Tegsedi seen to slow progressive muscle weakness, sensation loss

Phase 3 trial's post-hoc analysis also suggests ways of marking responders

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Tegsedi (inotersen) slows the progression of symptoms, particularly muscle weakness and sensation loss, in people with familial amyloid polyneuropathy (FAP), according to a post-hoc analysis of the Phase 3 NEURO-TTR trial.

“These results support previous evidence demonstrating the efficacy of [Tegsedi] in this patient population,” its researchers wrote. Post-hoc analyses are those specified and performed after a trial is complete.

The scientists also estimated thresholds, based on standard disease-relevant tests, that might mark patients who are responding to treatment with Tegsedi.

The study, “The impact of inotersen on Neuropathy Impairment Score in patients with hereditary transthyretin amyloidosis with polyneuropathy,” was published in the journal BMC Neurology.

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Trial findings in patients grouped by disease stage, other characteristics

FAP is a rare disorder caused by mutations in the TTR gene, which lead to the production of an abnormal transthyretin (TTR) protein. The TTR protein accumulates mainly in peripheral nerves — those found outside the brain and spinal cord — interfering with their function.

Tegsedi, developed by Ionis Pharmaceuticals, is designed to suppress TRR production in the liver, where the protein is mostly produced.

The Ionis-sponsored Phase 3 NEURO-TTR trial (NCT01737398) investigated Tegsedi’s safety and effectiveness against a placebo in 172 adults with FAP. Both were administered through under-the-skin injections for more than 15 months.

Results showed that Tegsedi significantly delayed nerve cell damage — as assessed with the Neuropathy Impairment Score (NIS) and the NIS-Lower Limbs (NIS-LL) — and improved patients’ quality of life. NIS is a clinician-reported measure of neuropathic disease progression based on an evaluation of the cranial nerves and upper and lower limbs, and NIS-LL is a subset of NIS items that addresses lower-limb function.

Both NIS and NIS-LL include parameters that assess motor weakness, sensation loss, and reflexes, with higher scores indicating poorer neurological function. Cranial nerves affect sensations involved in taste, smell, hearing, and feeling.

However, NIS and NIS-LL changes across patient subgroups, defined by certain clinical characteristics, remain to be assessed. Clinically meaningful changes in NIS or NIS-LL scores also need to be properly established.

To fill this knowledge gap, researchers at Ionis, joined by scientists at the University of Pennsylvania and QualityMetric, conducted a post-hoc analysis of NEURO-TTR trial data.

They analyzed data from 165 participants who received at least one injection of their assigned regimen and were assessed for efficacy at least once. These included 106 patients randomized to Tegsedi and 59 in the placebo group.

At study’s start, there were no significant group differences in patient characteristics or NIS/NIS-LL scores.

Subgroup analyses were done according to patients’ disease stage, type of underlying mutation (V30M, the most common TTR mutation, versus other mutations), age at symptom onset, heart involvement, or previous treatments.

Within each subgroup, Tegsedi-treated patients experienced a significantly smaller increase in NIS and NIS-LL total scores — indicating slower disease progression — than those on a placebo after 15 months of treatment, results showed.

Similar findings were observed for NIS/NIS-LL muscle weakness and NIS sensation subscale scores, as well as for NIS/NIS-LL reflex subscale scores with some, but not all, subgroups.

Responder threshold estimates may help in evaluating people on Tegsedi

Using statistical analyses, the team then estimated responder definition thresholds for the NIS and NIS-LL, as well as for their subscales. These new thresholds meant that patients showing smaller score changes than those estimated to “represent clinically meaningful progression of neuropathic symptoms” were considered responders, the researchers wrote.

Cranial nerve impairment, a part of NIS assessments, was not analyzed due to the small number of patients with these features.

By the study’s end, significantly more Tegsedi-treated patients were deemed responders than those in the placebo group based on score changes in the NIS (72% vs. 37%), and its muscle weakness (72% vs. 40%), and sensation subscales (74% vs. 52%).

Group differences in terms of the reflexes subscale also favored Tegsedi (64% vs. 48%), but they did not reach statistical significance.

The proportion of responders based on changes in the NIS-LL total score also was significantly higher in the Tegsedi group (78% vs. 38%), as well as in the muscle weakness subscale (75% vs. 46%), relative to those on a placebo. No significant group differences were seen for the sensation (74% vs. 60%) or reflexes subscales (71% vs. 56%).

“The recommended RD [responder definition] thresholds for the NIS and NIS-LL total scores (8.1 and 4.7 points, respectively), are much larger than the 2-point RD threshold considered in some previous studies and represent a greater change relative to the range of these scales (3.3% versus 0.8% on the NIS, and 5.3% versus 2.3% on the NIS-LL),” the researchers wrote.

These new thresholds also may be useful in clinical practice, allowing “clinicians to track progression of neuropathic impairments more accurately among their patients” and better judge treatment effectiveness, they added.

Overall, this analysis “supports previous evidence for efficacy of [Tegsedi] in this patient population and provides interpretation guidelines for clinically meaningful changes in NIS/NIS-LL scores,” the researchers concluded.