Arimoclomol, Orphazyme’s investigational therapy for Gaucher disease and other disorders, leads to clinically meaningful, dose-dependent reductions in liver and spleen size in patients with type 1 or 3 Gaucher, according to top-line results of a Phase 2 trial.
Despite failing at its primary goal — to show that arimoclomol’s use led to a statistically significant drop in levels of chitotriosidase, a disease biomarker — study findings support the company’s plans to continue its development as a potential treatment of Gaucher.
“We are very encouraged by the data from this exploratory study which show a clear dose-dependent effect of arimoclomol on liver and spleen size as early as 6 months,” Thomas Blaettler, chief medical officer of Orphazyme, said in a press release.
Arimoclomol is a small molecule that increases levels of the heat-shock protein 70 (HSP70), a chaperone that helps to fold glucocerebrosidase (GBA), the enzyme that is faulty in people with Gaucher. Chaperones are proteins that help other proteins to acquire their normal 3D structure, a process known as folding.
By increasing the amount of HSP70, arimoclomol aims to raise levels of functional GBA and ease disease symptoms. Due to its small size, arimoclomol is also thought to be able to cross the blood-brain barrier, and for that reason may possibly be used to treat the neurological symptoms experienced by some Gaucher patients. (The blood-brain barrier is the semipermeable membrane that separates the brain from circulating blood, to protect it from viruses and other blood-borne threats.)
The dose-finding ORARIGAU-01 Phase 2 trial (NCT03746587) is investigating the response of 39 people with type 1 or 3 Gaucher to different doses of arimoclomol. All enrolled have never received any form of enzyme replacement therapy or substrate replacement therapy.
During the study, conducted at seven sites in India, patients were assigned to either one of three doses of arimoclomol citrate (100, 200, or 400 mg) or a placebo, given orally three times daily for six months.
The study’s main goal was to assess the effects of arimoclomol on the levels of chitotriosidase in blood serum during the six-month treatment period. Secondary goals included the effects of arimoclomol on other clinical markers of Gaucher, such as spleen and liver size.
Top-line findings, based on data from 37 patients, showed that arimoclomol at all doses lowered the levels of serum chitotriosidase by 12%–29% over the course of the trial. However, these reductions were insufficient to achieve statistical significance compared with the placebo.
A statistically significant and clinically meaningful dose-dependent effect was observed in liver size, which was reduced by 15%–20% in patients given arimoclomol. A similar effect was also seen in spleen size, which decreased by 5%–21% compared with placebo — but this result did not reach statistical significance likely due to the small sample size, the company said.
Analyses also revealed the presence of arimoclomol in the cerebrospinal fluid, supporting the therapy’s ability to cross the blood-brain barrier. The cerebrospinal fluid is the fluid that circulates in the brain and spinal cord.
“Although some aspects of Gaucher disease are well-managed by existing drugs, these therapies do not readily cross the blood-brain barrier, leaving an urgent need for new products that can address the debilitating neurological symptoms of this disease,” Blaettler said.
“With its oral administration, ability to cross the blood-brain barrier and the overall body of evidence we have gathered, we are encouraged by the potential for arimoclomol to both address an unmet need in Gaucher disease as well as a range of additional neurodegenerative orphan diseases,” he added.
Despite a slightly higher incidence of adverse events (83% versus 70%) and serious adverse events (21% versus 0%) in patients treated with arimoclomol compared with placebo, treatment was found to be generally well tolerated.
Three people died during the study, one in each arimoclomol dose group. Two deaths were found to be unrelated to treatment, but one — reported as due to natural causes — was found to be possibly related to arimoclomol.
An open-label extension study of ORARIGAU-01 is underway to continue monitoring the safety and efficacy of all three doses of arimoclomol over a longer period of time. Orphazyme is planning to discuss findings from the trial and its open-label extension study with regulatory authorities soon.
Arimoclomol is currently also being investigated as a potential treatment for other lysosomal storage disorders, like Niemann-Pick disease Type C, and neurodegenerative diseases like sporadic inclusion body myositis (sIBM) and amyotrophic lateral sclerosis (ALS).
“This is the second of our studies to show a positive clinical effect of arimoclomol in lysosomal storage diseases. Together with the Phase 2/3 trial results in Niemann-Pick disease Type C (NPC), these data reinforce the potential of Heat-Shock Protein amplification and give us further confidence in arimoclomol as a potential game-changer for patients with lysosomal storage and neurodegenerative diseases,” said Kim Stratton, CEO of Orphazyme.
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