Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial

• Published in: BMC endocrine disorders Vol. 18; no. 1; p. 88
• Main Authors: Baig, Shanat, Veeranna, Vishy, Bolton, Shaun, Edwards, Nicola, Tomlinson, Jeremy W, Manolopoulos, Konstantinos, Moran, John, Steeds, Richard P, Geberhiwot, Tarekegn
• Format: Journal Article
• Language: English
• Published: England BioMed Central 26.11.2018; BMC
• Subjects: Adipose tissue; Alstrom Syndrome - blood; Alstrom Syndrome - diagnostic imaging; Alstrom Syndrome - drug therapy; Alström syndrome; Animal models; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - therapeutic use; Biopsy; Cell cycle; Children; Clinical trials; Cytokines; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Dyslipidemia; Fatty liver; Female; Fibroblasts; Fibrosis; Growth factors; Hereditary diseases; Humans; Inflammation; Insulin; Insulin resistance; International conferences; Kidneys; Laboratories; Life expectancy; Life span; Liver Cirrhosis - blood; Liver Cirrhosis - diagnostic imaging; Liver Cirrhosis - drug therapy; Liver diseases; Lung diseases; Magnetic resonance imaging; Male; Meta-analysis; Metabolic syndrome; Microdialysis; Mutation; NMR; Nuclear magnetic resonance; Obesity; Patients; Pulmonary fibrosis; Safety; Study Protocol; Systematic review; Treatment Outcome; Obesity; PBI4050; Magnetic resonance imaging; Cardiovascular; Alström syndrome; Diabetes mellitus; Liver; Fibrosis; Insulin resistance; Metabolic syndrome
• ISSN: 1472-6823; 1472-6823
• DOI: 10.1186/s12902-018-0315-6

Alström syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of multi-organ fibrosis in ALMS and severity of the disease often leads to organ failure with associated morbidities, resulting in reduced life expectancy. There are no specific treatments for this disease, and current management consists of only symptomatic therapies. PBI-4050 is a new molecular entity with demonstrated anti-inflammatory and anti-fibrotic activities in preclinical models, including animal models of human diseases characterized by progressive fibrosis in the kidney, heart, liver and lungs. Moreover, completed Phase 2 studies in type 2 diabetes mellitus with metabolic syndrome and idiopathic pulmonary fibrosis further support the anti-inflammatory and anti-fibrotic activity of PBI-4050. Together, these data suggest that PBI-4050 has the potential to treat the pathological inflammatory and fibrotic features of ALMS. The aim of this study is to evaluate the safety and anti-inflammatory & anti-fibrotic activities of PBI-4050 in subjects with ALMS. This is a Phase 2, single-centre, single-arm, open-label trial. A total of 18 patients with ALMS will be enrolled to receive PBI-4050 at a total daily oral dose of 800 mg for an initial 24 weeks with continuation for an additional 36 or 48 weeks. Standard assessments of safety include adverse events, clinical laboratory tests, vital signs, physical examination and electrocardiograms. Efficacy assessments include adipose tissue biopsy, hyperinsulinaemic-euglycaemic glucose clamp, adipose tissue microdialysis, liver transient elastography, liver and cardiac magnetic resonance imaging, and laboratory blood tests. This is the first clinical study of PBI-4050 in subjects with ALMS. Given the rarity and complexity of the disease, a single-centre, single-arm, open-label design has been chosen to maximise subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable safety and preliminary evidence of the effects of PBI-4050 in ALMS, a rare heterogeneous disease associated with progressive fibrosis and premature mortality. The trial is registered on ClinicalTrials.gov (Identifier; NCT02739217 , February 2016) and European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015-001625-16, Sept 2015).