Real-world Study: Tegsedi Slows FAP Progression, Preserves Life Quality
In a real-world study of patients with worse disease severity at the start of treatment, Tegsedi (inotersen) slowed the progression of hereditary transthyretin amyloidosis — a group of disorders that also includes familial amyloid polyneuropathy (FAP) — and preserved quality of life.
As progression is associated with disease severity at treatment initiation, the researchers stressed the importance of starting Tegsedi early on in the course of the disease.
“Our data confirm an increased therapeutic benefit with earlier treatment,” they wrote.
The patients in this study were treated under a compassionate-use program.
Despite having worse disease severity than those in Tegsedi’s clinical trials, “during the observed follow-up, FAP stage overall remained stable in 91.3% of patients, and [a disability score] reflecting ability in walking, was unchanged in 78.3% and improved in 4.3% of the patients,” the team wrote. This despite the fact that “progression is expected to occur more rapidly at higher disease stages.”
The study, “Real-life experience with inotersen in hereditary transthyretin amyloidosis with late-onset phenotype: Data from an early-access program in Italy,” was published in the European Journal of Neurology.
Hereditary transthyretin-mediated amyloidosis (hATTR) is a genetic disease caused by mutations in the TTR gene, which contains information to produce a protein called transthyretin. The faulty version of this protein clumps together and forms toxic aggregates, also known as amyloid deposits, in different tissues and organs, such as the heart, kidneys, eyes, and nervous system.
FAP is a form of hATTR in which these amyloid deposits mainly accumulate and damage nerves over time, leading to a condition known as polyneuropathy.
Tegsedi, developed by Ionis Pharmaceuticals, is designed to block TTR production and prevent its buildup in tissues. It does so by interfering with the way the gene encoding the protein is “read.”
The European Commission approved Tegsedi in the EU in July 2018 to treat adults with stage 1 and 2 polyneuropathies. Of note, patients at stage 1 are able to walk by themselves, while those at stage 2 are unable to walk without assistance.
An early access program was then opened in Italy to enable patients to have access to the therapy prior to its market launch.
To evaluate the real-world impact of Tegsedi, a total of 23 Italian hATTR patients with stage 1 and 2 disease were recruited from this early access program to participate in a multicenter, observational, retrospective study. Patients were given 284 mg of Tegsedi subcutaneously or via an under-the-skin injection once weekly, for up to 24 months (two years).
The trial’s primary goal was to assess the safety and tolerability of Tegsedi by calculating the percentage of patients who withdrew due to side effects. Investigators also assessed the participants’ platelet counts, and kidney and liver function.
The secondary goal of the study was to evaluate treatment efficacy. This was done by evaluating several measures of disease progression, including changes from the study’s start (baseline). Among the assessments were FAP stage, Polyneuropathy Disability (PND) score, the Neuropathy Impairment Score (NIS), and the Compound Autonomic Dysfunction Test (CADT).
Changes in blood levels of troponin and NT-proBNP, two markers of heart damage, and TTR, also were evaluated.
Researchers also assessed the patients’ life quality through the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire. All parameters were evaluated at baseline and every six months.
In the first six months, there was a significant reduction in platelet counts, but no patient dropped out of treatment because of this side effect. No severe reduction in platelet levels occurred. After six months of treatment, the mean platelet count remained stable. In a few cases, a temporary or permanent dose reduction was needed to maintain platelets at a stable level.
Other Tegsedi-related side effects included a decrease in blood pressure, which eased after treatment withdrawal. Kidney failure also was observed, but it was not related to treatment. Glomerulonephritis, an inflammation in the kidney filter units, was reported but was immediately reverted after treatment discontinuation. Moreover, no liver nor heart-related events were reported, and no deaths occurred.
“Considering safety, inotersen proved to be safe and well tolerated over 24 months,” the researchers wrote.
Overall, the FAP stage remained stable for most participants.
However, a moderate worsening in NIS was observed over the first six months of the study, with scores increasing from 77.0 at baseline to 85.9. Of note, the total NIS is graded on a scale of 0–244, with a higher score indicating greater impairment.
According to researchers, there may not have been enough time to see an effect of treatment. In fact, the NIS score stabilized up to 18 months of treatment and its annual progression was lower than that seen in disease natural history studies (9.96 vs. 14.3 points).
No significant worsening of CADT scores was found from the study’s start to end.
A significant reduction in blood TTR levels was observed in all patients at end of the treatment period (5.5 mg/dL) compared with those seen at the study’s start (24.75 mg/dL).
Researchers also found that patients with stage 1 disease at baseline had slower disease progression than those with stage 2. NIS scores were significantly different between patients with stage 1 and 2 disease after six, 12, and 18 months of treatment.
A progressive significant increase was observed in NIS scores in patients with stage 2 disease group over the course of treatment. Patients with stage 1 disease had significantly higher CADT scores compared with those with stage 2 disease, from baseline to 18 months.
The Norfolk QoL-DN score showed that quality of life was maintained over the course of treatment with Tegsedi in both groups. A mean annual change in Norfolk QoL-DN of 3.2 points was observed, which is significantly lower than the threshold that defines progression. Norfolk QoL-DN scores were significantly different between the two groups at 12 and 18 months of treatment.
According to the team, the comparative analysis between the two groups “revealed disease stability in patients starting inotersen in FAP stage 1 but not in those starting therapy in stage 2.”
These findings are consistent with those obtained in previous studies that showed higher rates of progression in patients with worse disease severity at treatment start.
Therefore, as disease severity at the study start is one of the main factors associated with progression, this study confirms a greater benefit with earlier treatment, the researchers noted.