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RAIN Clinical Trial

 The John C. Davis Myeloma and Amyloid Program at Tufts Medical Center in Boston is recruiting patients with systemic AL amyloidosis for a clinical trial using a new monoclonal antibody, NEOD001, produced by Prothena Biosciences.

The ‘RAIN’ trial is open to patients with kidney damage who are at risk of requiring dialysis in several years – RAIN stands for Renal AL-amyloid Involvement and NEOD001 (NCT03168906). RAIN is a multicenter trial open at Tufts MC and planned to open across America -- at centers in New York, Pennsylvania, Florida, Michigan, Wisconsin, Minnesota, Arizona, and California. On this trial, patients will be randomized to receive NEOD001, an anti-amyloid antibody, or placebo, and will be followed by their doctors to see if kidney function improves, worsens or stabilizes. Studying this reaction will help us understand why some patients respond and others don’t and why some patients progress to dialysis in months and others remain stable for years.

The RAIN team

Medical oncologist Cindy Varga, MD, FRCPC (photo) is the Principal Investigator for RAIN at Tufts Medical Center. Dr. Varga specializes in malignant hematology, multiple myeloma and AL amyloidosis. She completed medical school at the University of Montreal, her residency at McGill University and her fellowship at Dana Farber Cancer Institute.

At Tufts MC, Dr. Varga is supported by the hospital’s Neely Research Center’s RAIN trial managers, Livia Terezi and George Mensing and by clinical research associates, Emmanuel Larbi and Corey Michelson (group photo). She is also joined by Tufts MC colleagues Dr. Leslie Inker (photo), a physician-investigator from the Nephrology team, who will be overseeing novel renal clearance studies on AL patients in the Tufts MC Clinical and Translational Research Center (CTRC) and other RAIN centers, and Dr. Monika Pilichowska, an expert renal pathologist who will be participating in the scoring of renal biopsies from RAIN patients.

Key collaborating renal physician-investigators on the grant submission for RAIN research studies are Dr. Agnes Fogo (Vanderbilt), Dr. Sami Nasr (Mayo Clinic) and Dr Mathias Kretzler (University of Michigan).

NEOD-001- Current Treatments Available

Current available treatments for systemic AL amyloidosis include chemotherapeutic agents such as bortezomib, cyclophosphamide and dexamethasone or high-dose melphalan followed by the infusion of autologous stem cells.

Recent research efforts have led to the development of an investigational humanized monoclonal antibody, NEOD001, that may improve organ function by targeting amyloid fibrils, which are the misfolded light chains, and enhancing their resorption and clearance.

Preliminary data from the phase I/II study of NEOD001 are promising with a 60% organ response rate among the renal cohort. Preliminary safety data from this study reported no hypersensitivity reactions or drug-related serious side effects. The most common reported adverse events were fatigue, upper respiratory tract infections, nausea, diarrhea, edema and dizziness, though many of these symptoms could be attributed to underlying amyloidosis.  No dose limiting toxicities were observed and no patient discontinued treatment due to drug-related events.

The RAIN trial will use the recommended dose of 24 mg/kg every 28 days based on these safety data. Two additional clinical trials for patients with AL amyloidosis are investigating NEOD001 in previously treated patients with persistent cardiac involvement (Phase 2, PRONTO, NCT02632786) and in newly diagnosed patients with cardiac involvement (Phase 3, VITAL, NCT02312206); these trials have completed enrollment and are therefore closed to accrual of new patients.

Renal biopsies

The RAIN study is the first prospective trial of its kind to focus only on renal AL amyloidosis. Amyloidosis is a disease whose diagnosis cannot be established clinically but requires viewing the presence of amyloidosis in tissue under the microscope using a special dye).

All potential candidates of RAIN will undergo a screening kidney biopsy prior to randomization on the trial.  This kidney biopsy is standard of care and is critical in confirming amyloid deposition as a dominant contributor to ongoing renal dysfunction.

Renal biopsies are performed under ultrasound guidance usually by interventional radiologists. All renal biopsy slides will be reviewed by a renal pathologist who will confirm the presence and type of amyloid.

In addition to standard biopsy review, a novel histologic scoring system will be used to determine the degree and pattern of distribution of amyloid deposits and the extent of renal scarring.  Patients will also have the opportunity to consent for renal transcriptional profiling, a method used to measure the activity of thousands of genes at once using minimal tissue. With these molecular studies, we hope to further expand our understanding of kidney tissue injury and tissue recuperation in this disease.