The other shoe dropped today on Phase 3 monoclonal antibody trial results expected this summer. Eli Lilly and Company announced that solanezumab did not reach its cognitive or functional endpoints in either of two double-blind, placebo-controlled trials in patients with mild to moderate Alzheimer's disease (AD). It is the second in a one-two punch that casts doubt on the ability of these antibodies to treat symptomatic AD. Earlier this month, Janssen Alzheimer Immunotherapy had halted all studies of intravenous bapineuzumab in patients with mild to moderate AD (see ARF related news story). There may be a glimmer of hope, however. According to a Lilly press release, prespecified analysis of data pooled from the EXPEDITION and EXPEDITION2 solanezumab trials suggests cognitive decline slowed in people with mild, but not moderate, AD, hinting that earlier treatment could provide some benefit. "The fact that there would be any benefit in a population of people who already have cognitive deficits is a huge win for the amyloid hypothesis," said Ryan Watts, Genentech, San Francisco, California. "I am cautiously optimistic," he told Alzforum. Lilly will discuss the next steps with federal regulators, according to their press statement. Unlike bapineuzumab studies, solanezumab trials have not been terminated. An open-label extension study will apparently go ahead as planned.

Many researchers believe that Aβ plays a key role in AD pathology, but so far no amyloid immunotherapy has proven effective in slowing cognitive decline in AD patients. "Up until now we've had all discouraging results; there was no clear cognitive benefit, even in mild groups," said Stephen Salloway, Brown University, Providence, Rhode Island. "This is the first possible evidence that there is a cognitive benefit in a mildly affected population."

The EXPEDITION trials enrolled more than 2,050 people age 55 and older. Those randomly selected for active treatment received 400 milligrams of intravenous solanezumab every four weeks for 80 weeks. In neither trial did mild or moderate AD patients benefit in outcomes that measure cognition (Alzheimer's Disease Assessment Scale—Cognitive subscore) or function (Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory). But when scientists combined data from both studies, those with the mildest disease showed evidence of a modest slowing in cognitive decline, according to ADAS-Cog data.

"The fact that there isn't a functional benefit probably isn't that surprising because in milder patients, there's less of a functional deficit in the first place," said Watts. Plus, even though it was necessary to pool the data to find what is likely a very modest effect, the hint of one in early stages of the disease argues that going earlier may even be better, suggested Watts. Salloway agreed: "If there is a mild benefit, and the biomarker effect matches it, it would support the idea that at earlier stages we may have a bigger impact," he told Alzforum.

How early the treatment would need to start is unclear. Several prevention trials are on the horizon (see ARF related news story), including one that will test the efficacy of Genentech’s antibody therapy, crenezumab (see ARF related news story). However, all researchers interviewed for this article said they would wait for biomarker data before they get too excited over the slight benefit in mild AD patients. It would be important to make sure that cerebrospinal fluid analysis, brain volumetric analysis by magnetic resonance imaging, and positron emission tomography to estimate plaque burden reflect the somewhat crude measurements of cognitive benefit, said Ranjan Duara, Mount Sinai Medical Center, Miami Beach, Florida. Lilly has shared some of the trial data, including CSF, amyloid PET, and MRI measures, with the Alzheimer's Disease Cooperative Study (ADCS) for independent study. The ADCS analysis will be presented at the American Neurological Association Annual Meeting in Boston, Massachusetts, and at the Clinical Trials on Alzheimer's Disease Meeting in Monte Carlo, Monaco, both taking place next October.

Today's top-line disclosure includes no in-depth data. One question pundits might be asking is how the placebo groups fared, given that faster-than-expected decline in cognition in the control groups in a Phase 2 study raised hopes that bapineuzumab would work—at least in those free of the ApoE4 allele. Eric Siemers of Eli Lilly told Alzforum that the placebo controls declined "as expected” in the solanezumab trials.

On the safety side, some mild side effects occurred more often in the drug compared to placebo groups; these included lethargy, rash, and malaise in the EXPEDITION1 group, and angina in EXPEDITION2. Vasogenic edema, which limited dosing in bapineuzumab trials, did not emerge as a major concern. The limited success of solanezumab may have to do with dosing, which can be much higher with solanezumab, said Watts. The two antibodies also target different Aβ epitopes.

Meanwhile, in the extension trial, EXPEDITION-EXT, 1,275 volunteers from the two Phase 3 trials will continue to get the same solanezumab dose every month for 100 more weeks. That study will wrap up in July of 2014. "Given the fact we are encouraged by efficacy data, and that the safety profile is quite good, we felt that it was appropriate to continue with the extension study while we're further evaluating the data," said Siemers.—Gwyneth Dickey Zakaib.

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  1. Quantitatively Assessing Lilly’s Solanezumab Trials Disclosure: More Than Meets the Eye

    Reports on Alzforum and in the mainstream media revealed that expert opinions on the solanezumab outcomes varied widely, ranging from dismissive to expectant, and from "the drug is dead" to "there is life yet for the amyloid-β hypothesis." Various predictions and interpretations were made, despite Lilly’s sparse press statements and suggestion to wait until the data presentations in October and discussions with the FDA.

    Lilly is bound by the Sarbanes-Oxley Act to disclose all information that may affect an investor's assessment of the company’s prospects; some questioned whether the press release—carefully parsed as it was—met this requirement. We examined whether more information was provided than seemed apparent, and whether a less impressionistic and a more quantitative assessment of solanezumab’s clinical effects could be made. We found that solanezumab could be exerting a small, but potentially clinically meaningful cognitive effect in mild AD patients.

