Alterity Therapeutics reports topline data from open-label Phase 2 ATH434 trial

Alterity announced topline data from the ATH434-202 open-label Phase 2 clinical trial in individuals with multiple system atrophy. The ATH434-202 trial evaluated a patient population with more advanced disease than was studied in Alterity’s double-blind Phase 2 trial ATH434-201. ATH434 has been shown preclinically to reduce alpha-synuclein pathology and preserve neuronal function by redistributing iron in the central nervous system. The topline data showed that ATH434 conferred a clinical benefit on areas of impairment in MSA and stabilized key biomarkers that underpin the pathology of the disease. The results from the ATH434-202 trial indicate that ATH434 demonstrated a clinical benefit on the Modified Unified MSA Rating Scale Part I, as well as stabilization of overall neurological symptoms. Over the 12-month treatment period, disease progression as assessed with UMSARS I was reduced by approximately half as compared to historical controls. In addition, 30% of participants reported stable neurological symptoms over the course of the study. These outcomes are potentially promising as stabilization of MSA symptoms is unexpected in this patient population. On the important symptom of orthostatic hypotension3, ATH434 on average stabilized low blood pressure symptoms in study participants. Importantly, the aggregate data indicate that ATH434 has similar clinical efficacy in this advanced MSA population as was observed in the earlier stage patients in Study ATH434-201. Biomarker endpoints were used to evaluate potential drug effect and target engagement. Neuroimaging outcomes indicate that ATH434 slowed brain atrophy in MSA affected areas, as measured by the MSA Atrophy Index, when compared to placebo-treated participants in Study 201. Moreover, the effects on brain volume were comparable to those observed in participants in the 75 mg dose group in Study 201. In addition, ATH434 led to lower iron accumulation in the putamen and globus pallidus as compared to placebo treated patients in Study 201, providing further evidence of target engagement. The ATH434-202 Phase 2 clinical trial was an open label study in advanced MSA. Ten participants were enrolled in the trial and were diagnosed with MSA using a multimodal approach. Participants were treated with oral ATH434 75 mg twice daily for 12 months. The study assessed the safety and efficacy of ATH434 treatment on clinical and biomarker endpoints. The pre-specified key clinical endpoints included the modified UMSARS I, the clinical global impression of change, and the patient global impression of change. Enrolled participants were more advanced than those in the double blind ATH434-201 Phase 2 trial based on baseline variables including duration of motor symptoms, UMSARS I score, frequency of severe orthostatic hypotension, and plasma NFL levels. Based on the observed clinical and neuroimaging data, ATH434 improved overall neurological symptoms and slowed disease progression compared to historical data. Clinical Endpoints at 12 months: Modified Unified MSA Rating Scale Part I: The mean UMSARS scores increased from baseline to 12 months by 3.5 points. These study data compare favorably to historical data in a similar MSA population, where an increase of 6.5 points over 12 months was observed. 43% of participants who completed the study had stable UMSARS scores. Global Impression of Change: 30% of participants stabilized or improved on the Clinical Global Impression of Change scale, which asks the investigator to evaluate overall neurological symptoms as compared to immediately before starting therapy. 30% of participants also stabilized or improved on the Patient Global Impression of Change scale, which asks the patient to evaluate their overall neurological symptoms as compared to immediately before starting therapy. Orthostatic Hypotension Symptom Assessment: The OHSA is a patient reported outcome that evaluates 6 symptoms of low blood pressure associated with moving from a sitting to a standing position. On average, symptoms were stable over the 12-month treatment period. Biomarker Endpoints at 12 months: Brain volume The key biomarker endpoint was defined as the change in brain volume from baseline to 12-months, as measured by the MSA Atrophy Index, which compares brain volume change in MSA affected regions to age matched controls using a composite z-score: Brain volume decreased on average, with a mean z-score of -0.44, consistent with that seen in the 75 mg treatment group of Study 201. ATH434 slowed atrophy in MSA affected brain regions compared favorably to placebo-treated subjects in Study 201. Brain iron: A secondary biomarker endpoint was change in iron content in MSA affected areas from baseline to 12-months, as measured by MRI: Reduced iron accumulation in the globus pallidus and putamen, as compared to placebo in Study 201, provide evidence of target engagement and support the clinical efficacy of ATH434. The pattern of iron accumulation in the substantia nigra over 12 months was comparable to that observed in the 75 mg dose group in Study 201. Neurofilament Light Chain (NfL) is a marker of axonal injury in neurons and is elevated in individuals with MSA. On average, plasma and CSF NFL levels were stable over the 12-month treatment period. Safety Results The safety population includes all enrolled participants who received at least one dose of study drug. No serious adverse events related to ATH434 were reported. ATH434 was well-tolerated and most adverse events were mild to moderate in severity. There were 3 discontinuations from the study. Two participants discontinued due to progression of MSA and one discontinued for an AE that was not related to treatment. There was no evidence of adverse effects on hemoglobin or iron parameters