PRX004, an investigational treatment by Prothena, can reduce the progression of nerve damage (neuropathy) and improve heart function in people with hereditary transthyretin amyloidosis (ATTR), which includes familial amyloid polyneuropathy (FAP), according to results from a Phase 1 trial.
“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,” Radhika Tripuraneni, MD, chief development officer and ATTR program head at Prothena, said in a press release.
Hereditary ATTR amyloidosis is caused by mutations in the TTR gene, which lead to the production of faulty TTR proteins that form toxic deposits in tissues. Patients can have a spectrum of clinical manifestations. When they experience symptoms of polyneuropathy, or nerve damage, they have a subtype of the disease called FAP. Of note, neuropathies typically result in numbness, tingling, muscle weakness, and pain in the affected area, typically starting with the hands and feet.
PRX004 is an antibody designed to specifically target and clear the misfolded forms of this protein.
A Phase 1 clinical trial (NCT03336580), sponsored by Prothena, evaluated the investigational medication in people with hereditary ATTR amyloidosis, including in FAP patients and in individuals with other clinical manifestations. A total of 21 participants were enrolled.
In the first part of the study, the participants were divided into six dose groups — 0.1, 0.3, 1, 3, 10, and 30 mg/kg — and given up to three monthly infusions of their assigned PRX004 dose.
All 21 participants completed this initial portion of the trial, after which, 17 patients continued into the long-term extension part of the study.
To better understand PRX004, the researchers conducted pharmacokinetic and pharmacodynamic analyses. Pharmacokinetics assesses how a medication moves through the body, while pharmacodynamics evaluates how it affects the body.
These analyses indicated that doses of 3 mg/kg or higher would reach saturation of amyloid deposits —meaning that a higher dose wouldn’t lead to a more powerful effect. Thus, patients in the 3, 10, and 30 mg/kg dose groups were combined for analysis.
A total of seven participants in these groups received all infusions through nine months and were, therefore, included in the efficacy analysis. Of note, the trial was disrupted due to the COVID-19 pandemic, which resulted in the study’s early termination.
The main goal was to evaluate the treatment’s safety. PRX004 was found to be well-tolerated and generally safe at all dose levels. There were no serious side effects (adverse events) or on-study deaths reported. The most frequently reported adverse events were falls, anemia, an upper respiratory tract infection, back pain, constipation, diarrhea, and insomnia.
In the trial, the extent of nerve damage was evaluated with the Neuropathy Impairment Score (NIS), in which higher scores indicate more severe symptoms. The seven evaluable participants experienced a mean increase of 1.29 points in NIS at nine months. For comparison, untreated FAP patients would be expected to experience an increase of 9.2 points, on average, over the same time frame.
Furthermore, in three of the trial participants, NIS scores decreased by a mean of 3.3 points.
“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,” Tripuraneni said.
PRX004 treatment also improved heart function, as evidenced by a decrease in global longitudinal strain (GLS) in all participants. GLS is a measurement of the extent of strain put on heart muscles. The mean decrease in GLS was 1.21% at 9 months. Notably, in the three individuals with NIS score decreases, the GLS reductions were more pronounced, with a mean of 1.51%.
“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,” Tripuraneni said.
“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,” Tripuraneni said, adding, “We look forward to advancing PRX004 in 2021 to address this high unmet medical need.”
The trial was led by Suhr, MD, a senior professor at Umeå University, in Sweden, and Daniel Lenihan, director of the cardio-oncology center at Washington University in St. Louis.
“Given the expected clinical progression in patients with ATTR, this first report of clinical results for PRX004 are particularly encouraging,” Suhr said.
“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,” Suhr concluded.
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