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Information on amyloidosis is provided for informational purposes only and is not intended to be medical advice. Information concerning medical care or the suitability or use of any medication should be discussed with a medical doctor. Any information on specific treatment protocols in not an endorsement of said product.


FDA Approves Two Treatments for hATTR Amyloidosis in 2018

FDA Approves Two Treatments for hATTR Amyloidosis in 2018

 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.

 


FDA Approves Second Treatment for Hereditary Amyloidosis (hATTR)

FDA Approves Second Treatment for Hereditary Amyloidosis (hATTR)

Akcea Therapeutics, Inc., an affiliate of Ionis Pharmaceuticals, Inc., announced today that the U.S. Food and Drug Administration (FDA) has approved TEGSEDI (inotersen) for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. TEGSEDI is now approved in the U.S., European Union and Canada.

TEGSEDI powerfully reduces the production of TTR protein through a once-weekly subcutaneous injection offering patients an effective treatment for people living with polyneuropathy caused by hATTR amyloidosis.

In hATTR amyloidosis, transthyretin (TTR) protein misfolds and accumulates as amyloid deposits throughout the body. TEGSEDI targets the disease at its source by reducing the production of TTR protein.

Read the entire press release here.


Alnylam Receives Approval of ONPATTRO™ (patisiran) in Europe

Alnylam Receives Approval of ONPATTRO™ (patisiran) in Europe

Alnylam Pharmaceuticals, Inc, announced recently that the European Commission (EC) has granted marketing authorization for ONPATTRO (patisiran) for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis in adults with stage 1 or stage 2 polyneuropathy. ONPATTRO is the first-ever RNA interference (RNAi) therapeutic to be approved in the European Union.

Read the press release here.


New Results for Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy

New Results for Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy

Earlier this week at the European Society of Cardiology Congress in Munich, Germany, Pfizer announced that in patients with transthyretin amyloid cardiomyopathy, Tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life.

Read the entire press release here.


The Assistance Fund Announces New Hereditary Amyloidosis Financial Assistance Program

The Assistance Fund Announces New Hereditary Amyloidosis Financial Assistance Program

The Assistance Fund, an independent charitable patient assistance foundation, recently launched a new fund to support hereditary amyloidosis patients. This type of amyloidosis is one of the systemic amyloidosis diseases that are caused by inheriting a gene mutation.

“Finally, patients have hope for treating this disease,” said Mary O’Donnell, President and CEO of the Amyloidosis Foundation. “The Assistance Fund’s financial assistance program for hereditary (hATTR) amyloidosis will provide extremely important support for patients who may otherwise be unable to seek treatment due to high out-of-pocket costs.”

They provide financial assistance for medication copays, health insurance premiums, and basic healthcare needs to patients with certain disease types.

For more information, call (855) 512-2801.

Read the entire press release here.

To apply for assistance, click here.

 


Akcea and Ionis Announce Approval of TEGSEDI™ (inotersen) in the European Union

Akcea and Ionis Announce Approval of TEGSEDI™ (inotersen) in the European Union

TEGSEDI™ (inotersen) has received marketing authorization approval from the European Commission (EC) for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).

TEGSEDI™ is now the world’s first and only RNA-targeted therapeutic approved for patients with hATTR amyloidosis. This drug brings significant benefits in both measures of neuropathy and quality of life for people living with this rare disease.

Read the complete press release here.


Combination Therapy Holds Promise for Newly Diagnosed AL Amyloidosis Patients

Combination Therapy Holds Promise for Newly Diagnosed AL Amyloidosis Patients

Updated research regarding the ANDROMEDA study indicated the efficacy of subcutaneous daratumumab and cyclophosphamide, bortezomib, and dexamethasone (CyBorD) as a combination therapy in newly diagnosed light chain AL amyloidosis patients.

“The ANDROMEDA trial, [daratumumab is] being used in a novel way because the preparation of daratumumab is being given subcutaneously and not intravenously,” said Ray Comenzo, MD, professor at Tufts University School of Medicine. “This is a big deal for patients with systemic AL amyloidosis because these patients often have some degree of cardiac compromise, therefore, getting IV infusions can be challenging for them.”

“If daratumumab and CyBorD work better together than alone, we have a new standard of therapy for patients with light chain amyloidosis,” Dr Comenzo stressed. “It’s a very exciting prospect for the newly diagnosed amyloid patients of the future to potentially have a combination of 4 drugs that are safe, and that are almost 100% effective. That is what we expect; we expect many patients to be treated and to recover.”

Watch the video interview here.


Alnylam Receives Orphan Drug Destination from FDA to Treat ATTR Amyloidosis

Alnylam Receives Orphan Drug Destination from FDA to Treat ATTR Amyloidosis

Alnylam Pharmaceuticals, Inc. announced today that the FDA has granted Orphan Drug Designation to ALN-TTRsc02. This drug has the potential to be a once-quarterly, low volume, subcutaneously administered RNAi medication in the management of ATTR amyloidosis.

The FDA 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.

The European Commission also recently issued the decision to adopt the opinion of the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) and designate ALN-TTRsc02 as an orphan medicinal product in the European Union (EU) for the treatment of transthyretin-mediated amyloidosis.

Read the press release here.


Inotersen for hATTR Amyloidosis Received Positive Opinion by CHMP in Europe

Inotersen for hATTR Amyloidosis Received Positive Opinion by CHMP in Europe

The Akcea Team announced that the Committee for Medicinal Products for Human Use (CHMP) of the Eurpoean Medicines Agency (EMA) adopted a postive opinion recommending approval of TEGSEDI (inotersen) for the treatment of state 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).

From here, the positive opinion will be referred to the European Commission (EC), which grants marketing authorization for medicines in the European Union, as well as to European Economic Area members Iceland, Liechtenstein and Norway.

Click here for the press release.

 


FDA Grants Breakthrough Therapy Designation for Tafamidis

FDA Grants Breakthrough Therapy Designation for Tafamidis

Pfizer recently announced that tafamidis, its investigational therapy for the treatment of patients with, transthyretin (TTR) cardiomyopathy, received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA).

This decision is supported by topline results from the tafamidis Phase 3 Transthyretin Cardiomyopathy (ATTR-ACT) study, in which tafamidis demonstrated a statistically significant reduction in the combination of all-cause mortality and frequency of cardiovascular-related hospitalizations.

As defined by the FDA, a breakthrough therapy is a drug intended to be used alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies. If a drug is designated as a breakthrough therapy, the FDA may expedite the development and review of such drug.

In patients with this disease, TTR breaks up and may form fibrils called amyloid. Amyloid can build up around your nerves and in other places in your body, preventing them from working normally. Eventually, the amyloid causes the symptoms of this disease.

Click here for the press release.