Here’s something you don’t hear every day: A Phase 3 trial met both of its primary endpoints and halted disease progression. Those were the top-line results released by Ionis Pharmaceuticals on May 15. The NEURO-TTR trial is testing the antisense oligonucleotide therapy IONIS-TTRRx in people with familial amyloid neuropathy (FAP), a fatal disease caused by aggregation of the transthyretin protein. Alas, a shadow was cast over these otherwise rosy results by seven cases of severe side effects, including kidney malfunction, perilously low platelet counts, and a death due to intracerebral hemorrhage. In response, Ionis and co-sponsor Glaxo-Smith Kline stepped up monitoring efforts they claim will prevent these problems from recurring. If successful, the drug could be a boon to patients who suffer from this devastating disease. Complete results of the trial will be released in coming months.

Transthyretin (TTR) amyloidosis is a rare disorder in which the TTR protein forms amyloid fibrils that accumulate in peripheral nerves, the heart, and other organs throughout the body. Patients suffer progressive neuropathy, lose their ability to move (referred to as FAP when those are the primary symptoms) and can develop cardiac myopathy (called familial amyloid cardiomyopathy or FAC when cardiac symptoms predominate). TTR mutations can trigger the disease, but it can also occur without mutations. Because TTR is expressed primarily in the liver, transplant is one treatment option, although this procedure brings its own risks. Another drug—diflusinal—stabilizes nontoxic tetramers of TTR and slows disease progression in many patients. It is marketed by Pfizer as Tafamidis, and is approved in 37 countries, but not the United States (see Bulawa et al., 2012). 

Ionis applied its signature antisense oligonucleotide (ASO) approach to knock down TTR expression in FAP patients. This strategy—which uses short oligonucleotides to target RNA sequences for destruction—recently proved successful in the treatment of spinal muscular atrophy (SMA) (see Nov 2016 news). A direct competitor to IONIS-TTRRx is Alnylam Pharmaceuticals’ Patisiran, an RNA interference-based drug also about to complete Phase 3 trials.

The NEURO-TTR study enrolled 172 FAP patients in Stage 1 or 2 of the disease. According to Brett Monia, senior vice president of drug discovery at Ionis, Stage 1 patients have difficulty walking, while Stage 2 patients usually cannot walk independently, are in pain, and may have many other ailments including diarrhea and cardiac issues. The disease strikes young, often when people are in their 30s or 40s, and progresses rapidly. Patients typically move from Stage 1 to Stage 2 within a couple of years, and from Stage 2 to being bedridden within a similar amount of time, Monia said. Ultimately, many patients die from waning organ functions, including renal failure due to amyloid accumulation in the kidneys, he told Alzforum. Participants in the NEURO-TTR study were randomized 2:1 to treatment and placebo groups, respectively. They received weekly subcutaneous injections of 300mg IONIS-TTRRx or placebo for 15 months.

Co-primary endpoints were changes in baseline scores of the modified Neuropathy Impairment Score +7 (mNIMS+7) and the Norfolk Quality of Life Diabetic Neuropathy questionnaire. The NIMS+7 is a composite measure of nerve function, muscle strength, pain, and other neurological functions. Healthy people have a score of zero, while Stage 1 FAP patients typically score between 60 to 80 points and people in Stage 2 score around 100, Monia said. The Norfolk test takes stock of overall quality of life, which in FAP plummets not only because of loss of mobility, but also myriad other factors such as gastrointestinal problems and depression. The drug had highly significant effects on both measures—stabilizing scores in many patients and improving them in some others, Monia told Alzforum.

Eighty-one percent of participants completed the 15-month trial, and of those, 95 percent chose to continue receiving treatment in an ongoing open-label extension study. That the vast majority of trial completers opted for the extension speaks to the effectiveness and tolerability of IONIS-TTRRx, Ionis founder and CEO Stanley Crooke told reporters during a webcast.

However, three patients in the treatment group developed extreme thrombocytopenia, a drop in platelet count. One of them, at a study site in Argentina, died of an intracerebral hemorrhage. Four others in the treatment group dropped out due to renal problems, including one who developed chronic renal insufficiency, though one patient in the placebo group also discontinued due to renal malfunctions.

How might the ASO have brought about these side effects? On March 6, Ionis reported that dangerously low platelet counts forced five patients out of the company’s Phase 3 trial of volanesorsen, an ASO that targets the AOEC-III gene for treatment of familial chylomicronemia syndrome, but claimed that was due to reduced levels of triglycerides. Monia said that because platelet loss did not occur in trials of other ASOs the company has tested for other targets, thrombocytopenia was unlikely a general effect of the ASO strategy. He said that among the patients with thrombocytopenia in the NEURO-TTR study, anti-platelet antibodies were detected, suggesting that the drug somehow triggered an immune response to platelets in these patients. Why this would occur is unclear, he said. He attributed the intracerebral hemorrhage to a combination of the platelet drop along with amyloidosis in the patient’s brain resulting from FAP.

The renal problems, as well, could be a combination of drug and disease, Monia said. As amyloid build-up in the kidneys of people with FAP reduces renal function, it is possible some patients became unable to clear the drug efficiently, which may have exacerbated renal malfunction, he speculated. Another commentator raised the possibility of on-target effects, proposing that a loss of TTR function may have influenced platelets or renal function via an unknown mechanism.

In response to these problems, Ionis initiated weekly platelet counts and urinalysis to measure kidney function and since then, no further serious renal or platelet issues have popped up. The researchers hope this monitoring will nip the symptoms in the bud.

But will multicenter trials pull off such rigorous monitoring? On March 20, the FDA sent a warning letter to Merrill Benson of Indiana University, an investigator heading a Phase 2 trial of IONIS-TTRRx in patients with FAC. According to an FDA inspection, clinicians failed to measure platelets for two weeks in some patients during this investigator-led study. Patients in this trial did not have sufficient neuropathy symptoms to qualify for Ionis’s NEURO-TTR study, so Benson was treating them as part of a cardiac study, Monia said. Despite the warning, the FDA did not halt Benson’s study.

The platelet and renal problems that beset the Neuro-TTRRx study also stymied the initiation of a proposed Phase 3 study for people with FAC. In response to the adverse events reported earlier in the FAP study, the FDA slapped a clinical hold on the cardiac study before it began in April 2016, to allow Glaxo-Smith Kline to address those safety concerns before moving forward. However, the following month, GSK opted not to continue with the cardiac trial until more data was gathered from ongoing studies.

TTR amyloidosis is but one of many diseases Ionis is targeting with ASOs. Its ASO therapies are in various stages of development to suppress huntingtin, SOD1, C9orf72, and tau (see May 2013 newsJun 2012 newsNov 2015 news; and Jan 2017 news).—Jessica Shugart


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News Citations

  1. Positive Trials of Spinal Muscular Atrophy Bode Well for Antisense Approach
  2. Paper Alert: Antisense Oligonucleotide Therapy Safe for ALS?
  3. “Huntingtin Holiday” Helps Mice Back to Health
  4. Listen Up, Gene Silencing Strikes a Chord at RNA Meeting
  5. Antisense Oligos Tango with Tau Transcripts to Reverse Tauopathy

Paper Citations

  1. . Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9629-34. Epub 2012 May 29 PubMed.

External Citations

  2. reported 
  3. warning letter
  4. FDA slapped a clinical hold

Further Reading

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