September 4, 2012 10:09 pm

Eli Lilly’s solanezumab faces grim prospects of attaining conditional FDA approval in mild Alzheimer’s

This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com

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Eli Lilly’s (NYSE:LLY) Alzheimer’s disease (AD) therapeutic solanezumab has a low chance of attaining conditional US approval for mild AD, several physicians and regulatory experts told BioPharm Insight. One expert, however, noted mixed results seen in Lilly’s pivotal human trials coupled with the unmet medical need warrants approval.The Phase III assessment demonstrated a significant positive efficacy signal in a subgroup of mild AD patients.

Current FDA-approved medicines for AD include Pfizer (NYSE:PFE)/Eisai’s (TYO: 4523) Aricept and Forest Laboratories’ (NYSE:FRX) Namenda. While these agents claim to provide symptomatic relief to patients by improving cognitive status in mild-to-moderate AD, they do not reverse the effects of AD or stop the disease from progressing. Therapeutics such as solanezumab are said to be disease modifying and intend to target core biological aspects of the disease.

FDA conditional approval is modeled after accelerated approval, which is granted when a drug treating serious, life-threatening conditions shows great promise in earlier testing without the requisite large-scale Phase III assessment. Drug developers are required to study the drug further and verify clinical benefit as part of the conditional approval provision. The FDA can revoke approval if later testing does not reproduce previous findings, as was the case with Roche (VTX:ROG)/Genentech’s Avastin for breast cancer.

If conditional approval is granted, it would be the result of patient advocacy pressure and the desperation for therapy in an area of huge unmet medical need, the other experts said, rather than the Phase III data. However, William Thies, chief medical and scientific officer of the Alzheimer’s Association, indicated the non-profit organization does not intend to put any pressure on the FDA to grant solanezumab conditional approval in mild patients.

Experts noted at least one additional study is likely to be requested by the agency.

“We plan to meet with appropriate regulatory authorities in coming months to discuss next steps for solanezumab,” according to a Lilly spokesperson. “It’s premature to speculate on plans for future studies at this time.”

Lilly’s Phase III trials consisted of the EXPEDITION 1 and EXPEDITION 2 studies. The 1,000-patient EXPEDITION 1 study did not demonstrate statistically significant benefit on predefined assessment scales of cognitive and functional abilities in the overall mild-to-moderate patient population. Lilly then modified the predefined study goal in EXPEDITION 2 to include measurement of only the cognitive scale in the subgroup of mild patients. The revision, however, did not yield a statistically significant response, according to a Lilly press release.

Pooled data from EXPEDITION 1 and EXPEDITION 2 demonstrated a statistically significant slowing of cognitive decline in patients with mild AD but not in moderate AD, the release said.

Solanezumab’s approval chances slim

Solanezumab “does not have a snowball’s chance in a very hot place” of attaining conditional approval, said an ex-FDA official and a current drug industry consultant. Missing the primary endpoint in a Phase III is “essentially fatal” when dealing with FDA, he said.

While the FDA’s neurology division is unpredictable and occasionally has shown flexibility in the setting of rare conditions, conditional approval in mild AD is highly unlikely in this case, said a second industry consultant. FDA defines rare conditions as those afflicting fewer than 200,000 people in the US. According to Alzheimer’s Association data, 5.4 million Americans are living with AD.

The FDA neurology division seems to always want two studies and does not approve drugs on only one study, said an ex-FDA official and third consultant. With less-than-robust findings and the fact that another drug in the same class failed its Phase III trials, Lilly is unlikely to get a conditional approval, the consultant said. Pfizer, Johnson & Johnson (NYSE:JNJ) and Elan’s (NYSE:ELN) bapineuzumab failed in mild-to-moderate AD.

Chances for conditional approval are slim, agreed Virginia-based regulatory consultant David Lim, unless Lilly can show the data is both statistically and clinically meaningful.

However, according to Dr Marwan Sabbagh, research medical director at Banner Sun Health Research Institute, Arizona, the medical field is desperate enough that conditional approval is possible in mild AD patients. He noted the agency would then restrict use to only particular AD experts and would implement MRI monitoring.

While bapineuzumab can be deemed “dead,” Sabbagh noted solanezumab is “not as dead” based on the “mixed” signal seen in Phase III. Bapineuzumab did not meet predefined Phase III study goals assessing cognitive and functional scales in mild-to-moderate AD, recent company announcements revealed.

Solanezumab seems indeed to be more promising than bapineuzumab, the third consultant said, and there is some pressure on the FDA neurology division to modify its stance. She added though, it is still unlikely Lilly will be able to file for approval on the present data set.

Thies noted the Alzheimer’s Association would not intervene or put pressure on the agency despite the desperation for AD therapeutics. The organization has not received a swell of calls from patients seeking conditional approval nor has he heard that other advocacy groups plans to pressure the FDA, he said.

New trials likely if Lilly pursues mild AD

Lilly has done a retrospective data dredge and now needs to confirm the new hypothesis that the drug is effective in mild patients in a prospective trial, the first consultant said. The FDA hard-liners take the view that if a trial generates a new hypothesis, such as that a certain subset of patients may benefit, that is considered exploratory and needs to be confirmed in a subsequent trial or trials, he explained.

The FDA will very likely ask for another study, agreed the second consultant said. The question is, he noted, will it accept either of the current studies (or their combined result) as a supportive study requiring one further confirmatory study or will it require two new Phase III trials for approval.

Further study in mild AD would require a trial of at least 2,000 patients, Thies said. He noted the 18-month treatment period implemented in Phase III mild-to-moderate trials is likely to be adequate for mild assessment. Sangram Sisodia, professor of neurosciences, The University of Chicago, cautioned one may not see effects in mild patients if the treatment window is too short.

In both the EXPEDITION study protocols, mild AD was defined as a baseline Mini-Mental Status Examination (MMSE) score of 20 to 26 and moderate AD was defined as a baseline MMSE score of 16 to 19.

Solanezumab would need to have clear benefit on brain imaging scans and beta-amyloid levels that consistently support the cognitive outcomes seen in Phase III in order to gain conditional approval, said Dr Anton Porsteinsson, professor, Department of Geriatric Psychiatry, University of Rochester Medical Center. Beta-amyloid is a protein most often found in brains of AD patients.

The effect size seen in mild patients in Phase III seems small however, as a very large sample created by combining two large trials was needed, noted Dr Gregory Cole, associate director of the UCLA Alzheimer’s Center. The effect size is important if you have the inconvenience of hospital infusions and the high expense of treatment, he added.

There is no evidence of vasogenic edema, a potentially serious form of brain swelling previously associated with solanezumab and bapineuzumab, and there is good safety and tolerability overall with solanezumab, Porsteinsson said. The findings support the theory that beta-amyloid contributes to the disease and the field’s interest in targeting milder patient groups, he noted.

The second consultant said if Lilly chooses to focus its new study on mild patients, it runs the risk many companies have in chasing subgroups that looked good post hoc but then failed in subsequent clinical trials.

Full data from EXPEDITION 1 and EXPEDITION 2 are expected to be presented at the American Neurological Association meeting on 8 October and at the Clinical Trials Conference on Alzheimer’s Disease meeting on 30 October.

Eli Lilly’s current market cap is USD 52.1bn.

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