Report from the 2018 International Symposium on Amyloidosis

This past month, ARC CEO Isabelle Lousada headed to the International Symposium on Amyloidosis (ISA) in Kumamoto, Japan. The meeting has grown significantly over the past decade with over 750 attendees from 39 countries this year. Attendees from the amyloidosis community included; basic and translational researchers, academics, clinicians, leaders from patient organizations and pharmaceutical company representatives.

Traditionally the focus of this meeting has been on amyloidosis research. This year was noticeably different because, for the first time, there are multiple treatments in development for both AL and ATTR amyloidosis and, as a result, much of the focus this year was directed toward these treatments and evaluating the evolving treatment landscape.

Here is an overview from the presentations:

ATTR Landscape

Dr. Mathew Maurer, from Columbia University, gave a great overview of the ATTR landscape. The most significant advances since the last ISA meeting held in 2016 were in the ATTR field.  Inotersen (Ionis Pharmaceuticals and Akcea Therapeutics) and Patisiran (Alnylam Pharmaceuticals) both completed their phase 3 registrational trials in hereditary ATTR (hATTR). As previously announced, both trials met their primary efficacy endpoints, with inotersen looking at change in neuropathy and quality of life at 15 months compared to placebo and patisiran looking at change in neuropathy at 18 months compared to placebo.

Inotersen (Ionis Pharmaceuticals/Akcea Therapeutics)

Inotersen is an antisense therapy, which is designed to bind to a mRNA molecule that contains the genetic information for building the protein that causes a disease. This is sometimes referred to as “gene silencing” because instead of repairing the faulty gene, it aims to “silence” the gene’s effect. In this case, the antisense drug is silencing the gene responsible for the production of TTR.

In addition to sharing more detail from the original double-blind NEURO-TTR phase 3 trial, results were shared showing that patients who received inotersen in both the NEURO-TTR trial and the open label extension (OLE) study experienced a greater and continued benefit compared to patients who received placebo in the NEURO-TTR trial before crossing over to inotersen treatment in the OLE study. Additionally, patients who initially received placebo in the NEURO-TTR trial experienced rapid onset of benefit upon crossing over to inotersen treatment in the OLE study.

Results from an ongoing investigator-sponsored phase 2 trial in cardiomyopathy patients with hATTR and wild-type ATTR (ATTRwt) showed a reduction in left ventricular mass at 24 months, and a mean improvement from baseline in the 6-minute walk test.

Inotersen has been accepted for priority review by the U.S. Food and Drug Administration (FDA). The FDA has set a Prescription Drug User Fee Act (PDUFA) date of July 6, 2018, by which time the FDA must complete their review of the drug application.

Patisiran (Alnylam Pharmaceuticals)

Patisiran is an investigational RNAi therapy. RNAi is a technology that uses small interfering ribonucleic acid (siRNA) to interfere with and prevent RNA’s ability to produce the TTR protein.

Data presented from the Phase 3 APOLLO trial and Open Label Extension (OLE) study included patients who had received patisiran for up to four years. These patients showed sustained benefit in neuropathy. Patients who had originally received placebo in the APOLLO trial showed progression until crossing over to patisiran in the OLE and then showed stabilization.

56% of APOLLO patients who were included in a pre-defined cardiac subpopulation demonstrated that there were improvements in cardiac structure and function at 18 months.

Patisiran has been accepted for priority review by the FDA and the PDUFA date has been set for August 11, 2018, by which time the FDA must complete their review of the drug application.

Tafamidis (Pfizer)

Tafamidis is a transthyretin (TTR) stabilizer. The results of the phase 3 trial (ATTR-ACT), evaluating tafamidis in patients with hATTR and wtATTR cardiomyopathy, were announced moments after the close of the meeting. Pfizer’s press release stated the trial had successfully met its primary endpoint, achieving a statistically significant reduction in the combination of all-cause mortality and frequency of cardiovascular-related hospitalizations.

