Report from ISA Meeting 2020

A Report from ISA 2020

Every 2 years, amyloidosis researchers and physicians from all around the world engage in a week-long meeting, the International Symposium on Amyloidosis (ISA).

As the field of amyloidosis is rapidly changing, it is so important that experts share new discoveries, study outcomes, and other crucial findings and breakthroughs that have occurred since the last meeting. This year, the meeting was due to be held in March in Tarragona, Spain. Just days before the meeting, the difficult decision was made to postpone the meeting and hold it virtually in September, due to the COVID-19 pandemic. The virtual format allowed for the largest turnout in ISA’s meeting history, with over 1,000 attendees. ARC has provided an overview of this important meeting.

Giampaolo Merlini Award and lecture

In recognition of his outstanding and seminal contributions to amyloidosis, the ISA honored Dr. Giampaolo Merlini with instituting a lecture in his name. Dr. Merlini gave the inaugural lecture on Aiming for the cure of Amyloid Disease. Dr. Merlini set the stage for much of what was to follow at the meeting. He gave both a comprehensive overview of the history of the research field, current standards of care, novel therapies and future needs. Merlini stressed his belief that there is hope to achieve a cure in AL amyloidosis patients, he emphasized that the key to success is:

Early diagnosis
Rapid and deep reduction of amyloid protein (correct misfolding)
Removal of amyloid deposits and elimination of amyloid protein

Dr. Merlini closed by saying, “We have grave concerns about affordability and access to drugs. It is now necessary to develop novel collaborations to tackle these challenges involving all the players from pharma companies, to patient advocacy groups and scientific societies. We need to introduce innovative technologies for better clinical trials….all of this should accelerate the development of novel drugs and reduce the research and development costs” 

Imaging and other non-invasive diagnostic tools

Imaging is a mainstay for detecting cardiac amyloidosis and has potential for monitoring response to therapy. Florbetapir, used for cerebral amyloid, can detect cardiac amyloidosis.

Correct diagnosis of amyloid type remains fundamental.

With improving technology and techniques, invasive biopsies are not always necessary. For example, measurement of NT-ProBNP is an easy test to evaluate for cardiac disease.  There are several new biomarkers that are being investigated for their use for diagnostic purposes, but they lack extensive and external validation.

Another example of a noninvasive diagnostic tool being investigated is an imaging study out of the University of Tennessee led by Dr. Jonathan Wall. Dr. Wall is evaluating the safety and accuracy of an imaging agent on already-diagnosed patients across AL, TTR, and other types of amyloidosis. Early results show promise in detecting amyloid in various organs consistent with the known pattern of the disease. All patients had positive cardiac uptake independent of NT-proBNP levels and symptomology, indicating that this tracer (¹²⁴I-p5+14) may be sensitive enough to detect presymptomatic cardiac amyloidosis in ATTR patients.

We have provided a graphic to aid in understanding the targets of therapies in both diseases.

AL Amyloidosis Landscape 

There has been a recent explosion in the number of companies interested in amyloidosis and advances in development of new drugs for AL amyloidosis. In particular, daratumumab is a key player for this disease. Janssen recently applied for FDA approval for subcutaneous daratumumab for the treatment of AL Amyloidosis. It is currently approved for the treatment of multiple myeloma and trials have shown promise for its use in AL amyloidosis patients. The application is based on data from the phase 3 ANDROMEDA trial which demonstrated the superiority of subcutaneous daratumumab formulation plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD) over CyBorD alone. Results showed that the subcutaneous daratumumab combination resulted in deeper and more rapid hematologic responses, meeting the primary end point of the trial. “Without exaggeration, this is the most significant filing in the modern history of therapeutic developments for patients with AL amyloidosis,” Raymond L. Comenzo, MD, director of the John C. Davis Myeloma and Amyloid Program at Tufts Medical Center, told OncLive in a recent interview.

Bortezomib can further improve the outcome of ASCT both as induction and consolidation therapy by 10%. However, as demonstrated in Dr. Sanchorawala’s study, patients with AL amyloidosis and the presence of t(11;14) have inferior outcomes with respect to hematologic response, overall survival when treated with bortezomib based regimens as first line therapy. Therefore, alternative treatments should be considered when possible in this population.

