Safety and efficacy of arimoclomol for inclusion body myositis: a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis. METHODS: This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed. FINDINGS: Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 [76%] male and 36 [24%] female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 [77%] and 70 [90%], respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (-3·26, 95% CI -4·15 to -2·36 in the arimoclomol group vs -2·26, -3·11 to -1·41 in the placebo group; mean difference -0·99 [95% CI -2·23 to 0·24]; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group. INTERPRETATION: Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design. FUNDING: US Food and Drug Administration Office of Orphan Products Development and Orphazyme.

The insulin like growth factor system in cirrhosis. Relation to changes in body composition following adrenoreceptor blockade.

OBJECTIVE: Circulating levels of IGF-I and IGFBP-3 are low in cirrhosis and are related to liver dysfunction. Metabolic disturbances include malnutrition with altered body composition and osteopenia. Since the effects of IGF-I may be associated to changes in body composition and bone mineral content (BMC) in cirrhotic patients, we investigated the relations between changes in the IGF-system and body composition and the effects of long-term alpha- and beta-blockade. DESIGN: The study was designed as a combined cross-sectional and prospective randomised controlled study of 62 patients with cirrhosis. Twenty-three of these patients were randomised to treatment with beta- or combined alpha/beta-blocker for 3 months. Haemodynamics, body composition, and systemic and hepatic IGF-I and IGFBP-3 levels were determined in all patients. In the subgroup changes in body composition and IGF-I/IGFBP-3 levels after 3 months of beta- or combined alpha/beta-blockade were additionally examined. RESULTS: Both the hepatic and the systemic IGF systems were suppressed and correlated with liver dysfunction and anthropometrics (p<0.05-0.001). Multivariate analyses revealed that changes in the IGF-system were determined by metabolic liver dysfunction as well as anthropometrics. In the follow-up study, hepatic venous IGF-I (p=0.05) and IGFBP-3 (p=0.02) increased after 3 months only in the group who received beta-blocker. In both groups, fat body mass increased significantly after 3 months (p=0.05-0.001). CONCLUSIONS: In cirrhosis, the IGF-system is associated with both anthropometrics and synthetic capacity of the liver. Changes in IGF-I relate to changes in anthropometrics and there seems to be a differential effect depending on the type of adrenoreceptor blockade. Future longitudinal studies are needed to unravel these mechanisms in cirrhosis.

Insulin-like growth factor-I and the liver.

Insulin-like growth factors (IGFs) play an essential role in growth and development, as well as in the overall cellular regulation and metabolism in the human body. In chronic liver disease, IGF levels are decreased, and the circulating levels correlate to the extent of hepatocellular dysfunction. Patients with cirrhosis are characterised by a variety of metabolic disturbances, including nutritional and metabolic complications such as insulin resistance, malnutrition, osteopenia and hypogonadism, all related to IGF-I deficiency. The complex process of hepatic fibrogenesis and the systemic consequences in cirrhosis are only partly understood. Disruption of the growth hormone (GH)-IGF-I axis seems to be closely associated with the development of liver disease, and treatment with recombinant human IGF (rhIGF)-I has been shown to halt, and even reverse, the fibrotic degeneration. IGF-I in itself has a strong antifibrotic effect that acts directly through the GH/IGF system and indirectly by the regulation of hepatoprotective and profibrogenic factors. It is most likely that IGF-I deficiency contributes to the diverse metabolic complications of cirrhosis. At present, liver transplantation remains the only efficient treatment of cirrhosis, and thus new methods of managing the disease are called for. RhIGF-I supplementation and IGF-I gene therapy may represent future perspectives of treatment.