Full Results Released for Failed EXPEDITION3 Trial of Solanezumab for Mild AD Dementia

Deborah Brauser

December 09, 2016

Full results of the failed phase 3 EXPEDITION3 trial of solanezumab (Eli Lilly) for patients with mild dementia from Alzheimer's disease (AD) were presented last night to a packed room at the Clinical Trials on AD (CTAD) meeting in San Diego, California.

There weren't a lot of surprises, as topline results were reported 2 weeks ago showing that the trial did not meet its primary outcome of slowed cognitive decline, as measured on the AD Assessment Scale-Cognitive subscale (ADAS-Cog), compared with placebo.

But the new presentation, which was also streamed live via webcast, included more details on both the primary and secondary endpoints. And it, along with a panel discussion and a sometimes emotional audience participation session afterward, sought to answer what went wrong — and whether the so-called amyloid hypothesis is now on its last gasp.

EXPEDITION3 principal investigator Larry Honig, MD, PhD, professor of neurology at Columbia University Medical Center, New York City, reported that, although the finding was not significant, patients randomly assigned to the monoclonal antibody had an 11% reduction in decline on the ADAS-Cog at 80 weeks compared with those receiving placebo.

Dr Larry Honig

In addition, the treatment group had the following significant findings:

  • 13% greater slowing of cognitive decline on the Mini-Mental State Examination (P = .014) vs placebo;

  • 15% slowing in decline on the Clinical Dementia Rating-Sum of Boxes scale (P = .004); and

  • 14% slowing in decline on the AD Cooperative Study-Instrumental Activities of Daily Living (P = .02).

Although not significant, there was also a 7% reduction in decline on the Functional Activities Questionnaire compared with placebo.

However, Dr Honig said that the investigators had hoped for a 30% effect size instead of the 11% to 15% that was actually found among the outcomes.

"I think disappointment with these results is quite deep in the community," he told Medscape Medical News. "There was a lot of hope that this drug, that went through so many investigations, might be proven to modify the disease course of Alzheimer's."

"We didn't expect solanezumab to be a cure for Alzheimer's disease, but we did have hope that it would be the first treatment to slow down the relentless progression of the disease," Eric R. Siemers, MD, Eli Lilly, told attendees.

But in a statement that caused a stir both in the room and in the Twitter-verse, panel discussant Paul S. Aisen, MD, University of Southern California, San Diego, said that the results do not put a final nail in the coffin of the amyloid hypothesis — that AD is caused by the accumulation of amyloid protein.

Dr Aisen, who collaborated with Lilly on the analysis of the previous EXPEDITION1 and EXPEDITION2 trials, noted that all three EXPEDITION studies showed a slowing of cognitive and functional decline, even if the effects were too small to be significant.

"Solanezumab ties up monomeric amyloid-β," Dr Aisen said. "This isn't a refutation of the amyloid hypothesis. It's the confirmation of the hypothesis. I would say this is a negative study of a beneficial treatment. And I believe the treatment effect will be larger at an earlier stage of disease."

In EXPEDITION3, 2129 patients aged 55 to 90 years (mean age, 73 years) were enrolled and randomly assigned to 400 mg of solanezumab (n = 1057) or matching placebo (n = 1072) every 4 weeks for 80 weeks total. Discontinuation rates were similar at 13.5% and 15.3%, respectively.

All participants were amyloid positive, as shown by F18 florbetapir positron emission tomography (PET) or cerebrospinal fluid amyloid-β (CSF Aβ1-42).

Although change in cognition on the ADAS-Cog14 was significantly slower for the solanezumab group than for the placebo group at weeks 28 (P < .05), 40 (P < .01), and 52 and 64 (P ≤ .05 for both), it was no longer significantly different at week 80 (P = .095).

