5 biggest Alzheimer's trial blow-ups
Alzheimer's disease has been a therapeutic area that has eluded big pharma and other drug developers for decades. AD has become the white whale of the industry as one after another trial fails in the space. Drugs to treat the debilitating neurological disease are a huge unmet need as more of the world's population ages and more people become affected by the memory-robbing condition.
Despite the need, scientists are still unsure about what exactly causes the mental decline. Some researchers link the cognitive decline to amyloid beta plaques that develop in the brain. But the link is still tenuous and it's unclear whether the plaque is a cause or an effect of the disease. Still, big pharma has spent billions trying to prove the amyloid plaque theory and many drugs in the pipeline are based on this.
The rub with AD drug development is that it requires large clinical trials due to the large patient population, making the trials especially expensive. Trials are often based on patient or caregiver reported outcomes that can be unreliable.
In early December, Eli Lilly & Co. reported data from one of these large AD trials for its drug solanezumab. The EXPEDITION 3 trial is in an earlier patient population than the two earlier trials testing the experimental drug and patients were screened to make sure they have the amyloid plaque in their brain. Despite the different patient population, Lilly notched a third failure.
The trial results were a blow to the company and have many investors questioning whether the amyloid hypothesis is valid, even as they wait for further data from companies like Biogen that also have AD drugs in the pipeline.
In the wake of EXPEDITION3, BioPharma Dive took a look at some of the trial blow-ups that have marked this therapeutic space:
- Lundbeck and Myriad Genetic's Flurizan (tarenflurbil): Weeks after Lundbeck paid $100 million upfront for a stake in Myriad Genetics AD drug, the results of a Phase 3 trial showed that the amyloid beta lowering drug failed to show any improvement in cognition or daily living tasks. Development of the drug was promptly discontinued. Lundbeck had jumped on the deal after promising Phase 2 results in hopes of getting the drug on the cheap before positive late-stage results. Myriad spent nearly $60 million in development of the drug and another $8 million winding down the program.
- Pfizer and Medivation's Dimebon (latrepiridine): After showing promise in early clinical trials, Dimebon had become a highly anticipated, albeit unlikely, treatment for Alzheimer's disease. The drug had been used as an over-the-counter antihistamine in Russia since the early-1980s and was patented and licensed by Medivation after some small, early trials showed promise in neurodegenerative diseases. In September 2008, Medivation linked up with its future acquirer in a deal that had Pfizer shelling out $225 million upfront and the possibility of $500 million more in milestone payments. Yet, in March 2010 the pair announced two major Phase 3 failures of the drug and Pfizer ended the partnership, as well as all development of the drug.
- Eli Lilly's semagacestat: At the time, Lilly had one of the largest patent cliffs in the industry and was relying on revenues from its AD pipeline to deliver the blockbusters that could dig it out of the hole. Development of the gamma secretase inhibitor was halted in 2010 after it failed to outperform a placebo in two long-term Phase 3 trials. Not only that, but semagacestat was also actually worsening patient's cognitive symptoms and ability to conduct daily tasks, as well as showing an increased likelihood of skin cancer. The failure raised alarms about several other gamma secretase inhibitors that were being developed by other companies.
- Eli Lilly's solanezumab: That's right, another failure for Lilly in AD. After a whole lot of optimism and hype, Lilly announced in 2010 — months after halting semagacestat — that solanezumab failed to deliver on either the cognitive or functional endpoints in the EXPEDITION 1 and EXPEDITION 2 trials in mild to moderate AD patients. After reviewing the raw data, Lilly chose to resurrect the drug two years later and conduct the EXPEDITION 3 trial in hopes of sola working in AD patients with mild cognitive impairment. In 2016, Lilly once again delivered disappointment.
- Johnson & Johnson, Elan and Pfizer's bapineuzumab: In 2012, two years after its Dimebon disappointment, Pfizer (this time with partner J&J) announced another major blow up in AD. Bapineuzumab, nicknamed bapi by the market, failed in two late-stage trials — one in patients that carried the ApoE4 genotype, another in patients who didn't. The failures prompted the companies to end development and had critics crying that the amyloid plaque theory was dead, again. It was a big hit for everybody, J&J had paid $1 billion in 2009 for an 18% stake in Elan to get bapi rights, while Pfizer got its stake through its acquisition of Wyeth, which was previously partnered with Elan.
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