#AANAM – Onpattro Effective in Lowering TTR Protein Levels After Transplant

Editor’s note: The FAP News Today team is providing in-depth coverage of the 2021 Virtual AAN Annual Meeting, April 17–22. Go here to read the latest stories from the conference.

Among adults with familial amyloid polyneuropathy (FAP) whose disease progressed following a liver transplant, Onpattro (patisiran) was able to lower TTR protein levels in the bloodstream by more than 85%, according to six-month interim data from a Phase 3b study.

Researchers are hoping Onpattro will be a new treatment option for FAP patients whose disease progressed following transplant.

The trial findings were featured in a poster, “Open-label Study of Patisiran in Patients with hATTR Amyloidosis Post-Orthotopic Liver Transplant,” presented at the 2021 American Academy of Neurology (AAN) Virtual Annual Meeting, held online April 17–22.

A liver transplant — also known as an orthotopic liver transplant or OLT — can slow disease progression in early FAP, or hereditary transthyretin (hATTR) amyloidosis, by preventing the production and circulation of faulty TTR protein variants. In FAP, these variants clump together, forming protein aggregates that accumulate in peripheral nerves and cause nerve damage. The peripheral nerves extend from the spinal cord to relay information between the brain and the rest of the body. 

While performing such transplants can greatly slow FAP progression, it still has been reported post-OLT. It is driven by the accumulation of protein clumps made up of healthy TTR in nerves, as well as in the heart.

In these circumstances, treatment options are fairly limited. 

Developed by Alnylam Pharmaceuticals, Onpattro is an RNAi therapy that is currently approved to treat FAP in more than 30 countries worldwide. It works by reducing the production of TTR protein, including its faulty variants and healthy version, in the liver by silencing its messenger RNA — the molecule that cells use as a template to make proteins.

Onpattro’s approval was mainly supported by data from the Phase 3 APOLLO study (NCT01960348), which demonstrated the medicine was able to halt or reverse nerve damage and improve patient quality of life in most participants. 

Now, researchers at the Hospital de Santo António, in Portugal, along with scientists from Alnylam and other institutions, conducted an open-label Phase 3b study (NCT03862807) to assess whether Onpattro was safe and effective in adults with FAP whose disease continued to progress after OLT. 

Among the study’s 23 patients were 13 men and 10 women, ages 43–76. On average, these participants had undergone OLT 3.8 years after being diagnosed, and received their first dose of Onpattro more than nine years after the transplant.

After the transplant and before starting treatment with Onpattro, most patients (70%) showed 1-stage PND worsening, while four (17%) worsened by two stages, and three (13%) by three stages. Of note, the polyneuropathy disability (PND) scoring system is often used to assess FAP progression, with higher stages indicating an increasingly greater degree of disease severity and progression.

Before treatment (baseline), one patient (4.3%) had PND stage 1, indicating no walking difficulties but some sensory disturbances, while nine (39.1%) had PND stage 2, characterized by walking impairments not requiring aid. There were 13 patients (56.5%) with PND stage 3, meaning they had walking impairments requiring aid.

Most patients (56.5%) showed no signs of heart failure, while five (21.7%) had mild symptoms of heart disease.

Participants received 0.3 mg/kg of Onpattro infused directly into the bloodstream (intravenously) once every three weeks for one year, with assessments after six and 12 months.

At the time of this analysis, the patients had received Onpattro for a mean of 7.9 months, ranging from about three weeks to 10.5 months. After six months of treatment, TTR protein levels in the blood dropped by a mean of 89.2% from baseline. 

All participants experienced at least one adverse event (side effect), with the majority being either mild or moderate in severity. Infusion-related reactions, observed in four (17.4%) patients, were the most common treatment-related adverse events reported. Other side effects observed in at least 10% of the patients included diarrhea, swelling, back pain, urinary tract infections, and fatigue.

Five participants experienced serious adverse events, with only one being considered related to treatment. That, specifically, was an infusion reaction. While eight patients (34.8%) temporarily stopped taking Onpattro due to side effects, none of the participants withdrew from the study due to adverse events.

Liver function tests were normal in most patients, with seven (30.4%) experiencing mild and temporary elevations in liver enzyme levels, which are indicative of liver damage and inflammation. No treatment-related liver disorders were reported. 

“To date, the safety profile remains consistent with the Phase 3 APOLLO study,” the researchers wrote. “The efficacy, safety, [and pharmacological properties] of [Onpattro] treatment in patients with disease progression post-OLT will be further investigated in this ongoing study.”