by Frederick L. Ruberg, MD – Boston University, BUMC, Amyloidosis Center

What a momentous Summer of 2018 it has been for transthyretin (ATTR) amyloidosis. First, in July 2018, in the same issue of the New England Journal of Medicine, two different phase 3 clinical trials were reported demonstrating the efficacy of two different pharmaceuticals as treatments for ATTR amyloidosis polyneuropathy. In randomized, double-blinded, placebo-controlled trials, each of these agents showed efficacy in slowing of progression or even improvement of peripheral neuropathy associated with hereditary ATTR (hATTR) amyloidosis.

These trials were accepted as sufficient demonstrations of efficacy to permit the US FDA to approve both patisaran or OnpattroTM (Alnylam Pharmaceuticals) and inotersen or TegsediTM (Ionis/Akcea Therapeutics) as the first treatments for ATTR amyloidosis. Both drugs were approved for hereditary ATTR amyloidosis with evidence of neuropathy. Furthermore, in August, a third phase 3 clinical trial was reported in the New England Journal of Medicine – this one describing the efficacy of yet another medication (tafamidis or VyndaqelTM, Pfizer) but tested in patients with ATTR cardiomyopathy. This trial (ATTR-ACT, Maurer MS et. al, NEJM 2018), in distinction from those above, showed that tafamidis was superior to placebo for survival among patients with congestive heart failure meaning that patients randomized to the drug lived longer than those who were not. FDA has yet to act on approval of this agent, but the community of patients and caregivers with ATTR amyloidosis with cardiomyopathy is eagerly awaiting its decision.

Each of these 3 new drugs acts through different mechanisms to achieve the same clinical objective – that is to arrest or reverse the progression of neuropathy or heart failure associated with ATTR amyloidosis. Thus, we have gone from a disease without pharmaceutical treatment (previously only treated with organ transplantation) to one where we now have 3 effective agents, albeit with different target populations, in a few short months.

Each of these new agents already approved by FDA was done so through accelerated pathways including Fast Track, Priority Review, and Breakthrough Therapy designations. In addition, the drugs have received Orphan Drug designation, which FDA defines as: “The Orphan Drug Designation Program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug.” Cost remains a key sticking point, as now that we have approved drugs, discussions/negotiations are ongoing between sponsors (ie, pharmaceutical companies) and 3rd party payors (insurers) over pricing. As a care provider for patients with ATTR amyloidosis, I am grateful that so many of our partners in industry looked to ATTR amyloidosis as a space in which to develop desperately needed treatments. Further, I think we all can agree that the sponsors which invested great resources in dollars and time should be permitted the opportunity to recover their investment. However, the cost of these new drugs, which would in theory be given for years to decades (i.e., the duration of a patient’s life), must be balanced with the cost to the patient directly, and further the cost to our healthcare system. Such decisions are even more difficult when we are speaking about individuals, with real symptoms, and real disabilities.

Determination of a drug cost naturally considers the numbers of potential patients who can be treated. If more patients can be treated, than the cost per unit can be lower for a similar return. As I noted above, FDA considers hATTR amyloidosis an Orphan disease affecting < 200,000 people at any given time, and while this appears undoubtedly true for hATTR polyneuropathy, is it also true for ATTR cardiomyopathy? A disease is rare because it truly doesn’t affect a large number of people, or it is rare because it is unrecognized. In the case of ATTR amyloidosis cardiomyopathy, which includes both hereditary and wild-type amyloidosis (ATTRwt) the answer is probably a combination of the two.

This October, in the Journal of the American College of Cardiology, a team of cardiologists and orthopedic surgeons at the Cleveland Clinic collaborated on an innovative screening study for amyloidosis. Led by Mazen Hanna, MD (Sperry BW, J Am Coll Cardiol 2018), the investigators looked at sequential patients undergoing carpal tunnel release surgery and analyzed the resected tissue under the microscope for the presence of amyloidosis. Bilateral carpal tunnel syndrome has long been associated with systemic amyloidosis, but up to this point no one has actually examined whether one could use carpal tunnel release surgery as a means to screen for the disease. The authors placed relatively few exclusions on their study population casting the broadest possible net to include all men over age 50 years, all women over age 60 years, and excluded only those with known amyloidosis, prior trauma, or rheumatoid arthritis. Of the 319 surgeries performed over the course of a year, 98 patients were included in the final analysis, and previously unrecognized amyloidosis was found in 10 total (or 10%) patients. As predicted, 100% of patients with amyloidosis had a history of bilateral carpal tunnel syndrome, but so did 83% of those without amyloidosis. What we learned from this important study is that bilateral carpal tunnel syndrome is indeed common in systemic amyloidosis, but it is also common in patients without systemic amyloidosis, so as a clinical filter it is relatively non-specific. But we also learned that unsuspected amyloidosis can be diagnosed with carpal tunnel surgery, and furthermore, amyloidosis in this population may be seen in as many as 1 in 10. Uncommon yes, but not a rare disease. So, if this rate proves accurate in larger populations, there are likely more patients with amyloidosis than currently appreciated. How many is not yet clear. Such data feed directly into the determination of cost for these promising new agents.

Another important aspect of this study is that screening afforded a means to identify patients early in their amyloidosis disease course. In fact, 3 of the 10 identified (1 case of AL amyloidosis, 1 ATTRwt, and 1 hATTR) were given amyloidosis specific therapy. Early identification is critical in any medical disease, but particularly so in the case of systemic amyloidosis where the damage done by amyloid deposits is either slow to reverse (as in the case of neuropathy) or largely irreversible (as in the case of cardiopathy) with currently available treatments. In fact, in the ATTR-ACT trial of tafamidis, those who had less severe congestive heart failure (a marker of earlier disease) did better. Unlike in cancers such as breast or prostate, we have yet to settle upon the best screening approach for amyloidosis to apply to larger populations. In addition, we know that for AL amyloidosis patients often remain undiagnosed for months to years and see many providers before the final diagnosis of amyloidosis is made correctly (Lousada I, Advances in Therapy 2015). The same is likely also true for ATTR amyloidosis. Studies showing therapeutic success in prominent medical journals, FDA approvals, and high-profile screening reports all raise awareness of amyloidosis. These advances all work synergistically to bring amyloidosis onto the clinician’s differential diagnosis when seeing potential new cases. Screening algorithms will definitively involve integration of different modalities of testing and collaboration between providers. It is now our challenge to translate these new discoveries into clinical practice.

Disclosures

Dr. Ruberg acknowledges consulting income from Pfizer and research support from Eidos Therapeutics.