Background Gaucher Disease
Gaucher disease (Gaucher) belongs to a group of sphingolipidoses in lysosomal storage disorders. It is a rare, inherited metabolic disorder caused by a mutation in the GBA1 gene, which results in misfolding of the glucocerebrosidase (Gcase) lysosomal enzyme. This leads to an accumulation of waste lipids in macrophages called Gaucher cells. The major organs are affected; the usual symptoms are an enlargement of the spleen and liver.
There are approximately 15.000 prevalent cases in the US and Europe, which makes it the most common lysosomal storage disorder. Of those, roughly 30% develop neurological symptoms, including 5-7% with Parkinsonism.
Interestingly, mutations in the GBA1 gene are one of the most well-known genetic risk factors for developing Parkinson’s disease. An estimated 7-12% of patients with Parkinson’s disease carry a GBA1 mutation.
This was a multicenter, double-blinded, randomized, placebo-controlled phase II study conducted in treatment naïve patients to standard treatment. The study was conducted at seven sites in India. It was a six-month treatment study, where participants either received three active arms of arimoclomol (100 mg, 200 mg or 400 mg) or placebo three times a day. Randomization took place in a 1:1:1:1 manner.
The primary endpoint was chitotriosidase, an established biomarker in Gaucher. This was the first-in-patient trial with arimoclomol in Gaucher, and we note the exploratory nature of the study. Various clinical measures and biomarkers served as secondary endpoints, as well as safety and tolerability.
The study outcome saw a relative reduction in chitotriosidase from baseline compared to placebo in all doses evaluated. However, the results were not statistically significant (p=0.4). Key highlights of the secondary clinical endpoints include (below bullets are directly from Orphazyme’s presentation):
–Clinically meaningful dose-dependent reductions in liver size (dose-trend analysis p<0.05) and spleen size (dose trend analysis p<0.10) relative to placebo; strong correlation observed (correlation coefficient: 0.53)
–Patients anemic at baseline in higher dose group showed time-dependent increase in hemoglobin (time-trend analysis p<0.05)
–Directional dose-dependent reduction in clinical composite measure ClinicalGD1 severity score (not statistically significant)
Another exploratory biomarker, glycosylsphingosine (lyso-Gb1), saw a dose-dependent increase in plasma. This is interesting, as it could be due to the release of this biomarker from the affected cells into the blood. This is also in line with arimoclomol’s mechanism of action.
Arimoclomol was generally well-tolerated, with a slightly higher incidence of adverse events (AE) and Severe Adverse Events (SAEs) in the active arms. Three deaths occurred in the trial, and all were on arimoclomol. It is to remember the severity of the disease, and the larger number of patients receiving arimoclomol compared to placebo. Two of the deaths were considered non-related to the treatment, and one possibly related. Possibly related means that it cannot be rule-out that it is related to study drug.
The phase II study now enters an open-label extension (OLE) phase for another six months, where patients will roll-over to arimoclomol. 34 patients have continued to OLE. From these results, we hope to learn more about arimoclomol’s efficacy on the neurological symptoms. The score that monitors the neurological manifestation in Gaucher will be measured at 12-months.
In our update from February, we said we would adopt a holistic view to the overall results, being the exploratory nature of the trial. The results are not a home-run, and we question the sample size, given the p-values observed, and if chitotriosidase is a fair endpoint for neurological Gaucher. Still, we have contained excitement towards the results:
– A strong signal of a dose-dependent reduction in spleen and liver size supports efficacy on the underlying disease pathology after six months of treatment
– A sustained level of CSF at all doses confirms arimoclomol as CNS-acting
– A generally good safety and tolerability profile in this fragile patient group
Together this strengthens our confidence that arimoclomol has the potential to treat the neurological symptoms associated with Gaucher. Further, the results reinforce our belief in the mechanism of action by arimoclomol. We also argue that the study has generated essential data on how to design future studies in Gaucher, both on endpoints, sample size, patient segmentation, study location etc.
This early data suggests that arimoclomol could demonstrate efficacy on the underlying disease pathology. In this regard, it is interesting to discuss the positioning of arimoclomol in a future treatment paradigm in this indication, in relation to Enzyme Replacement Therapy (ERT) and Substrate Reduction Therapy (SRT). We will elaborate further on this in a subsequent update.
The stock reacted with some uncertainty about the news. After mainly trading in red territory, it closed at some -2.6%. We understand this stock reaction, as the data-set is complex and early. When Orphazyme reported the top-line phase II/III results in NPC in September 2018, we saw a similar and rather modest stock price reaction but where the stock gained momentum on further data and progress along the road.
To reinforce our support in continuous development, in Gaucher but possibly also in other sphingolipidoses, as well as Gcase-Parkinson’s, we raise the probability by 5 percent in Gaucher, leading to an overall LoA of 30 percent. It leads to a new Base Case of DKK 160 per share, effective immediately. It is a rather modest increase, but we emphasize the complex dataset in this first-in-patient trial. There is still a long road ahead in this indication.
Upcoming news flow in this indication include updates on regulatory interactions, and OLE data by the end of the year. As we stated above, the OLE data on the neurological symptoms are essential to scrutinize eventually.
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