New Agents Show Promise for Severe and Fatal Genetic Disease

Batya Swift Yasgur, MA, LSW

July 10, 2018

Two new agents — inotersen and patisiran — each show promise in the treatment hereditary transthyretin amyloidosis (hATTR), results of two trials suggest.

In the NEURO-TTR trial, investigators randomly assigned patients with stage 1 or stage 2 hATTR to receive weekly injections of inotersen or placebo for 15 months.

Half of participants showed improvements in quality of life, and over a third showed improvements in neuropathic disease progression compared with those receiving placebo.

"Results from the NEURO-TTR study demonstrated that patients treated with inotersen, a once-weekly, subcutaneous injection, experienced early and highly significant benefit compared with placebo in both co-primary endpoints: neuropathy, as well as quality of life," senior author Teresa Coelho, MD, neurologist and neurophysiologist, Santo António-Centro Hospitalar do Porto, Portugal, told Medscape Medical News.

The APOLLO trial compared patisiran with placebo in patients with hATTR with polyneuropathy. Treatments were offered once every 3 weeks via intravenous injection for 18 months.

Participants showed improvements in multiple disease manifestations, including neuropathic impairment, quality of life, and gait speed, with only mild or moderate infusion-related adverse reactions.

"The study [finding] is positive," lead author David Adams, MD, PhD, head, Department of Neurology, CHU de Bicêtre (APHP), France, and coordinator for the French Network for FAP (familial amyloid polyneuropathy), told Medscape Medical News.

"But not only for the first time, patisiran antiamyloid therapy is able to improve polyneuropathy and quality of life at 18 months, compared to baseline, showing reversal of the disease, and efficacy is observed regardless of the stages of the disease," he said.

Both studies were published online July 5 in the New England Journal of Medicine.

Severe and Fatal Disease

hATTR is a severe and rare systemic disorder caused by a mutation in the transthyretin (TTR) gene that results in amyloid deposition in multiple organ systems, resulting in progressive peripheral polyneuropathy, cardiomyopathy, nephropathy, and gastrointestinal dysfunction.

Because the liver is the primary source of systemic transthyretin protein, liver transplantation has historically been the standard of care for hATTR, but its effectiveness is limited, the investigators note.

"hATTR is a severe, rare, and fatal disease which progressively robs people of their quality of life and ability to function independently," said Coelho.

"To date, limited treatment options have been available for patients living with this condition," leading to investigation of new agents, she added.

Inotersen (Tegsedi, Ionis USA) is a 2'-O methoxyethl-modified antisense oligonucleotide inhibitor of the hepatic production of transthyretin protein.

The phase 3 NEURO-TTR trial studied adults (ages 18 to 82 years; mean, 59 years) with stage 1 (patient is still ambulatory) or stage 2 (patient requires assistance with ambulation) hATTR.

After a 6-week screening period, eligible patients were randomly assigned 2:1 to receive 300 mg of inotersen or placebo (n = 112 and n = 60, respectively).

Patients were stratified according to mutation, disease stage, and previous treatment with tafamidis or diflunisal vs no previous treatment.

At baseline, the characteristics were well balanced between the two groups.

During the first week, patients received two subcutaneous injections, followed by once-weekly injections for the next 64 weeks.

The primary endpoints were change from baseline to week 66 in the standardized Neuropathy Impairment Score+7 (mNIS+7) composite score and in the total score on the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire.

Prespecified sensitivity analyses showed a "robust and beneficial inotersen treatment effect under all assumptions."

The differences in least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) for the mNIS+7 and the Norfolk QOL-DN score were −19.7 points (95% confidence interval [CI], −26.4 to −13.0) and −11.7 points (95% CI, −18.3 to −5.1), respectively (both P < .001).

Further analysis of patients who completed the intervention period revealed that 36% of those in the inotersen group showed improvement on the mNIS+7 and 50% showed improvement on the Norfolk QOL-DN scores.

These improvements took place regardless of disease stage, mutation type, or the presence of cardiomyopathy.

The most frequent adverse events in the inotersen group were glomerulonephritis (3%) and thrombocytopenia (3%), with one death associated with a patient with grade 4 thrombocytopenia. After this event, all patients received enhanced monitoring.

"Many hATTR patients, especially those who are younger and more active or juggling families and jobs, will want the option of administering the subcutaneous injection themselves, and the increased flexibility also provides a benefit for centers managing patients further from their clinics," Coelho commented.

"I believe the safety and efficacy profile [of inotersen] will be extremely attractive to all types of hATTR patients," she said.

