Eli Lilly conducts an autopsy of an Alzheimer’s megaflop

For four years Eli Lilly $LLY committed one of the biggest clinical efforts in the company’s history to proving that it could get solanezumab right on Alzheimer’s. Having navigated through multiple trial failures already, investigators were convinced that if they took what they had learned, changed the patient population, sticking to only patients with a mild form of the disease while using better diagnostics — even changing the endpoints in the lead up to the final read out — they could make a case that this drug could make a significant improvement for patients.

Instead, they came up with a set of modest figures indicating that at best they had merely tapped the brakes on the disease. And today they spelled it all out in what will likely be the post mortem on what once factored in as one of the biggest clinical gambles in the history of biopharma.

Solanezumab was designed to flush amyloid beta, a toxic protein which often clusters in the brains of Alzheimer’s victims. The investigators offered some mixed messages on just how effective sola was in reducing a-beta deposits. Investigator tracked significant changes in plasma levels of the protein, but checking amyloid deposits with PET imaging produced no significant changes. Researchers in other programs will be following that closely as they make their own assaults on amyloid, which remains a key focus. There is a growing consensus in the field, though, that it will take combination therapies to have a real impact on the memory-wasting disease that afflicts millions.

Looking for a dominant new blockbuster, they had to settle for encouraging patients to hope for something better.

Lawrence S. Honig MD PhD, Columbia

Lawrence S. Honig, MD, PhD, Columbia

“Alzheimer’s is a challenging disease that researchers have been committed to studying for some years,” said Lawrence S. Honig, MD, PhD, professor of neurology at Columbia University Medical Center and principal investigator of the EXPEDITION3 study, presented the data at the meeting. “Now is not the time to give up. While the outcome of this study is not what we had hoped for, it is reasonable to believe that disease modifying therapies to slow down the progression of Alzheimer’s disease will be discovered.”

The key failure point was on ADAS-Cog14, which measures a person’s cognitive functions, including memory, attention and language abilities. Investigators tracked an 11% reduction in the rate of decline, a clear miss with a p-value of .095.

The secondary endpoints weren’t that much different.

  • There was the Mini-Mental State Examination, or MMSE, with a 13% slowing in cognitive decline.
  • The Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale showed a 15 percent slowing in decline (p=0.004) between patients treated with solanezumab and patients treated with placebo.
  • There was a 14 percent slowing of decline (p=.019) as measured by the Alzheimer’s Disease Cooperative Study- Instrumental Activities of Daily Living (ADCS-iADL). The ADCS-iADL scale measures a person’s independent performance in complex activities of daily living such as participating in a conversation, preparing a meal or shopping.
  • The Functional Activities Questionnaire did not show a statistically significant difference between patients treated with solanezumab and patients treated with placebo (7 percent reduction in decline, p=0.140). The FAQ scale is a different informant-based measure of functional abilities. Informants provide performance ratings of the patient on ten complex higher-order activities.

There was, though, a greater chance that the drug arm would suffer from spinal osteoarthritis: 1.1 percent in the solanezumab group, 0.4 percent in the placebo group. And there was a 0.9 percent rate of dysuria in the solanezumab group.

In the meantime, you can rack up another setback in a field that has known only late-stage failure in the past decade.

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