AL landscape

Dr. Angela Dispenzieri of the Mayo Clinic and Dr. Giampaolo Merlini of Fondazione IRCCS Policlinico San Matteo gave keynote talks about AL amyloidosis. Dr. Merlini shared details of the growing knowledge around the mechanism of disease and said, “In the near future the treatment of systemic amyloidosis will include the combination of agents targeting critical steps of the amyloid cascade.” Dr. Dispenzieri presented a comprehensive view of the landscape of novel therapies for AL. These included:

Daratumumab (Janssen)

Daratumumab, which is an anti-CD38 antibody approved for myeloma, showed impressive results in two phase 2 trials achieving hematologic response in patients who had received an average of three prior treatments. There is an ongoing multi-center phase 3 trial in newly diagnosed AL patients evaluating daratumumab plus cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared with CyBorD alone. The trial is currently enrolling, and patient involvement is expected to last 8 years.

NEOD001 (Prothena)

Results from the phase 1/2 trial of NEOD001 showed the therapy to be safe and well tolerated. Over half the patients with cardiac, renal or peripheral neuropathy responded to treatment and had improved function. The results from the phase 2b trial PRONTO in patients who had previously received therapy, with partial or better response and with persistent cardiac dysfunction, will be announced later this year. The VITAL phase 3 trial in treatment naive patients with a confirmed diagnosis of AL amyloidosis and cardiac involvement is ongoing. NEOD001 is also being tested in the ongoing RAIN trial sponsored by Tufts Medical Center, which is assessing the efficacy and safety of NEOD001 in AL patients who have achieved a stable hematologic response to prior therapy but still exhibit persistent kidney disease.

UPDATE April 23, 2018: Prothena is discontinuing development of NEOD001 for AL Amyloidosis based on negative results from the Phase 2b PRONTO study and a futility analysis of the Phase 3 VITAL study. Full press release here.


Retrospective outcomes of adding doxycycline to standard chemotherapy in 30 patients with cardiac AL amyloidosis were compared to 73 matched controls (cardiac, disease stage, nt-proBNP, age, dFLC.). 94% of patients had Mayo stage III disease. The results showed an encouraging impact of adding doxycycline to standard chemotherapy on early mortality in cardiac AL amyloidosis.

CPHPC + Anti-SAP antibodies

CPHPC + Anti-SAP antibodies has been studied in a small number of patients and has shown evidence of change in amyloid load. A phase 2 trial has been planned and is aiming to confirm clinical efficacy and patient benefit.


Venetoclax is a plasma cell directed therapy which induces cell death in MM cell lines. It has been shown to be successful in multiple myeloma. Data was shared on a patient who had a partial response to CyBorD therapy. The addition of venetoclax to bortezomib and dexamethasone made it possible to achieve a complete response.  Further studies are being done.


Data was shown on the open-label, dose-escalation phase 1 a/b trial of an amyloid-fibril reactive monoclonal antibody IgG1k 11-1F4 (CAEL-101) in for patients with relapsed or refractory AL amyloidosis. 24 patients were evaluable for a response. 67% (12 out of 18) of patients with a cardio/renal involvement showed a response, and 3 patients with involvement of other organs also showed response. Data from the trial showed treatment with CAEL-101 was safe, well tolerated, and clinically efficacious. CAEL-101 will move forward in a planned multicenter phase 2 SWOG trial and future industry-sponsored phase 3 trial.


EGCG was studied in patients with cardiac AL amyloidosis in a randomized, placebo-controlled clinical trial of GERAMY (TAME-AL). The results showed no significant difference between the two groups.

To learn more about open clinical trials and to see if you may be a match, you can sign up for ARC’s My Amyloidosis Pathfinder here:

Moving toward earlier diagnosis

There is consensus among the community that amyloidosis is massively underdiagnosed, and for many patients diagnosis can take many years. At the meeting, ARC presented data from our cardiac patient study that looked at the patient’s journey to diagnosis. One of the highlighted findings from the study showed 36% of patients with cardiac involvement had previously been diagnosed with carpal tunnel, yet 43% of patients reported 6 or more years between their diagnosis of carpal tunnel and their diagnosis of amyloidosis. Additional presentations at the meeting highlighted possible other early indicators of amyloidosis including stenosis. This is an area where there will be an increasing amount of focus. There was also a lot of discussion around women with wtATTR not being diagnosed, noting that around 96% of patients in the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry with wtATTR are male. All of these factors reiterate the great need to improve diagnostic tools to help ensure earlier diagnosis.

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