Real-world study shows long-term benefits in FAP with Tegsedi…

Tegsedi (inotersen) safely and effectively slowed the progression of polyneuropathy, or damage to multiple nerves, when taken for up to about six years for 10 adults with familial amyloid polyneuropathy (FAP) in Brazil, according to a real-world study.

While the data add to results of Tegsedi clinical trials, “further studies with larger sample sizes, longer follow-up periods, and comprehensive outcome assessments are needed to confirm and expand upon these findings,” the researchers wrote in “Real-life experience with inotersen at CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro,” whhich was published in Arquivos de Neuro-Psiquiatria. It was supported by Ionis Pharmaceuticals, Tegsedi’s developer, and PTC Therapeutics, which markets the therapy in Latin America.

In FAP, genetic mutations lead to the protein transthyretin being produced and building up, causing tissue and organ damage. This buildup occurs mainly in the peripheral nerves outside the brain and spinal cord, but also in the heart muscle.

Administered via injections under the skin, Tegsedi targets the intermediate molecule derived from DNA that guides transthyretin’s production. For this reason, the therapy should reduce transthyretin and the chance it will form the clumps that drive the disease’s progression.

In the Phase 3 NEURO-TTR clinical trial (NCT01737398), weekly Tegsedi injections outperformed a placebo at slowing polyneuropathy progression and improving life quality over more than one year. Data from NEURO-TTR’s open-label extension study (NCT02175004), where all the participants were given Tegesdi, showed these benefits were sustained for more than three years.

The most common side effects of Tegsedi included injection site reactions, nausea, headache, fatigue, fever, and low counts of platelets, the tiny blood cell fragments that promote blood cell clotting.

Long-term benefits of Tegsedi

Here, researchers in Brazil described the long-term outcomes of 10 patients who completed NEURO-TTR and its extension study and then entered a post-approval study, where they continued on Tegsedi for at least 1.5 more years.

All the patients (six men, four women) carried Val30Met, the most common FAP-causing mutation. Six were on Tegsedi since NEURO-TTR’s start, while the remaining four had been originally assigned to the placebo and switched to Tegsedi in the extension study. The patients’ mean age at the start of Tegsedi treatment was 46.8 and they were treated with it for an average of 67 months, or about 5.5 years, and up to 76 months (about 6.3 years).

Polyneuropathy was measured using the polyneuropathy disability (PND) system, which is divided into five stages based on neurologic health and walking skills, and the Neuropathy Impairment Score (NIS), where a higher score indicates more advanced disease and greater disability.

Six patients (60%) maintained their PND stage from the start of Tegsedi to their last evaluation in June 2022, while four (40%) progressed to the following stage, indicating worse disability.

Mean NIS changed from 48.2 (range, 12-129.8) to 56 (7-123.5) points from the start of treatment to the last visit, indicating slightly worse disability after up to six years of treatment. This score increase was still lower than that estimated for FAP patients without treatment.

Two of the nine evaluable patients at the last follow-up showed a drop in NIS and three had a NIS increase greater than 10 points. Two of these three patients had more severe disease at the start of Tegsedi, and showed both polyneuropathy and heart damage, or cardiomyopathy.

The ability to perform daily tasks, measured by the Karnofsky Performance Status, stayed consistent over time for most patients (70%). One of the remaining three patients showed better function at the last assessment, while the other two showed worse skills.

During the long-term follow-up, two patients needed pacemakers to help their heart beat at a normal rate and rhythm. Their kidney function remained stable, but low platelet counts prompted treatment interruption for some months in three patients.

“Although no new safety signal was detected, platelet and [kidney] function monitoring is paramount to maintain the safety of the patients,” the researchers wrote, who noted that while the number of patients included was small, it “represents patients who have transitioned from the controlled environment of the main study to the dynamic setting of real-world circumstances, … adding a more realistic perspective.”

“We conclude that treatment with [Tegsedi] was effective and well tolerated for an average of 67 months and up to 76 months,” they said.