Considerations and Opportunities With Approval of Eplontersen for Hereditary ATTR Polyneuropathy


Sami Khella, MD, professor of clinical neurology at the Perelman School of Medicine at the University of Pennsylvania School of Medicine, shared his reaction to the approval of eplontersen for the treatment of hereditary transthyretin-mediated amyloid polyneuropathy.

Sami Khella, MD, chief in the department of neurology at Penn Presbyterian Medical Center at the University of Pennsylvania School of Medicine

Sami Khella, MD

Eplontersen (Ionis, AstraZeneca), formerly known as IONIS-TTR-LRX, is designed to reduce the production of serum transthyretin (TTR) protein at its source in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN). After years of clinical development, the FDA approved eplontersen, a ligand-conjugated antisense oligonucleotide, as a new treatment for adult patients with ATTRv-PN.1 Approved under the market name Wainua, the therapy can be self-administered via an autoinjector and will be available in the U.S. starting in January 2024.1

Interim data from the phase 3 NEURO-TTRansform trial (NCT04136184) was the basis for the approval, with results indicating that eplontersen reduced serum TTR at 35 weeks. NEURO-TTRansform randomly assigned patients 6:1 to eplontersen (n = 144) or inotersen (Tegsedi), AstraZeneca’s previously approved therapy for hATTR, for a 66-week double-blind period, followed by an open-label extension. After 35 weeks of treatment, investigators observed a least square mean percent reduction of 81.2% in serum TTR, compared with a 14.8% reduction for those on placebo group (P <.0001). Also of note, the treatment resulted in reductions in neuropathy impairment and improvements in quality of life compared with placebo.

Following the news, principal investigator Sami Khella, MD, chief in the department of neurology at Penn Presbyterian Medical Center at the University of Pennsylvania School of Medicine, shared his immediate reaction with NeurologyLive®. In addition, he talked about how this approval can change the landscape of care for patients with ATTRv-PN. Khella, who also serves as a professor of clinical neurology at the Perelman School of Medicine, spoke about the considerations physicians should keep in mind when prescribing as well as how this approval might influence future development and accessibility of therapies for this condition.

NeurologyLive: What was your immediate reaction to this FDA approval?

It's appropriate. Eplontersen reached its primary end point in the trial and when compared with historical placebo control from the phase 2/3 NEURO-TTR trial, originally. It also reached its secondary end points, and it was safe and well tolerated by patients. So, those are the criteria that I believe are meaningful to patients and it's very exciting.

How do you think this approval will change the landscape of care for patients? Do you see any positive downstream effects of this for future drug development?

For sure. First, it is another treatment modality and another choice for patients if they are unable to tolerate one of the already approved drugs. This is yet another alternative, which is always wonderful. I think it's good to have competition in the marketplace. Hopefully, the price of these very expensive drugs will come down and that will also be good for patients. I think that having this drug available now will be yet another treatment that we can use to add on therapy perhaps in the future with new drugs that have different mechanisms of action. That's another aspect in terms of the future landscape for the treatment of this really devastating, often fatal disease.

Are there any considerations that physicians should take when prescribing this therapy to patients, in terms of interest in adverse events or monitoring?

For new molecules and new drugs, one always has to be vigilant because you need a very large number of patients to detect small adverse effects. Until thousands of patients have taken a drug, even already FDA approved therapies, you probably need more than 150,000 patients before you can really say, “Oh, this molecule is really safe.” The alternative is that if you're too worried about that for this disease, and withhold it because of a theoretical consideration like that, you're liable to do your patient more harm than good. While we must be vigilant, for right now I wouldn't hold back and would use a new drug like this.

I think the other consideration from a physician's point of view is how easy is it to get this drug to a patient. It's one thing for a drug to be approved, it's another thing for it to be approved by not only by the regulatory authorities but also the insurance companies. Especially pharmacies and all the middle people that are involved in getting a drug from the manufacturer to the patient. I think that's also an important consideration and hopefully, it will be relatively easy and straightforward to get this drug to a patient.

Is there anything else you think is important for the clinical community to know about this treatment or you thought was notable in the results from the clinical trials?

I think for the treating community the important thing is that this is a drug that's available for patients with amyloid polyneuropathy in the United States. The most common form of hereditary amyloidosis is the V122I variant that primarily affects nearly exclusively African Americans, and that is primarily a cardiomyopathy and not a peripheral neuropathy illness. I would advise the cardiologists primarily who see patients with cardiomyopathy to be aware of the presence of a peripheral nerve neuropathy in their patients as it occurs in about 10% to 20% of these patients. To be aware of that neuropathy and to look for that neuropathy, because that will then avail that patient, if it's appropriate, to this new drug and to the current drugs that are already available on the market.

The only other thing I would say is to address also the orthopedic surgeons because they see patients with carpal tunnel syndrome which may predate the onset of amyloidosis in a small but measurable percentage of patients. Orthopedic surgeons also need to be aware that this is potentially a disease in their patients that they must consider when they see patients with carpal tunnel syndrome, which is a very common problem.

Transcript edited for clarity.

1. WAINUA™ (eplontersen) granted regulatory approval in the U.S. for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis. News Release. Ionis Pharmaceuticals. Published December 21, 2023. Accessed December 22, 2023.
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