A possible new treatment option for transthyretin amyloidosis has shown promising results in an initial clinical trial.

Transthyretin amyloidosis (ATTR amyloidosis) is a rare, progressive, and fatal disease characterized by deposition of abnormal, non-native forms of the transthyretin protein in vital organs. The condition, which can be hereditary or occur sporadically, is brought about when transthyretin, a protein primarily made in the liver, misfolds or changes its shape in an abnormal way, and forms into fibrous amyloid clumps.

Patients can experience a spectrum of clinical manifestations because of deposition of amyloid that can affect multiple organs, most commonly the heart and/or nervous system.

It is estimated that between 400,000 to 1.4 million patients suffer from ATTR-cardiomyopathy, many of whom have moderate or advanced heart failure.

Symptoms of ATTR can include an inability to lie flat in bed due to shortness of breath; numbness, tingling or pain in the hands or feet; diarrhea or constipation; and unintentional weight loss.

The new agent, currently known as PRX004 (Prothena Biosciences) is an investigational humanized monoclonal antibody designed to deplete amyloid associated with disease pathology, without affecting the native, normal tetrameric form of the protein.

Initial clinical trial data with the drug was presented by Ole Suhr, MD, Umeå University, Umeå, Sweden, at the the American Academy of Neurology (AAN) 2021 Annual Meeting.

Suhr noted current treatments for ATTR amyloidosis slow the transthyretin protein from entering the pathogenic pathway by stabilizing the tetramer or supressing production of the protein, but they do not target amyloid deposits and are not adequate because patients already have substantial amyloid deposition in their organs.

PRX004 has been shown in preclinical studies to promote clearance of insoluble amyloid fibrils through antibody-mediated phagocytosis and inhibit amyloid formation. This depleter mechanism of action has the potential to provide benefit for ATTR patients at high risk for early mortality due to amyloid deposition in vital organs, Suhr said.

The current study was a phase 1, open-label, dose escalation study with a long-term extension in patients with hereditary ATTR amyloidosis.

For the dose escalation phase, 21 patients received PRX004 intravenously once a month for up to 3 months at one of six different doses (0.1, 0.3, 1, 3, 10, and 30 mg/kg). 

Patients who completed dose-escalation could enroll into the long-term extension portion of the study. All 21 patients enrolled in the phase 1 study successfully completed dose-escalation and 17 patients subsequently enrolled in the long-term extension.

A pharmacokinetic/pharmacodynamic model based on observed reductions in free non-native transthyretin protein in plasma of patients after PRX004 administration, predicted that dose levels ≥ 3 mg/kg were needed to saturate amyloid deposits.

Monthly intravenous (IV) infusions of PRX004 were generally safe and well tolerated at all dose levels tested, with 233 separate infusions given in total and each patient receiving between 3 and 17 infusions throughout the study.

No drug-related serious adverse events or dose-limiting toxicities were reported. The extension study was discontinued early because of the COVID pandemic, with only 7 patients receiving all infusions throughout the 9-month study period.

Neuropathy improvement was measured by the neuropathy impairment score (NIS), with a reduction in NIS indicating an improvement.

Results showed that PRX004 was associated with a slowing of neuropathy progression compared with published historical data, with a mean increase in NIS of 1.29% vs 9.2% in untreated cohorts at 9 months. Three of the seven patients showed an improvement in neuropathy, Suhr reported.  

Cardiac systolic function was measured by global longitudinal strain (GLS) with a reduction showing an improvement in cardiac function. All seven patients showed an improvement, with a mean reduction in GLS of 1.21%, Suhr noted.

“For the 7 evaluable patients, we found benefits in neuropathy and cardiac function that was more favourable than natural history data,” he said.

“Taken together, these results support the potential of this depleter mechanism to provide new treatment option for ATTR patients and warrants further investigations as there is an unmet need for treatments for this condition,” Suhr concluded.  

Commenting on the study for Medscape Medical News, Morie Gertz, MD, professor of medicine at Mayo Clinic, Rochester, Minnesota, who was not involved in the current work, said this was a completely new approach to treatment. 

“PRX0004 represents a monoclonal antibody that binds to the amyloid fibrils and stimulates phagocytosis dissolving existing amyloid deposits,” he explained.

“This phase 1 trial was primarily designed for toxicity; however, patients showed improvement in neurological impairment and the echocardiogram also improved in 7 patients,” he noted.

“The ability to eliminate existing amyloid deposits is a completely new approach and would offer synergy with current therapies that stabilize the TTR tetramer and silence the gene responsible for TTR production,” Gertz said.

This study was funded by Prothena Biosciences. Suhr has served as a consultant for Prothena.

American Academy of Neurology (AAN) 2021 Annual Meeting: Emerging Science. Presented April 18, 2021.

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