Inotersen, An Exciting Prospect for hATTR Amyloidosis Treatment

A new hereditary ATTR (hATTR) amyloidosis treatment, inotersen, an investigational antisense drug, may not be far from a US Food and Drug Administration (FDA) approval. Positive phase 3 data released this past March displayed an improvement in quality of life by 50% in patients with the disease, and with no effective treatment available, a lot hangs on the line.

In an effort to learn more about the prospective treatment, Rare Disease Report^® (RDR^®) spoke with Morie A. Gertz, MD, oncologist, internist, hematologist, and chair of Internal Medicine, Minnesota, at Mayo Clinic, to discuss how the impact the treatment could have on the hereditary hATTR patient population and how close it may be to receiving an approval from the FDA.

On July 11, 2018, inotersen was approved in the European Union for the treatment of the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).

Rare Disease Report^® (RDR^®): What is the burden of hATTR amyloidosis? What are the struggles and challenges present for this patient population?

Gertz: The actual worldwide prevalence [of hATTR amyloidosis] is really not known because the disease clusters in certain areas of the world. In the United States, it’s quite sporadic. I think because it’s a difficult diagnosis to make; we don’t have good data on what the true prevalence of the disorder is. Most patients, two-thirds—not all patients though—will present with sensory loss in the lower extremities that will ascend over time.

From a diagnostic standpoint, there will turn out to be a peripheral neuropathy. The issue that comes is that there’s probably 50 different causes of peripheral neuropathy that are more common than hereditary TTR amyloidosis. Consequently, in the patients that are diagnosed, there’s a delay [in diagnosis], on average, [ranging] anywhere from 2 to 3 years—and that’s only for patients who get the diagnosis.

There is probably a significant number of patients who simply aren’t aware. Even when there is a family history, the diagnosis is not made. Sometimes people are misdiagnosed with hereditary neuropathy, but they won’t undergo the screen to recognize this as a type of neuropathy.

A third of the patients present with heart amyloid without much peripheral neuropathy, and again, there are a multitude of causes of heart failure that are unrelated to amyloid, and so it’s an easy diagnosis to overlook. Because it’s so rare, amyloid testing is simply not in the general workflow of cardiologists and neurologists. The necessary testing, whether it’s biopsies for amyloid, is not a general practice, nor is, alternatively, screening the blood for TTR mutations.

The symptoms themselves are very nonspecific. Patients are misdiagnosed as chronic inflammatory demyelinating polyneuropathy and often undergo plasma exchange or intravenous immunoglobulin, which won’t work.

Alternatively, given the high prevalence of diabetes in the United States, there are potentially a fair number of patients who are also diabetic and assume they have diabetic neuropathy. There is a significant unmet need [for education] from a physician’s standpoint and patient recognition standpoint.

RDR^®: Can you discuss inotersen for the treatment of hATTR amyloidosis? What makes it unique in its function?

Gertz: The reality is this treatment is the only one these patients have had that is recognized to be as beneficial as liver transplantation, which is resource intensive and frequently not available in underserved countries. It’s also a very radical undertaking; there’s no changing your mind after you’ve had your liver transplanted. In fact, liver transplant is not always effective in preventing progressive amyloid in nerve damage or amyloid heart damage.

There has been 1 study on the use of an agent called diflunisal, a nonsteroidal agent that has been used, but it’s clear that patients continue to progress and succumb to the disease.

Now, we have an agent that lowers the production of the protein that is ultimately dispositive of amyloid in tissue. I think it’s a big deal; it [inotersen] has a Prescription Drug User Fee Act (PDUFA) date of October 6, 2018, and I think it’s likely this could be approved. This would be a real boom for the hATTR patient population.

Since these trials, like the phase 3, demonstrated met primary endpoints with regards to neurologic disability and quality of life, my hope is that it will be registered and available to patients in the future.

RDR^®: From a clinical standpoint, if inotersen were to reach FDA approval, how would this be clinically significant for the physicians treating these hATTR patients?

Gertz: When there [is] a treatment, it becomes mandatory not to overlook the diagnosis. It is a difficult diagnosis, and I think it’s fair that it’s possible some physicians who don’t see much of amyloidosis think, ‘If I don’t make the diagnosis, it’s not that critical because we don’t have effective therapy for the disease.’

Now that there’s a rising effective therapy, this disease is a not-to-miss diagnosis. I think there’s going to have to be a major educational initiative for a diagnostic evaluation of this disease to get into the walls of the workflow of neurologists and cardiologists in practice. Now, if you miss it, there really is the potential of harming the patient for failing to provide effective therapy.

RDR^®: What do you think more education would look like in terms of spreading the awareness to other physicians?

Gertz: With a disease this rare, it’s not going to be a type of marketing where a medical science liaison would call on a physician’s office because physicians are going to see this once every 10 or 15 years.

My sense is to begin educational symposia at the critical national meetings that neurologists and cardiologists attend in large numbers. There, they can be educated on the prevalence of this problem in practice and how one might incorporate diagnostic scenarios in patients that fit the clinical profile.

I think you have to go where the providers are, and so that means national meetings. For neurologists, I think about the American Academy of Neurology, the American Neurological Association, and the Peripheral Nerve Society. Those platforms role through my mind as places where we want to have summits, corporate sponsor symposia, or ideally, educational sessions about this new treatment and the importance of not missing this diagnosis [if it obtains FDA approval].

It’s similar for cardiology. I think of American Heart, Heart Failure Society of America, and the American Cardiology Association.

Simply, no treatment has been available for these patients before, and so inotersen is an exciting prospect for hATTR patients.

Editor’s Note: This article has been updated on 7/13/2018 at 9:18 AM EST to reflect the recent approval of inotersen for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).