Ixazomib

Although the primary endpoint of hematologic overall response rate was not met for the TOURMALINE study, Ixazomib induced a more profound, enduring hematologic response leading to significantly better cardiac and renal responses. Considering that the duration of the treatment in the ixazomib/dexamethasone arm was double the physician’s choice therapy arm, ixazomib was generally well-tolerated and may be considered a new option for relapsed/refractory AL amyloidosis.

CAEL-101

Therapy with the investigative therapy, CAEL-101 can lead to durable long-term organ responses as well as excellent overall survival based on the small studies completed thus far in patients with systemic AL Amyloidosis. Trials are underway for more evaluations of this Anti-Amyloid Monoclonal Antibody.

More research is being done on the application of Multiple Myeloma therapies in AL Amyloidosis treatment. This includes melflufen, isatuximab, elotuzumab, and STI-6129.

Translocation (11;14)

T(11;14) Is the most common primary cytogenetic abnormality in AL amyloidosis, and is  associated with lower response to proteasome inhibitors. There was quite a bit of focus on cytogenetics in AL amyloidosis. About 50% of patients with AL amyloidosis have translocation (11;14). This is important to note, as some current and future clinical trials for AL amyloidosis may require participants in the study to have that specific translocation, like the phase 2 study of Venetoclax which is expected to start shortly.

Toxicity of light chains

Light chains and fibrils are thought to be toxic, causing damage to the heart, and this is believed to be a major determinant of survival. Due to the toxicity of light chains an important therapeutic goal should be to preserve the stability of the light chains to stop them forming amyloid fibrils. Work is being done by the Jeffery Kelly group, who developed the stabilizer tafamidis for TTR amyloidosis.

Organ response

A study by Giovanni Palladini shows that organ response strictly depends on quality of hematologic response. This study confirmed that the achievement of negative MRD is associated with organ response that translates into survival. An MRD negative result means that no disease was detected after treatment.

Maintenance therapy

Most in experts agreed maintenance therapy is not usually the preferred path, and instead recommend tracking the light chains regularly and consider treatment if anything changes. They did say the one exception would be Daratumumab since the protocol appeared to be to use it for quite a while. All wanted to see more data before prescribing maintenance and more MRD (minimum residual disease) studies.

Other topics in AL Amyloidosis

• Organ response is needed to achieve peripheral and autonomic neuropathy improvement.
• When patients have had deeper hematologic response at time of stem cell transplant, the overall survival was impressive, over 12-15 years.
• With the recent experience of new drugs, there is optimism for long term-control of the disease.

TTR Amyloidosis Landscape

While the 2018 ISA meeting was focused around the new and exciting TTR amyloidosis treatments coming to market after successful clinical trials, there was much discussion in this meeting on the longer-term use of these drugs and also the real prevalence of both hereditary and wild-type TTR amyloidosis.

Here are some key points made this year:

Trends with specific mutations can help with understanding disease presentation, disease progression and treatment response. Much has been done in specific populations (i.e. Val30Met in Portugal) but there is a need of larger collaborative work with different mutations, phenotype and across different geographical regions.

In the symposium sponsored by Akcea Therapeutics entitled “Hereditary Transthyretin Amyloidosis,” Dr. Teresa Coehelo discussed potential predictors of progression and response to treatment of hereditary TTR amyloidosis and the potential value of the serum biomarker, plasma neurofilament light chain (pNfL). Levels of pNfL have been shown to correlate with disease severity and can establish disease conversion from asymptomatic to early-stage in patients with V30M hATTR.

Dr. Yukio Ando of Japan presented on the clinical features of polyneuropathy of hATTR, as well as the below interesting data on variants in geographic areas of East Asia:

Recently developed clinical tests may detect asymptomatic amyloid neuropathy:

• • Intraepidermal nerve fiber density (IENFD)
  • Quantitative sensory testing
  • Electrochemical skin conductance using Sudoscan® device
  • High-resolution magnetic resonance neurography
  • Laser-evoked potentials

Prevalence

Wild type TTR amyloidosis is not as rare as previously thought. It is estimated that as many as 25% of males over 80 have amyloid deposits in their heart. Most do not get diagnosed during their lifetime.

