The long and frustrating search for something--anything--that can treat Alzheimer's or blunt its symptoms ran into yet another Phase III roadblock this morning as Baxter International ($BAX) reported that its Phase III study of the immune-bolstering treatment Gammagard had ended in failure. But following Eli Lilly's ($LLY) example, stubborn investigators are hanging on to data from a subgroup analysis as a sign that the treatment may yet work for specific patient populations.
Hopes were raised for Gammagard last year after investigators reported that a group of patients in a small study of Alzheimer's patients appeared to respond to the therapy, with 11 of 16 patients demonstrating improvements in thinking and behavior as well as routine, day-to-day functions. Four of the patients who were in the most responsive treatment arm experienced no decline across a range of symptoms.
The theory was simple: Infusing immune globulin rich in antibodies could tackle both amyloid beta and tau, knocking out two toxic materials believed linked to Alzheimer's. Skeptics, though, wondered how a significant dose of the specific antibodies needed would enter the brain.
The Phase III data were conclusive, with Gammagard failing to produce an improvement over placebo in two groups receiving either the 400 mg/kg or 200 mg/kg dose over 18 months. There was no slowing in cognitive decline and no improvement in function, the FDA's two key measures for efficacy--a traditional trial standard that is now being modified.
Baxter doesn't have the data needed to make its case, but its researchers also said that the 400mg/kg treatment arm "showed a positive, numerical difference in change from baseline versus placebo in cognition as measured by the Alzheimer's Disease Assessment Scale--Cognitive Subscale (ADAS-Cog) and Modified Mini-Mental State (3MS) Examination among both moderate patients and carriers of the ApoE4 genetic marker. These differences ranged between 16% and 29%." Interestingly, Baxter found the biggest potential signal in patients with a more advanced moderate case, rather than the early-stage patients which Eli Lilly believes solanezumab benefited.
''The study missed its primary endpoints, however we remain interested by the pre-specified sub-group analyses, particularly among patients with moderate disease and those who carry a genetic risk factor for Alzheimer's disease, two patient groups that are in great need of advances in care. A detailed analysis of the results from the GAP study continues, and we look forward to a greater understanding of the full data set,'' said Ludwig Hantson, Ph.D., president of Baxter's BioScience business, in a statement. ''We are grateful for the participation of the patients and physicians in the study and for the dedicated support of the patients' caregivers.''
The next step, says Baxter, is to study the subgroup analysis and see if they can identify a path forward for this program. This trial, though, is over. Baxter's shares slid 3.5% in early trading this morning.
Baxter's failure follows a long lineup of bitter clinical disappointments. Eli Lilly's solanezumab and J&J/Pfizer's bapineuzumab both failed major Phase III studies last year. Those setbacks followed Medivation's Dimebon fiasco. And industry groups report that there have been more than 100 clinical failures of Alzheimer's therapies, making this disease a disaster zone for developers.
The consistent record of failure, though, hasn't soured biopharma's taste for new drug development. Alzheimer's afflicts millions of people, and with no therapy that can effectively treat this disease, any new drug that can get past regulators is likely to garner mega-blockbuster returns. Like Baxter, Eli Lilly made a case that solanezumab improves cognition in a particular group, focusing on early-stage patients. But any chance of an accelerated approval based on subgroup analysis was dashed by the agency's insistence on a new study.
The FDA has also begun work on changing the standards of Alzheimer's drug development, hammering out new rules intended to steer more investigations to early-stage patients--who regulators believe are more likely to respond to a drug--before the disease seriously damages the brain. The FDA is also focusing more on cognition, ready to forfeit improvement in function provided patients can clearly benefit from a new therapy.
- here's the press release