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Two different oligonucleotide drugs to treat hereditary transthyretin amyloidosis with polyneuropathy succeeded in phase III randomized, double-blind, controlled trials, according to results published in the New England Journal of Medicine.

Over 18 months, designed to reduce mutant and wild-type transthyretin production, improved neurological impairment and clinical manifestations of hereditary transthyretin amyloidosis over 18 months, reported David Adams, MD, PhD, of Bicêtre Hospital, France, and colleagues for the .

And over 15 months, of transthyretin protein production, bettered the neurologic disease course and quality of life in patients with stage 1 or stage 2 hereditary transthyretin amyloidosis, according to results of the from Teresa Coelho, MD, of Centro Hospitalar do Porto in Portugal and co-authors.

Formerly known as familial amyloid polyneuropathy, hereditary transthyretin amyloidosis is a rare, rapidly progressive disease caused by a mutation in the TTR gene that results in the buildup of misfolded transthyretin protein, leading to amyloid deposits in the heart, gastrointestinal tract, and peripheral nerves. Life expectancy of patients is about 3 to 15 years after the onset of neuropathy, less in patients who have cardiomyopathy.

The liver is the primary source of systemic transthyretin protein and liver transplantation is a treatment for the disease, with limited effectiveness. Other options include transthyretin stabilizers tafamidis (Vyndaqel), available in European and other countries but not the U.S., and diflunisal, a non-steroidal anti-inflammatory drug (NSAID).

Patisiran is the most advanced drug that works via , meaning that it's intended to target and silence specific messenger RNA, potentially blocking the production of transthyretin protein before it is made. Inotersen works somewhat differently, binding to the TTR messenger RNA (mRNA) and causing its degradation. For both agents, the end result is to lower transthyretin levels.

These trials build on earlier studies showing that "TTR-specific oligonucleotides, as either small interfering RNA (patisiran) or 'antisense' (inotersen) constructs, can reduce levels of TTR messenger RNA, the amount of transthyretin synthesized, the serum concentrations of transthyretin, and presumably the amount of misfolded monomer available to aggregate and form deposits," wrote Joel Buxbaum, MD, of Scripps Research Institute in La Jolla, California, in an .

These results, plus observations of patients who received liver transplants and other interventions, show only 56% of patients, at best, had a response to any treatment, Buxbaum observed. And while both trials showed significant drops in serum levels of transthyretin -- patisiran achieved a mean reduction of 81% and inotersen lowered serum concentration by 71% -- that may not be enough to achieve a more robust tissue response, he suggested.

Nonetheless, these trials "represent a landmark: together, they show that the rate of progression of a peripheral neurologic disease can be slowed, and perhaps ameliorated, through the use of oligonucleotide drugs that are administered systemically," Buxbaum wrote.

The primary endpoint in both drug trials was the change in mean modified Neurologic Impairment Score + 7 (mNIS+7), an assessment of nerve conduction, muscle weakness, reflexes, autonomic function, and sensation. Higher scores indicate more impairment, and a 2-point change in mNIS+7 is considered clinically meaningful.

Trial Details

In the patisiran trial, researchers randomly assigned 225 patients to patisiran infusions (n=148) or placebo (n=77), administering 0.3 mg/kg of patisiran once every 3 weeks for 18 months to the treatment group. Most patisiran patients (93.2%) completed the study, but 29% of placebo patients withdrew due to disease progression.

At baseline, mean mNIS+7 was 80.9 in the patisiran group and 74.6 in the placebo group. At 18 months, placebo patients had a mean increase in mNIS+7 of 28 points, while the treatment group demonstrated a drop of 6.0 points (difference, −34.0 points; P<0.001). Approximately 20% of patisiran patients and 10% of placebo patients had mild or moderate infusion-related reactions; adverse events were similar in the two groups. Death occurred among 5% of patients in the patisiran group and 8% in the placebo group, primarily cardiovascular-related and consistent with expected disease progression.

In the inotersen study, researchers randomly assigned 172 patients to receive weekly self-administered subcutaneous injections of 300 mg inotersen (n=112) or placebo (n=60) for 15 months. At 66 weeks, the least-squares mean change in mNIS+7 from baseline between the two groups was -19.7 points (P<0.001), favoring inotersen. These improvements were independent of disease stage, mutation type, or cardiomyopathy presence.

Five deaths occurred in the inotersen group, and none in the placebo group. The most frequent serious adverse events among inotersen patients were glomerulonephritis (3%) and thrombocytopenia (3%), including one fatal intracranial hemorrhage. The mechanism of thrombocytopenia in patients receiving inotersen was unknown.

Coelho and colleagues said the deaths with inotersen were a concern, but it's unclear to what extent the drug was responsible. "We cannot be sure whether this imbalance was due to acceleration of the underlying disease in some cases, the play of chance, or some other cause," they wrote. The researchers said they implemented "enhanced monitoring" for thrombocytopenia and glomerulonephritis after these events were noted, with no further severe cases developing.

Patisiran is under FDA priority review as a breakthrough therapy, , with an FDA decision date of August 11. The FDA recently extended its deadline to decide on inotersen, which also has breakthrough designation, to October 6, , an affiliate of Ionis Pharmaceuticals.