demonstrated that a cognitive benefit was achieved will be offered an open label 12-month extension treatment protocol to collect additional long-term safety and efficacy data. ArmaGen expects to complete the Phase 2 POC study by the end of 2016.
In advance of this Phase 2 study, a six-patient, Phase 1 safety study in adults (ages 18 or older) was conducted. The open-label, single-dose, dose-escalation study consisted of three cohorts (0.3, 1 and 3 mg/kg) of adult patients with Hurler-Scheie or Scheie syndrome, which are attenuated or less severe forms of MPS I. The primary objective was to determine the safety and tolerability of a single infusion of AGT-181. Secondary objectives included evaluation of the pharmacokinetics (PK) and pharmacodynamics (PD) of single doses of AGT-181, determination of well-tolerated dose(s) to take into the pediatric multi-dose stage of the trial, and evaluation of the occurrence of single-dose infusion reactions. AGT-181 was shown to be safe and well-tolerated and a review of the collected data supported the decision to move into the pediatric Phase 2 POC.
