Prothena Corporation plc (NASDAQ: PRTA) today reported positive results from the Phase 1 study of PRX004, the first anti-amyloid immunotherapy designed to deplete amyloid to demonstrate efficacy in ATTR amyloidosis. In the first report of clinical results with this depleter mechanism of action, PRX004 showed favorable results as demonstrated by slowing of neuropathy progression for all 7 evaluable patients at 9 months, including improvement in neuropathy in 3 of the 7 patients, and improved cardiac systolic function for all 7 patients. In this Phase 1 study, PRX004 was found to be generally safe and well tolerated across all dose levels. Prothena management will host a webcast to discuss the Phase 1 results today at 8:30 AM ET and will be joined by Dr. Ole Suhr, Senior Professor, Department of Public Health and Clinical Medicine, Umeå University, gastroenterologist and internist who was a principal investigator in the study, and Dr. Daniel Lenihan, Director, Cardio-Oncology Center of Excellence Advanced Heart Failure, Clinical Research Cardiovascular Division, Washington University in St. Louis.

As previously reported, the long-term extension portion of the Phase 1 study was disrupted by the COVID-19 pandemic. As a result, 7 patients received all infusions through 9 months and were considered evaluable for efficacy. For all of the evaluable patients, slowing of neuropathy progression was demonstrated by a mean change from baseline in Neuropathy Impairment Score (NIS) of +1.29 points at 9 months. This compares favorably to a calculated mean change in NIS of +9.2 points at 9 months in untreated and placebo-treated patients with hereditary ATTR peripheral neuropathy (hATTR-PN) based on analysis of published historical data. In addition, the change in NIS for each of these evaluable patients was more favorable than the published historical data. In this highly progressive disease, it was encouraging to see 3 of 7 patients demonstrate improvement in neuropathy with a mean change in NIS of –3.33 points at 9 months. These positive results were observed in patients with or without concomitant use of stabilizer therapy. PRX004 also demonstrated improvement in cardiac systolic function in each of the 7 evaluable patients, with a mean change in GLS of –1.21% at 9 months (centrally read). For the 3 patients who improved on NIS, GLS improvement was more pronounced, with a mean change of –1.51% at 9 months. Taken together, these positive clinical findings suggest PRX004’s depleter mechanism of action can result in benefits in both neuropathy and cardiac function.

“We are pleased to see evidence of both a slowing of disease progression as well as a rapid improvement in neuropathy after only 9 months of treatment with PRX004. In this progressive disease, the more favorable than expected change in NIS for all 7 patients is an encouraging finding, as is PRX004’s favorable safety and tolerability profile,” stated Radhika Tripuraneni, MD, MPH Chief Development Officer and ATTR Program Head, Prothena. “The improvement on GLS, a key measure of cardiac systolic function, in all evaluable patients was even more pronounced in the 3 patients who improved on NIS. These results demonstrate the potential of PRX004’s depleter mechanism of action as uniquely suited for patients at high risk of early mortality due to amyloid deposition in vital organs. We look forward to advancing PRX004 in 2021 to address this high unmet medical need.”

“Given the expected clinical progression in patients with ATTR, this first report of clinical results for PRX004 are particularly encouraging,” stated Ole Suhr, MD. “These consistent results on neuropathy and cardiac assessments demonstrate the potential of this novel depleter mechanism to provide a new treatment paradigm that is highly needed to treat this deadly disease, especially for patients with more advanced ATTR cardiomyopathy, where amyloid removal is needed to improve heart function.”

PRX004 Phase 1 Study

The Phase 1, open-label, multicenter dose-escalation study (NCT03336580) enrolled 21 patients with hereditary ATTR Amyloidosis (hATTR) to receive PRX004 intravenously once every 28 days for up to 3 infusions in the dose escalation phase of the study. Patients were enrolled into 1 of the following 6 PRX004 dose cohorts: 0.1, 0.3, 1, 3, 10, and 30 mg/kg, starting with the lowest dose. Eligible patients who completed dose-escalation were provided the opportunity to enroll in the long-term extension (LTE) portion of the study. All 21 patients enrolled in the Phase 1 study successfully completed dose-escalation and 17 patients subsequently enrolled in the LTE.

In order to inform dose selection, a pharmacokinetic/pharmacodynamic (PK/PD) model was developed and subsequently confirmed by observed reductions in free non-native TTR (transthyretin) in plasma of patients following PRX004 administration. Based on this model, dose levels ≥3 mg/kg were predicted to saturate (occupy ≥90%) amyloid deposits. Therefore, cohorts 4, 5 and 6 were considered equivalent, and efficacy was assessed in these patients and pooled. Out of 12 patients, 7 from cohorts 4 (n=3), 5 (n=3), and 6 (n=1) received all infusions through 9 months and were therefore considered evaluable for efficacy. The remaining 5 patients did not meet these criteria due to COVID-19 pandemic-related disruptions.

PRX004 demonstrated a PK profile consistent with an lgG1 monoclonal antibody and exposures increased proportionally with dose.

Monthly intravenous (IV) infusions of PRX004 were generally safe and well tolerated at all dose levels tested, with 233 separate infusions and up to 17 infusions per patient in the study. No drug-related serious adverse events (SAEs), drug-related ≥grade 3 adverse events, deaths or dose-limiting toxicities were reported. The most frequent treatment-emergent AEs (≥10%) were fall, anemia, upper respiratory tract infection, back pain, constipation, diarrhea and insomnia. No clinically relevant anti-drug antibodies were observed. Consistent with the proposed mechanism of action, PRX004 administration did not impact levels of native, normal tetrameric TTR.