New hope with NEOD001?
AL amyloidosis candidate generates favorable cardiac and renal response in Phase 1/2
DUBLIN, Ireland—Prothena Corporation plc had good news for investors in February, announcing that interim data from its Phase 1/2 clinical study of NEOD001 in patients with amyloid light-chain (AL) amyloidosis and persistent organ dysfunction showed monthly infusions were well tolerated and that patients demonstrated improvements in functional biomarkers predictive of improvement of disease and survival.
NEOD001 is a humanized monoclonal antibody that targets the circulating soluble amyloid and deposited insoluble amyloid that accumulates in both the AL and amyloid A forms of amyloidosis. The FDA granted NEOD001 Fast Track designation in December 2014, and it is currently being evaluated in three clinical trials in AL amyloidosis patients.
The Prothena study found that monthly infusions of NEOD001 were safe and well tolerated, with no drug-related serious adverse events, discontinuations due to drug-related adverse events, dose-limiting toxicities or antidrug antibodies reported. The data appeared online in the Journal of Clinical Oncology, and data from the study’s ongoing expansion cohort are expected in the second quarter of this year.
Systemic amyloidoses are a complex group of progressive diseases caused by the deposition of misfolded proteins, which in turn results in progressive organ damage. The most common type, AL amyloidosis or primary amyloidosis, is a hematological disorder caused by plasma cells that produce misfolded immunoglobulin light chain, resulting in deposits of abnormal AL protein (amyloid) in the tissues and organs. AL amyloidosis can occur spontaneously, but it is often associated with other blood disorders, such as multiple myeloma and Waldenström's macroglobulinemia—in fact, some 10 percent to 15 percent of patients with multiple myeloma are estimated to develop overt AL amyloidosis.
AA amyloidosis (secondary amyloidosis) on the other hand, tends to result from such chronic inflammatory diseases as lupus, rheumatoid arthritis, tuberculosis, Crohn’s disease, ulcerative colitis and certain cancers.
Twenty-seven patients with AL amyloidosis and persistent organ dysfunction were enrolled in seven dose cohorts in the dose escalation portion of this study, with cardiac and renal responses as the exploratory endpoints.
Of 14 cardiac-evaluable patients, 57 percent met the criteria for cardiac response, compared to the expected cardiac best response rate of 26.5 percent from data in patients treated with off-label standard of care. Forty-three percent of participants had stable disease. Among responders, the median NT-proBNP, a clinical biomarker used to predict disease progression and mortality, decreased from 1,768.5 pg/mL at baseline to 1,054 pg/mL at the best response assessment, and NT-proBNP decline was significantly correlated with an increased number of NEOD001 infusions.
Of the 15 renal-evaluable patients, 60 percent met the criteria for renal response, compared to the expected renal best response of approximately 24 percent in patients treated with off-label standard of care, and 40 percent of patients had stable disease. In the responders, the median proteinuria value decreased from 4,834 mg/24 hours at baseline to 1,647 mg/24 hours at the best response assessment, predicting a delayed time to dialysis.
“The positive results from our Phase 1/2 study of NEOD001 in patients with AL amyloidosis suggest that NEOD001 may effectively recruit the immune system to clear the circulating soluble and deposited insoluble proteins that cause organ dysfunction in this progressive and life-threatening condition,” said Prothena President and CEO Dr. Dale Schenk. “Based on these data, Prothena has initiated the VITAL Amyloidosis Study, a global registration study for NEOD001, and is planning to initiate the PRONTO study, which will evaluate cardiac response as assessed by changes in NT-proBNP, a cardiac functional biomarker that has been shown to be highly predictive of survival in patients with AL amyloidosis.”
According to Dr. Gene Kinney, chief scientific officer and head of research and development at Prothena, the culprit in AL amyloidosis is a protein called light chain. Light chain is typically produced by plasma cells, which produce light chain and heavy chain proteins that in turn combine to make immunoglobulin. In AL amyloidosis, he explains, plasma cells replicate and overproduce light chain, which then begins to self-aggregate, misfold and form amyloid.
“The median survival, regardless of what peripheral organ is involved, tends to be about three years, and if you have cardiac involvement, which is probably about 70 percent of the cases, median survival can be as short as a year,” he continues. “And the most commonly affected organs would be heart and kidneys.”
NEOD001 is designed to interact solely with the misfolded light chain protein, says Kinney. “When it’s normally folded, the part of light chain our antibody needs to see isn’t accessible, so it doesn’t interact with normally folded, normally functioning light chain or immunoglobulin. But when it misfolds, the part of the light chain that our antibody needs to see is exposed, and we can bind to it and neutralize all that toxicity.”
There are no approved treatments for AL amyloidosis, which affects about 30,000 to 45,000 patients in the United States and Europe. Kinney notes that off-label treatments for the disease generally consist of chemotherapeutic cancer drugs that target plasma cells, in hopes of reducing the production of new light chain. However, the success rate is very low.
“Everything that’s currently used off-label today focuses on the production factory, if you will. The way I think about this disease, I think about it like a bathtub—the faucet is on running full, the bathtub is full of water. And what all the current chemotherapeutic agents do by trying to kill B cells or plasma cells is they try to turn the faucet off. What NEOD001 does is it goes after the water in the tub; it’s the other side of the biology equation, if you will. We’re uniquely targeting the toxic moiety itself, and I think that’s one of the kind of key differentiating characteristics of NEOD001, even relative to what’s used in off-label fashion in the field today.”