Confirmatory sola study plan takes Lilly down a peg

Lilly’s decision not to file its Alzheimer’s disease antibody solanezumab without conducting an additional study means a delay of several years, giving the lie to the most bullish expectations and bringing into play several other amyloid beta-based strategies in this intractable disease.

True, most analysts had assumed that a new phase III trial would be needed to confirm the glimmers of efficacy seen in retrospective analyses from the large Expedition studies. But that did not stop them hinting heavily that an immediate filing was possible, and the degree to which success had been priced into Lilly’s shares became apparent when the stock fell 3% in early trade today, erasing $1.5bn off the Indianapolis company’s overheated valuation.

Lilly said the decision to run another trial was based on talks with the FDA – implying that the agency remains unimpressed with its analysis of the Expedition study data. These two trials, in a total of 2,000 patients, missed their primary endpoints, but pooled data showed a statistically significant slowing of cognitive, but not functional, decline in the mild and mild-to-moderate population.

Unanswered questions

Although Lilly trickled out further positive updates from the trials, key unknowns remained as to the approvability of solanezumab based on the current data (Lilly’s sola takes one step back as big question remains unanswered, October 25, 2012).

However important an unmet need Alzheimer’s disease is, the market had little idea as to the real significance of the positive cognition result in milder disease, given that Lilly would not reveal how many times it had analysed the data to hit it. It might even be that the FDA has raised doubts about approvability without an improvement being shown in a functional endpoint, which would represent a major blow to solanezumab and other amyloid beta-targeting agents.

Whatever the reason, investors should really have seen the warning signs (Lilly’s sola dream stays alive but expectations depart from reality, October 9, 2012).

Now it will take Lilly almost a year to finalise the design of the new phase III trial; if this starts in the third quarter of 2013, given that results are unlikely for two years, at best that implies a filing in late 2015 and launch a year later. Right now, the only positive signal the market can cling to is Lilly’s hope that a filing without awaiting further data might be pursued outside the US.

Analysts at ISI Group, Bernstein, Leerink Swann and UBS all said Lilly’s move was not unexpected, and in any case they had not factored in a solanezumab launch before 2016. “We are not surprised, but some may be,” wrote UBS, which had earlier compared the exuberance around solanezumab to “that around hepatitis C, but with more questionable data”.

Size and scope

Lilly’s decision on the size and scope of the new trial will be eagerly awaited, as will the company’s choice of dosing and endpoints. Clearly, testing solanezumab in patients with mild Alzheimer’s disease is backed up both by what was seen in the Expedition studies and by the amyloid beta hypothesis.

The trouble for Lilly is that several companies are already kicking at solanezumab’s heels here, most notably Roche’s gantenerumab, which is in a phase III trial in 770 patients with prodromal Alzheimer’s – a very early form of dementia. Another means of targeting amyloid beta build-up – inhibiting beta secretase – also recently gained prominence (Merck & Co puts its faith in amyloid beta hypothesis, December 4, 2012).

There is also the outside chance that Elan and Johnson & Johnson might dust off bapineuzumab, although given that bapi's performance was worse than solanezumab's in its pivotal studies an additional programme at least as big as Lilly’s would have to be designed.

Certainly, with solanezumab out of the frame for at least four years, the Alzheimer’s race looks a lot more interesting.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobEPVantage on Twitter

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