On 4/23/18 two important events occurred at Tufts Medical Center. In one, the first patient in human medical history was treated with a monoclonal antibody, PRX004, against the protein that causes hereditary and wildtype transthyretin amyloidosis (ATTR). This patient has both cardiac and peripheral nervous system involvement with hereditary ATTR and tolerated the first-in-human PRX004 treatment without incident.
In the other, the RAIN trial that opened in mid-2017 was closed because the company supporting RAIN stopped clinical development of the monoclonal antibody against light-chain (AL) amyloidosis, NEOD001, that was being tested in the trial. This decision was made because two other large trials conducted by the company, Prothena Biotech, were not successful although there were no adverse events and the drug was very safe to administer. The weight of these outcomes on the community of AL amyloidosis patients cannot be underestimated.
What is NEOD001 and why is the RAIN trial closing?
At Tufts MC, we have participated in all of the clinical trials of NEOD001. Dale Schenk, the scientific genius behind Prothena, hypothesized that monoclonal antibody therapy (like NEOD001) could be directed against amyloidosis, both AL and ATTR, and could eliminate the amyloid deposits in AL and the culprit transthyretin monomeric protein in ATTR.
The preliminary data from the early trials of NEOD001 were very exciting – both heart and kidney markers of disease decreased in over 50% of patients and in those with peripheral nervous system involvement the response rates were higher. We enrolled several dozen patients on all of the studies and numerous patients received NEOD001 safely for over 3 years.
After the early trials showing a possible benefit to NEOD001, Prothena conducted two large trials named PRONTO and VITAL. It was the lack of success of these two large trials that led Prothena to discontinue development of NEOD001. In PRONTO, patients with previously treated AL with cardiac involvement who were in remission were randomized 1:1 to receive NEOD001 or placebo. The study was double blinded, meaning that neither the patients nor their doctors knew who was getting what. The goal was reduction of a cardiac biomarker measured in the blood. There are 2 hypotheses for the failure of PRONTO to show reductions in the biomarker
First, we now know that even small amounts of toxic light chains – amounts below the level of detection of our lab tests – can cause ongoing damage in the organs they target. The two groups on the study then may have been imbalanced, despite the stratification performed before randomization. with more patients in the treatment group who had low levels of light chains. Second, we know that, as the heart recovers from amyloid damage, scarring can occur over years and NEOD001 may have had the unintended consequence of enhancing the scarring process and enabling the biomarker levels to drift up instead of down.
In VITAL, newly diagnosed untreated patients with AL with cardiac involvement received standard therapy with bortezomib combined with dexamethasone and usually with cyclophosphamide (CyBorD) and were randomized 1:1 in double-blinded fashion to receive NEOD001 or placebo. The goal of the trial was to determine whether one group or the other had fewer hospitalizations and deaths. The preliminary results of the trial, analyzed in a ‘futility analysis’ to determine whether it was worth continuing to treat and observe the subjects in the study, indicated futility, that is, that the trial was unlikely to achieve its goal. Nevertheless, there were hints of promise in several areas such as the 6 minute walk test and the response of patients with kidney involvement. A case can be made that the reasons this trial did not succeed were that it was too small to see the impact of NEOD001 on survival and that the trial excluded the sickest cardiac patients who had very high biomarker levels.
Closing the RAIN trial at Tufts Medical Center and lessons for future research
The RAIN trial, sponsored by Tufts Medical Center, asked whether patients with AL and kidney involvement who were in remission after initial therapy would improve with NEOD001. It was also randomized and double-blinded. RAIN had enrolled patients from coast-to-coast and was open in 4 centers at the time it was closed. We had to close RAIN because Prothena was no longer producing the drug NEOD001. We will still learn useful knowledge from RAIN thanks to the work of Dr. Cindy Varga at Tufts, Drs. Agnes Fogo at Vanderbilt and Samih Nasr at Mayo Clinic, and Dr. Matthias Kretzler at University of Michigan. We look forward to the publication of the limited information on the pathology of kidney amyloid and the feasibility of studying the gene expression profiles of kidney biopsies from RAIN patients.
I am grateful to all of the physicians and clinical research staff who contributed to the development of RAIN, particularly to Dr. Varga, to the Tufts Research Administration and Data Safety Monitoring Board staff, to Livia Terezi, Liz Kendricken and George Mensing in the Clinical Trials Office, and to all of the patients who participated in RAIN. I must also thank all of the patients who participated in the NEOD001 trials for their patience, generosity and courage. One of the most important lessons of clinical research is to take the negative outcomes and use them to fuel positive efforts going forward. This habit of mind and spirit within the clinical investigator, although personally useful, pales in importance when compared to the profound impact of the disease on patients, families and care-givers.
Despite the current setback with NEOD001, AL patients continue to do better today than ever before, the future for ATTR patients is brighter than it has ever been, and the fight to improve survival and quality of life for patients with amyloidosis endures and marches on here at Tufts.
RL Comenzo, MD