Orphazyme reported results from the phase 2 ORARIGAU-01 trial, evaluating arimoclomol in Gaucher disease (GD) type 1 and 3 patients naive to enzyme and/or substrate replacement therapy. In the trial Arimoclomol demonstrated a marked and clinically meaningful dose-dependent reduction in liver and spleen size, as well as sustained levels of arimoclomol in the cerebrospinal fluid (CSF), providing further evidence of arimoclomol’s ability to cross the blood-brain barrier.
The double-blind, randomized, placebo-controlled, phase 2 dose-finding ORARIGAU-01 trial was conducted at seven sites in India. A total of 39 patients were randomized 1:1:1:1 to receive placebo or 100mg, 200mg, or 400mg arimoclomol citrate (weight-adjusted) three times per day. The objective of the phase 2 study was to evaluate the response of the three dose levels of arimoclomol on various clinical and disease-specific biomarkers over a 6-month treatment period. Overall, 37 patients were included in the analysis set (2 patients excluded due to negative confirmatory GD genotype), of which 21 were type 1 GD and 16 were type 3 GD patients.
Arimoclomol demonstrated a relative reduction in serum chitotriosidase activity from baseline to 6 months, the primary endpoint, across all dosages compared to placebo ranging from -12% to -29%, although statistical significance was not achieved. However, a statistically significant and clinically meaningful dose-dependent reduction in liver size ranging from -15% to -20% relative to placebo was observed. In addition, a clinically meaningful dose-dependent reduction in spleen size ranging from -5 to -21% relative to placebo was observed, although statistical significance was not achieved likely due to small sample size.
Orphazyme plans to proceed with pivotal stage clinical development in Gaucher disease and will discuss these data, along with results from the open-label extension, with Gaucher disease experts and regulators.
Arimoclomol is an investigational drug candidate that amplifies the production of heat-shock proteins (HSPs). The production of HSPs is regulated by a transcription factor, heat shock factor 1 (“HSF1”). A transcription factor is a protein that regulates production of other proteins in the cell. In the case of HSF1, the proteins being regulated are HSPs. Activation of HSF1 starts the production of the major stress-inducible HSP70-chaperone along with other HSP-chaperones, which help reshape the cells’ misfolded proteins and take care of the recycling systems. Under normal cellular conditions, HSF1 is inactive. However, the transcription factor can be activated by an initial cellular stress, such as protein misfolding, and becomes fully activated under a sustained stress signal.
Arimoclomol amplifies and prolongs the activated, HSP-producing state of HSF1. This leads to an amplification in the production of cell protective HSPs, but only in physiologically stressed cells.
About Gaucher disease
Gaucher disease is a rare, inherited metabolic disorder causing certain sugar containing fats to abnormally accumulate in the lysosomes of cells, especially within cells of the blood system and nerve cells, thereby affecting organs such as the brain, bone marrow, spleen and liver. The typical systemic symptoms of Gaucher disease, which can appear at any age, include an abnormally enlarged liver and/or spleen and low levels of circulating red blood cells and platelets. Gaucher disease is the most common lysosomal storage disorder (LSD) with an estimated incidence of 1:40,000 to 1:60,000, and affecting approximately 15,000 individuals in the United States and Europe combined.