    Lilly stated that the two trials included more than 2,050 patients (the planned sample size for each was 1,000). About two-thirds of each sample was mild AD, MMSE 20-26, and one-third was moderate AD, MMSE 16-19. Neither trial was significant on the ADAS-cog, but the two trials pooled were significant. The mild AD subgroups of EXPEDITION1 and 2 showed significance and a “trend” for solanezumab, respectively. The pooled mild AD groups showed significance. Neither the moderate AD subgroups nor the pooled moderate AD group showed significance.

    We used standard formulae to convert p values and sample sizes to z scores and standardized effect sizes (ES); that is, z = ES/([sqrt (2/N]), assuming that the standard deviation of the change in ADAS-cog and sample size N are about the same in each group. We then considered “best-case” and “worst-case” scenarios based on Lilly’s stated outcomes, and tabled the results below.

      EXPEDITION1 EXPEDITION2 Pooled
    Mild AD Sig*, N = 666 “Trend,” N = 666 Sig*, N = 1332
      “Best-case” P = .001, ES = 0.26 P = .06, ES = 0.15 P = .003, ES = 0.20
      “Worst-case” P = .049, ES = 0.15 P = .15, ES = 0.11 P = .02, ES = 0.13
    Moderate AD NS, N = 360 NS, N = 360 NS, N = 720
      “Best-case” P = .80, ES = -0.14 P = .54 , ES = 0.06 P =.37, ES = -0.04
      “Worst-case” P = .98, ES = 0.00 P = .98, ES = 0.00 P = .97, ES = 0.00
    Total NS, N = 1026 NS, N = 1026 Sig*, N = 2052
      “Best-case” P = .06, ES = 0.12 P = .06, ES = 0.12 P =.008, ES = 0.12
      “Worst-case” P = .11, ES = 0.10 P = .24 , ES = 0.07 P = .049, ES = 0.09

    We considered the “best-case” scenario for the ADAS-cog for the mild AD subgroups as p = .001 for trial 1 and p = .06 for trial 2, allowing for the strongest “statistical trend.” Calculated ESs for this scenario are ES = 0.26 and ES = 0.15, for trial 1 and 2, respectively; and for the pooled mild AD group, it is ES = 0.20. For the ES to be 0.26 in trial 1, however, the ES for the moderate AD group must trend negative at -0.14 in order to ensure that the trial overall has a non-significant p value = .06. The ES for the moderate AD group in trial 2 must be 0.06 in order for trial 2 also to be non-significant at the strongest trend, p = .06. (The pooled ES for the moderate subgroups would be ES = -0.04). Finally, the best case when the two non-significant trials are pooled is p = .008 and ES = 0.12.

    The “worst-case” scenario assumed p = .049 and p = .15 for mild AD in each trial, i.e., the highest p values for significance and trend, yielding a pooled ES = 0.13 for mild AD. The p value for the combined trials could be as high as p = .049 with an ES = 0.09, or as low as p = .01 with an ES = .12, with the moderate AD effect sizes ranging from 0.00 or 0.10.

    In sum, the best- and worst-case effect size scenarios for the pooled mild AD subgroups are 0.20 and 0.13, and for the pooled trials, 0.12 and 0.09.

    Drug-placebo differences in ADAS-cog points can be estimated by multiplying the ES by the SD of ADAS-cog change. Thus, an ES = 0.20 can represent from 1.2 to 1.8 points' difference if the SD of the placebo group is from 6 to 9 over 18 months, as it is in other trials. Similarly, the slope reduction—viewed by some as an indicator for “disease modification”—may range from 13 percent to 30 percent if the mean ADAS-cog worsening in the placebo group ranges (also) from 6 to 9 over 18 months.

    It is possible that solanezumab—if its statistical effect is robust and an MRI biomarker is properly supportive—could gain marketing approval for mild AD on the basis of these trials alone, as the FDA has stated it would accept a single cognitive outcome criterion and a single trial (rather than two) under certain conditions. This, however, seems to us to be very unlikely. More likely, a confirming trial needs to be done, and would involve about 1,000 mild AD patients to avoid unwanted outcomes due to play of chance. Of course, it is quite possible that both trials were unlucky in randomly estimating the true effect size and the truth lies elsewhere. On the plus side, adverse events don’t appear to be issues.

    These best- and worst-case estimates—requiring certain assumptions—provide information on why Lilly apparently is not discontinuing solanezumab’s development. These estimates can be used as a framework on which to compare the fuller presentations of the outcomes of both the solanezumab and the bapineuzumab trials.

  2. That there may be a pale silver lining doesn't change the fact that clinical trials consistently show no benefit. As the article says "Up until now we've had all discouraging results; there was no clear cognitive benefit, even in mild groups."

    When the evidence goes against a hypothesis, surely it is sensible to question it? I suggest that the amyloid hypothesis is false and we should fund more promising avenues of research.

  3. I think it is time to finish this "long goodbye" to the hypothesis of Aβ as the cause of AD. Why long? Twenty-seven years of failures in research based on a flawed hypothesis of oligomers, Aβ, and tau accumulation. As we are seeing now, that flawed hypothesis led to dollars spent without a consistent result.

    It is time to "think big" about new ways for research to find drugs that can enhance micro- and macrovascular brain function, reduce the high oxidative stress in the neurons, and enhance mitochondrial function and energy supply to the neurons. Maybe then we will be able to prevent and treat Aβ disorders.

References

News Citations

  1. Clinical Trials of Intravenous Bapineuzumab Halted
  2. Collaborative Umbrella CAPs Three Prevention Trial Initiatives
  3. A Close Look at Passive Immunotherapy Newbie, Crenezumab

Therapeutics Citations

  1. Solanezumab

External Citations

  1. Lilly press release
  2. EXPEDITION
  3. EXPEDITION2
  4. EXPEDITION-EXT

Further Reading