Biotech Tracker News - Learning from Betabloc Trials
March 19, 2003 The failure of Betabloc in clinical trials left many unanswered questions about the future of priming the immune system to recognize ß-amyloid as a therapeutic approach to treating Alzheimer disease (AD). Betabloc was Élan (NYSE: ELN) and Wyeth’s (NYSE: WYE) ill-fated AD immunotherapy. An analog of ß-amyloid, the drug was supposed to prime an AD patient’s immune system to seek out and subdue or destroy the endogenous ß-amyloid protein that makes up the disease-associated plaques found in AD patients’ brains.  Betabloc clinical trials were suspended in January 2002 and halted the next month after several patients developed clinical signs consistent with meningoencephalitis. Insufficient information was present at that time to determine whether the drug was able to reduce human plaque burden. If Betabloc were efficacious at this surrogate marker level, then similar drugs that lack its adversities would be promising. A new study published in Nature Medicine shows that, at least for one Betabloc recipient, plaque burden and the concentration of ß-amyloid in the brain was indeed low.  This analysis of a 75-year old woman who died one year after receiving Betabloc is the first published case report describing post-mortem findings in a Betabloc recipient. The patient had received five Betabloc injections over a 36-week period. Her cognitive function had been unchanged 4 weeks after the last injection. 6 weeks after the last injection she developed a dexamethasone-unresponsive syndrome of dizzy spells, drowsiness, unsteady gait, and fever. She became nursing care-dependent and died from a pulmonary embolism 12 months after the last injection. Three pathological features suggested that Betabloc has beneficial biological properties despite its lack of clinical efficacy for this patient:  extensive areas where ß-amyloid plaques and related biopathological markers were rare  ß-amyloid immunoreactivity (marking the protein’s location) was limited to microglia in areas lacking plaques  cerebrovascular amyloid (amyloid angiopathy) persisted even in areas without plaques.  A major caveat to this analysis is that the level of ß-amyloid was not measured in this patient’s brain prior to Betabloc administration. Therefore, one cannot rule out that she had a low amyloid burden prior to the initiation of Betabloc therapy. But since microglia are brain scavengers, the co-localization of these materials suggests “prolonged persistence of phagocytosed amyloid-ß or continuing phagocytosis.” Most importantly, the woman’s brain showed clear evidence of T cell meningoencephalitis and associated pathological findings leading to Dr. Bradley Hyman and colleagues’ related commentary that included, “although it is impossible to draw firm conclusions from a single case, the data presented here suggest that the cellular immune response to any candidate therapy must be weighed heavily.… The current case highlights not only the risks awaiting future attempts at (AD) immunotherapy, but also the considerable promise for the potential effectiveness of this approach.”  This study suggests that if adversities can be addressed, second-generation ß-amyloid therapeutics have a good chance at reducing plaque burden in the brain of AD patients. Whether such a reduction in ß-amyloid can translate into clinical efficacy remains to be seen. Several such drugs are already in development, but none have yet demonstrated entirely reassuring pre-clinical evidence of maintained or improved therapeutic properties and at the same time diminished toxicity. However, experiments using improved animal models of AD are beginning to yield data more suitable for translation of this biological promise into clinical reality. In addition to Élan and Wyeth, Eli Lilly, Washington University, New York University, and other investigators are developing an array of novel anti-amyloid immunotherapeutic constructs. Exelixis and Pharmacia are developing drugs that target related proteins aph-1 and pen-2.
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