As for biomarkers, plasma changes in Aβ1-40and Aβ1-42 were significantly different between the treatment and placebo groups (P < .001 for both comparisons). But changes in amyloid deposition, as shown by PET, showed no significant difference between the groups. CSF total tau at 80 weeks increased for both groups and at a greater rate for the treatment group, but it just missed significance (P = .06).

In addition, group differences between whole brain atrophy and ventricular enlargement, as measured by MRI, were not significant.

Adverse Events

The percentage of participants reporting serious adverse events (AEs) was similar, at 16.6% of the treatment group and 18.9% of the placebo group. Also similar were the percentages of deaths (0.9% vs 1.5%, respectively), treatment-emergent AEs (84.5% vs 83.4%), and discontinuations due to an AE (4.5% vs 3.6%).

Events reported significantly more frequently by those taking solanezumab vs those taking placebo included spinal osteoarthritis (1.1% vs 0.4%; P < .05), dysuria (0.9% vs 0.2%; P = .04), vitamin D deficiency (1.4% vs 0.6%; P = .05), and nasal congestion (1.2% vs 0.4%; P = .03).

Events reported more frequently by the placebo group included gait disturbance (1.7% vs 0.4% of the treatment group; P = .004) and somnolence (1.2% vs 0.2%; P = .007).

"The factors relevant to interpretation of these results certainly include drug targeting, the disease stage studied, and the dosage of drug delivered in the solanezumab arm," said Dr Honig, who also pointed out that they don't have all of the results yet because the dataset was still locked less than 2 months ago.

"We're very disappointed that we didn't reach our primary outcome, especially for the patients and for their families," said Dr Siemers after Dr Honig's presentation.

In this patient population, this dosage didn't work, added Dr Honig, so the company won't be seeking approval from the US Food and Drug Administration (FDA) for this indication.

Other studies of solanezumab remain ongoing, albeit in different populations. These include the Anti-amyloid Treatment in Asymptomatic Alzheimer's (A4) trial and the Dominantly Inherited AD (DIAN) trial.

Questions Remain

Disappointment was palpable once the session was opened to the audience. Many of the questions raised were about why exactly the treatment didn't work. Dr Honig noted that the bottom line is: They don't know. They can speculate that the dosing maybe should have been higher and that it could have worked better in a different patient population, "but we don't have all the answers."

Another audience member echoed others when he said, "I don't consider this trial a failure because we learned a lot." When he asked whether the company would have filed with the FDA if just the cognitive function outcomes had been positive, Dr Siemers answered, "We'd have certainly had a discussion about that."

When another participant asked whether discussions could start moving again if further subanalysis were to find something "interesting," Dr Siemers said that if that were to happen there would need to be replication "to make sure it's a real finding."

When asked whether the ongoing studies will increase treatment dosage, Dr Siemers answered that there has been a lot of discussion already about that very question. "All I can say at this point is that it isn't as straightforward as you might think."

"These results, though disappointing, stress the urgency for pushing forward even harder," panel member Maria Carrillo, PhD, chief science officer of the Alzheimer's Association, told attendees at the end of the session. "This is not a time to slow down; it's a time to ramp up our efforts.

Dr Maria Carrillo

"Not all monoclonal antibodies are created equal, with different mechanisms of action," she added. "And some remain hopeful. This isn't a time for companies or anyone else to give up on this amyloid pathway. But we need to also pursue other pathways and strategic approaches."

"This might not have been a win, but it gets us closer to a win."

EXPEDITION3 was funded by Eli Lilly and Co. Dr Honig has received support as a consultant/steering committee member from Lilly, Forum, Fujirebio, and Lundbeck and has received research funding as an investigator for Lilly, AstraZeneca, Bristol-Myers Squibb, Forum, Genentech, Janssen, Lundbeck, Pfizer, Roche, and TauRx. Dr Siemers is an employee and a shareholder of Lilly. Dr Carrillo has disclosed no relevant financial relationships.

9th Annual Clinical Trials on Alzheimer's Disease 2016. Presented December 8, 2016.

 

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