Eplontersen held neuropathy scores steady whatever the starting severity, which is an argument for starting early

Design

Post hoc tertile analysis of the NEURO-TTRansform trial against the NEURO-TTR historical placebo group (NCT04136184)

Population

200 patients with hereditary transthyretin amyloidosis with polyneuropathy, split by baseline Neuropathy Impairment Score into three tertiles of 67, 67 and 66

Primary outcome

Neuropathy impairment (modified NIS+7), quality of life, physical functioning, nutritional status and transthyretin levels at 65-85 weeks

Effect

Mean modified NIS+7 change -4.5, -1.3 and -2.6 points across increasing severity tertiles, all maintained; placebo worsened across outcomes

Hereditary transthyretin amyloidosis with polyneuropathy progresses relentlessly untreated, and the question that decides referrals is whether a patient who already has advanced neuropathy still benefits. This post hoc analysis of NEURO-TTRansform split its patients into tertiles by baseline Neuropathy Impairment Score - least impaired 3.5 to under 27.5 (n=67), middle 27.5 to under 55.0 (n=67), most impaired 55.0 to 127.8 (n=66) - and compared each against the NEURO-TTR historical placebo.

Over 85 weeks, mean modified NIS+7 composite scores were maintained in all three tertiles, changing by -4.5, -1.3 and -2.6 points respectively, where negative indicates improvement on this scale. Quality of life, physical functioning, nutritional status and transthyretin levels were similarly maintained or improved across tertiles. Patients on placebo worsened across outcomes. Unsurprisingly, the least-impaired tertile had better absolute scores throughout.

That is the point, and it needs stating carefully. Benefit was consistent across severity, but the level at which a patient is held is the level they started at. Treatment stops the decline; it does not restore what has already gone. So the argument is not that late treatment fails - it is that late treatment locks in a worse baseline, permanently.

The comparison is against a historical placebo group from a different trial, not a concurrent one, and this is a post hoc analysis of tertiles rather than a prespecified comparison. Both weaken it. But the practical instruction is unaffected and applies immediately: when a patient with a family history or a suggestive progressive neuropathy is under investigation, do not wait for disability to accumulate before completing genetic testing and referring. In India, where diagnosis of hereditary transthyretin amyloidosis is frequently delayed by years, that delay is the modifiable variable.

• Test for transthyretin variants early in progressive neuropathy with autonomic features or a family history
• Refer at diagnosis - benefit is maintenance of function, so the baseline you preserve is the one you have
• Ask about carpal tunnel surgery, cardiac symptoms and gastrointestinal disturbance: the phenotype is systemic
• Do not use advanced neuropathy as a reason to withhold treatment; all severity tertiles were maintained
• Note the comparison is with a historical placebo, not a concurrent control arm

The statistics, in plain English

Changes of -4.5, -1.3 and -2.6 points on the modified NIS+7 are small movements in either direction, and the meaningful comparison is not with zero but with the historical placebo group, which deteriorated. That comparison is the weak link: placebo patients came from a different trial at a different time, so any difference in enrolment or care between the two studies is confounded with the treatment effect. Tertile analyses are also post hoc, meaning the cut-points were chosen after the data existed, and each tertile of about 66 patients is small enough that a few individuals move the mean.

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