"Excellent" Safety

"RNA interference (RNAi) is an endogenous mechanism for controlling gene expression," resulting in the cleavage of target messenger RNA (mRNA) by small interfering RNAs bound to the RNA-induced silencing complex, the authors of the APOLLO study write.

Patisiran is a hepatically directed investigational RNAi agent that "harnesses this process to reduce the production of mutant and wild-type transthyretin by targeting the 3' untranslated regions of transthyretin mRNA."

The phase 3 APOLLO trial focused on 225 patients, aged 18 to 85 years, with hATTR with polyneuropathy who were randomly assigned 2:1 to receive intravenous patisiran (n = 148) or placebo (n = 77) for 18 months.

The primary endpoint was change from baseline to 18 months in the mNIS+7.

Secondary endpoints were changes in quality of life (determined by the Norfolk QOL-DN questionnaire), motor strength, disability, and gait speed.

Additional endpoints were nutritional status and patient-reported autonomic symptoms.

Pharmacodynamic biomarkers (transthyretin and vitamin A), measures of cardiac structure and function, and assessment of neuropathy stage were "exploratory endpoints."

Overall, 93% of patients in the patisiran group and 71% in the placebo group completed the trial.

In the patisiran group, the reduction in serum transthyretin levels was rapid and sustained over a period of 18 months, with a median reduction of 81% (range, −38% to 95%), and was similar across age, sex, and genotype.

At baseline, the mean (± standard deviation [SD]) mNIS+7 score in the partisan and placebo groups was 80.9 ± 41.5 and 74.6 ± 37.0, respectively.

At 18 months, the least-squares mean change (± standard error of the mean [SE]) from baseline was −6.0 ± 1.7 vs 28.0 ± 2.6, representing a difference of −34.0 points (P < .001).

At baseline, the mean (±SD) Norfolk QOL-DN scores were 59.6 ± 28.2 in the patisiran group and 55.5 ± 24.3 in the placebo group.

At 18 months, the least-squares mean (±SE) change from baseline was −6.7 ± 1.8 vs 14.4 ± 2.7, representing a difference of −21.1 points (P < .001).

Patisiran also improved gait speed and modified body mass index.

The frequency of severe and serious adverse events was similar in the two groups, with approximately 20% of patisiran and 10% of placebo recipients experiencing mild or moderate infusion-related reactions.

"The safety [of patisiran] is excellent — there were no deaths due to patisiran, only minor or moderate adverse events," Adams commented.

He described a patient in the patisiran group who started out with stage IIIb gait disability (walking with two crutches) and disabling explosive diarrhea that prevented him from having a social life.

"He is now able to walk with only one cane, his balance disorders decreased, he had no more diarrhea, and he gained 4 kg. He began again to hunt and to have projects," Adams reported.

"Landmark" Trials

In an accompanying editorial, Joel N. Buxbaum, MD, professor emeritus, Department of Molecular Medicine, California Campus, Scripps Research Institute, La Jolla, said that although "there remains much work to be done, the trials by Adams et al. and Benson et al. 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."

However, he cautioned, many questions remain.

Moreover, "it is also possible that a combination of interventions would elicit a more pronounced, durable therapeutic effect."

Adams cautioned that polytherapy with patisiran and inotersen "is not indicated."

He noted that although both therapies aim to "knock down TTR production," the mechanisms of action and pharmacokinetics of these agents are different. Patisiran targets only hepatocytes with lipid nanoparticle formulation.

"Patisiran's improvements begin with baseline, and include disease reversal, while inotersen only slows disease progression," Adams said.

Coelho added that 2018 "represents a turning point for people living with hATTR amyloidosis" because "patients are likely to benefit from two new effective options that will hopefully be made available."

The NEURO-TTR trial was funded by Ionis Pharmaceuticals. The APOLLO trial was funded by Alnylam Pharmaceuticals. Adams reports receiving grants from Alnylam while the study was conducted. The other authors' disclosures are listed with the article. Coelho reports receiving nonfinancial support and other support from Ionis during the conduct of the study, as well as personal fees and nonfinancial support from Pfizer and Alnylam and personal fees from GlaxoSmithKline outside the submitted work. The other authors' disclosures are listed with the article. Buxbaum reports being the consulting chief medical officer for Protego Biopharma and receiving personal fees from Arcturus Therapeutics, Eidos Therapeutics, and Intellia.

N Engl J Med. Published online July 5, 2018. NEURO-TTR abstract, APOLLO abstract, Editorial

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