In a symposium sponsored by Eidos Therapeutics entitled “Wild-type Transthyretin Amyloidosis – An epidemic hiding in plain sight,” Dr. Esther Gonzalez-Lopez from Spain referenced data from Dr. Ron Witteles’ article in JACC from 2019. The data shows the following population is deemed at risk for ATTR-CM and screening for amyloid should be incorporated into everyday practice:

Patisiran

Patients in the Global Open-Label Extension study (OLE) represent those with the longest treatment with an RNAi therapeutic, including patients receiving >5 years of patisiran. Through an additional 24 months of treatment in the Global OLE, patients treated with patisiran earlier in their disease continued to demonstrate maintained efficacy and reversal of polyneuropathy from parent study baseline, as measured by mNIS+7.

Despite marked disease progression while receiving placebo during the 18-month APOLLO study, treatment with patisiran in previously untreated patients halted polyneuropathy progression and improved QOL and mBMI in majority of patients following 24 months of patisiran treatment.

Tafamidis

Treatment with tafamidis was associated with a significant overall survival benefit. With results limited to those with cardiac involvement and stage 2 polyneuropathy, significant overall survival benefit was also seen. Treatment with tafamidis also slowed progression of neurological impairment associated with a wide range of mutations, demonstrated in studies from Dr. Merlini, Dr. Palladini, and other renowned physicians in Pavia, Italy.

Inotersen

Results of the open label extension study on inotersen were shared by Dr. Carlos Casasnovas. In the study, patients had a dramatic reduction of serum TTR after long term use, and no serious adverse events were attributed to inotersen use.

Patisiran in patients with concomitant use of a TTR Stabilizer

The open label extension study of patisiran demonstrated TTR reduction and a consistent safety profile that was unaffected by concomitant use of a TTR stabilizer.

Other topics in TTR Amyloidosis:

• Need predictive genetic testing for ultimate early diagnosis; amyloid imaging is also important for early diagnosis
• Follow-up visit policy of asymptomatic carriers: Visit the genetic counseling once a year at annual follow-up and have provided genetic counseling and medical checkup
• When looking at autopsy studies, prevalence of amyloid is very high. When looking at patients (those with symptoms), the prevalence is 30% lower. This demonstrates a difference of anatomic penetrance versus clinical penetrance.
• With the now available therapies, new therapies should be compared against an existing treatment rather than a placebo as with earlier studies.
• Combination of therapies will likely be the future, as we have already seen some safety with tafamids + patisiran combination therapy

As we learn more about these diseases and how to treat them, promising data is being published and used to advance the development of different therapies. The ISA meetings are vitally important to share clinical experiences, best practices, and critical data so that physicians around the world can provide their patients with the best possible care and outcomes. After each meeting, we at ARC are more energized than ever to drive our mission forward. We are excited to see what another 2 years of research and studies will bring to the amyloidosis treatment landscape and ARC remains dedicated to keeping you informed along the way!

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

ARC at ISA

The Amyloidosis Research Consortium had three abstracts accepted for poster submission to ISA 2020. Our 3 posters are:

1. The Amyloidosis Forum: A Public-Private Partnership to Advance Drug Development in AL Amyloidosis. The PPP allows ARC to convene with researchers, physicians, pharmaceutical companies, and the FDA, to identify and bridge the scientific gaps in the drug discovery and development for the treatment of AL amyloidosis. Click here to see our Amyloidosis Forum poster.
2. Amyloidosis Appointment Companion: A Novel Tool to Improve Patient Care and Communication with Health Care Providers The Appointment Companion aims to help the patient make the most of a patient’s time with their provider, helps to keep all the patient’s thoughts and concerns organized, lets the provider know how the patient has been feeling since the last appointment, and outlines the goals of treatment. More information can be found on the poster here.
3. What should an ATTR Amyloidosis Patient-Reported Outcome Survey Measure? Results from a Literature Review and Interviews with Key Opinion Leaders. Our third poster is regarding the Patient-Reported Outcome (PRO), a survey that we are in the process of developing. We have reviewed numerous articles and consulted with many experts in the field to discuss what needs to be included in our PRO. More details can be found on our poster here .