Alterity Therapeutics (NASDAQ:ATHE) is preparing to advance its lead candidate, ATH434, into a Phase III study in multiple system atrophy (MSA) after what Chief Executive Officer Dr. David Stamler described as a positive end-of-Phase II meeting with the U.S. Food and Drug Administration.
Speaking at the 46th Canaccord Annual Boston Growth Conference, Stamler said the company has reached agreement with the FDA on elements including the primary endpoint population, dosing regimen and key secondary endpoints for the planned registrational trial. The company is conducting site and vendor selection as it prepares for the study.
MSA Program Targets Aggressive Parkinsonian Disorder
Patients can require a cane or walker within several years of symptom onset, while more than half may require a wheelchair within five years, according to Stamler. He characterized MSA as a Parkinsonian disorder with an aggressive progression more comparable in some respects to amyotrophic lateral sclerosis.
ATH434 is an orally administered small-molecule iron chaperone designed to address excess iron accumulation in the central nervous system. Alterity’s thesis is that excess iron contributes to the aggregation of alpha-synuclein, oxidative stress and cellular damage in MSA and Parkinson’s disease.
Stamler said ATH434 crosses the blood-brain barrier and enters cells, where it is intended to redistribute excess iron rather than remove iron entirely. The company has orphan-drug designation in the U.S. and Europe for the program, as well as U.S. Fast Track designation.
Phase II Results and Patient Selection
Alterity’s completed Phase II trial enrolled 77 patients with clinical criteria for MSA. Participants also had elevated brain iron on MRI and elevated neurofilament light chain, or NfL, a biomarker the company used to help distinguish MSA from Parkinson’s disease. Patients were randomly assigned to receive ATH434 at 50 milligrams or 75 milligrams twice daily, or placebo, for 12 months.
The primary clinical measurement was the Unified Multiple System Atrophy Rating Scale, or UMSARS, in which higher scores indicate more severe disease. Stamler said placebo patients worsened by about eight points over one year, while the two active-treatment groups showed 34% to 46% less decline, representing a difference of approximately 2.7 to 3.7 points versus placebo.
He said both dose groups exceeded the 1.5-point minimal clinically important difference cited by the company. While the 50-milligram group showed a larger apparent treatment effect, Stamler attributed part of the difference to a baseline imbalance in severe orthostatic hypotension, a condition associated with faster disease progression. He added that pharmacokinetic analyses indicated a saturation of effect at 50 milligrams, which the company plans to take into Phase III.
The company also reported results across secondary measures that Stamler said were directionally consistent with the primary endpoint. These included assessments of orthostatic hypotension symptoms, swallowing disturbance, clinicians’ global impressions of disease severity and wearable-sensor measures of mobility.
- On orthostatic hypotension symptoms, placebo recipients deteriorated by about six points, while active-treatment groups remained stable, according to Stamler.
- On the Swallowing Disturbance Questionnaire, the 50-milligram dose showed a statistically significant difference versus placebo, he said.
- Wearable-sensor data indicated smaller declines in walking time and step-related activity among treated patients than among placebo recipients.
Stamler said adverse-event rates were similar between ATH434 and placebo groups. He also reported no severe or serious adverse events attributed to the study drug and no hematologic side effects.
Imaging Findings and Phase III Design
Alterity also examined MRI-based measures of brain iron and brain volume. Stamler said placebo-treated patients showed increased iron over 12 months in several brain regions implicated in MSA. The 50-milligram group showed trends toward reduced iron accumulation in certain regions compared with placebo, while the company also observed what it characterized as potential iron redistribution in the cerebellar dentate nucleus.
The company found a strong relationship in placebo patients between increasing iron measures and worsening UMSARS scores, Stamler said. That relationship was reduced in treated patients, which he said supports the hypothesis that ATH434 may redistribute iron in a way that reduces its harmful effects. Alterity also observed a trend toward reduced brain atrophy in treated patients, an exploratory finding it plans to further evaluate in Phase III.
The planned Phase III trial is expected to enroll approximately 200 patients with clinical criteria for MSA, evidence of atrophy in affected brain regions and elevated NfL. Participants will be randomized equally to ATH434 50 milligrams twice daily or placebo for one year. The UMSARS measure is planned as the primary endpoint, with secondary assessments including measures used in the Phase II study.
Separately, Stamler said Alterity surveyed 100 U.S. neurologists using a target product profile based on the company’s data. More than 70% were extremely or very likely to prescribe under that profile, according to the company. Alterity estimated potential peak sales of $2.4 billion using what Stamler described as conservative assumptions, while also continuing work on patent protection for MSA and Parkinson’s disease opportunities.
About Alterity Therapeutics (NASDAQ:ATHE)
Alterity Therapeutics is a clinical-stage biotechnology company focused on the development of novel treatments for neurological and neurodegenerative disorders. The company’s research portfolio centers on small molecules designed to target underlying disease mechanisms, with an emphasis on improving synaptic function and mitigating neuroinflammation.
Among its lead assets is trofinetide (NNZ-2566), a peptide analog derived from insulin-like growth factor 1, which is being investigated for the treatment of Rett syndrome and Fragile X syndrome in ongoing clinical trials.
