Lilly’s AD Compound: Perhaps Not Dead Yet

Lilly effectively made a small cup of lemonade out of 2 big lemons on Friday, when the company released its expected, negative phase 3 results of solanezumab in mild-moderate Alzheimer disease. The anti-amyloid MAb, when compared with placebo, did not significantly alter the cognitive or functional primary outcomes* in either study of approximately 1000 patients each.

But—but, Lilly says—when data were pooled from both studies, the firm was able to squeeze out a “statistically significant slowing of cognitive decline” in the overall population and in patients with mild AD specifically. Although Lilly didn’t say what the specific secondary cognitive outcome was (there are only a few prespecified options**) and what the actual difference was. It seems unlikely that the difference would be related to the crudest, secondary cognitive measure, the MMSE score.

The next best option, unless Lilly added another secondary cognitive outcome after its interim assessment of data (which may be the case), is a statistical difference in the Clinical Dementia Rating—Sum of Boxes (CDR-SB). Although the CDR-SB is more of a global functioning score, assessing memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. When calculating the CDR-SB, each of the 6 domains is rated (based on information from patient and caregiver interviews) on a 4- or 5-point scale (from 0 or 0.5 to 3). The domain scores are then added for the sum-of-boxes score (which ranges from 0 to 18). I can only surmise that Lilly is implying some kind of statistical difference on the basis of this more qualitative and less precise score between the pooled placebo- and solanezumab-treated groups, which I don’t find to be a particularly promising outcome in the face of the other negative results. To me, this seems like more smoke from a phase 3 crash and burn than anything. But the result may provide momentum to those who want to test the drug in earlier phases of AD, specifically mild cognitive impairment (MCI). The forward-looking statements from Lilly execs:

• John Lechleiter,CEO: “We
  intend to discuss these data with regulatory authorities to gain their
  insights on potential next steps.”
• Jan Lundberg, President of Lilly Research Laboratories: “We believe the pooled data support the amyloid hypothesis, as these
  are the first Phase 3 data with an anti-beta amyloid agent that appear
  to show a slowing of cognitive decline.”

That last statement appears to be a bold one.

As far as adverse events from the phase 3 trials are concerned, the most common with solanezumab treatment were lethargy, rash, malaise, and angina (?). Importantly no vasogenic brain edema was reported, as in studies of another (and now defunct) anti-amyloid MAb, bapineuzumab. It’s a curious finding, or lack of a finding, if the side effect is believed to indicate the immune-mediated mobilization of amyloid out of the brain through vascular channels. Like in the bapineuzumab studies, what will be interesting to learn is whether Lilly’s compound removed brain amyloid (via PET or other biomarkers), particularly in those patients who ostensibly experienced some clinical benefit with treatment.

The phase 3 results will be independently assessed by the AD Cooperative Study, and the group will present the results at the upcoming ANA meeting in early October, according to Lilly’s press release. Just how Lilly manipulated the phase 3 studies to achieve the positive secondary outcome, what the secondary measure was, what the quantitative difference was, and the nature of the placebo-treated group (eg, the group’s level of cognitive decline) will be vital to know.

MMSE = Mini-Mental State Examination; PET = positron emission tomography.

* Change from baseline to endpoint in
Alzheimer’s Disease Assessment Scale—Cognitive subscore (ADAS-Cog11) at 80 weeks; and change from baseline to
endpoint in Alzheimer’s Disease Cooperative Study—Activities of Daily
Living Inventory (ADCS-ADL) at 80 weeks.
** The secondary outcomes measures for both EXPEDITION trials were the Clinical Dementia Rating—Sum of Boxes (CDR-SB), the Neuropsychiatric Inventory (NPI), the MMSE, the Resource Utilization in Dementia—Lite (RUD-Lite), 2 quality-of-life measures, a volumetric MRI measure, and 2 biomarker measures.