FDA lays out donanemab concerns ahead of meeting, as Lilly vigorously defends safety

The docs for Eli Lilly’s donanemab advisory committee meeting are in: the FDA has raised concerns about the use of tau PET imaging during the clinical trials, the cessation of dosing after amyloid clearance and whether the small risk of brain bleeds in patients taking antithrombotics outweighs the benefits.

It’s a lot to unpack, but many of the issues raised were already on Lilly’s radar. The Peripheral and Central Nervous System Drugs Advisory Committee is set to convene on Monday to debate the merits of Lilly’s Alzheimer’s disease therapy donanemab, which is being considered for approval. It would follow Biogen and Eisai’s Leqembi, which is already on the market.

Donanemab was tested in the 1,736-patient phase 3 TRAILBLAZER-ALZ 2 trial (referred to as Study AACI in the briefing documents), which measured a change in baseline on the Alzheimer’s Disease Rating Scale (iADRS) at 76 weeks. This scale detects disease progression and treatment differences.


Issue 1

The first issue raised by the FDA is the use of PET imaging to determine which patients were likely to progress during the study. Patients had to show the presence of tau on these scans to be included. Lilly used this criteria to split the populations based on low/medium tau and the overall participants. Lilly thought that it might be tougher to discern a treatment effect in patients with high tau since their disease would be more advanced.

Despite using this in the trial, Lilly did not suggest tau scanning be included in the prescribing information. The FDA seems to be taking issue with the company’s exclusion of patients with very low or no tau from the controlled portion of the study and for prioritizing the low to medium group.

In response, Lilly said the science on tau PET imaging has allowed clinical trial sponsors to select patients with less severe cognitive impairment where intervention is likely to be more beneficial.

Throughout the decades of clinical failure in Alzheimer’s, sponsors have theorized that if they could only get to patients before the disease pathology was too advanced, they might be able to slow the progression of the disease. That science officially arrived around 2012 with the FDA’s approval of an amyloid-imaging agent.

“Over the past 3 decades, AD development programs have evolved from enrolling patients solely based on clinical symptoms, to now enrolling patients based on the confirmed presence of amyloid pathology,” Lilly explained.

So Lilly used this imaging strategy to ensure treatment groups were well balanced for disease burden, increase the likelihood that the study could determine a treatment effect, further the field’s scientific understanding of Alzheimer’s and to innovate on the clinical trial paradigm and accelerate the development of future therapies.

Lilly did not intend for tau burden to be a selection criterion for patients in the real world because donanemab is expected to have benefits regardless of tau levels, as shown in the clinical trials, and because tau testing is not standard practice outside of clinical trials.

Finally, tau levels are not predictive of disease progression and not predictive of drug response, whereas assessing the presence of amyloid is crucial to determine the drug effect, Lilly said. 


Issue 2

The second issue raised by the FDA is that patients ceased treatment with donanemab after reaching a certain clearance of amyloid as detected on PET scans.

“The applicant theorized that cessation of donanemab dosing once brain amyloid on PET was reduced beyond a specific threshold would not adversely affect clinical outcomes,” the FDA explained.

The percentage of patients who were gradually able to stop treatment increased over time, with 17%, 42%, and 60% of patients at weeks 24, 52, and 76, respectively, reaching the threshold.

Lilly confirmed a statistically significant treatment effect on the primary endpoint, with patients showing less decline on iADRS as compared to placebo in the low/medium tau population and the overall population.

The company defended this approach with evidence showing that half of the patients achieved treatment-related amyloid clearance by week 52. After treatment, patients slowly regained amyloid but there was no rebound in the 12 months after stopping at the six-month mark.

Lilly also saw significant efficacy at 18 months in patients who had achieved early amyloid clearance.

This regimen, while new to the Alzheimer’s field, is used for chronic, life-long treatment and could help reduce the treatment burden, Lilly said.

Lilly acknowledged that the trial did not test the dosing regimen with some patients stopping at one point and others continuing, but said that would have been a massive and expensive trial to conduct.

“However, the statistically significant and clinically meaningful efficacy results demonstrated in Study AACI reflect the implementation of this personalized approach and therefore should provide confidence to the scientific community as to the suitability of this approach,” Lilly explained.


Issue 3

On safety, the FDA raised issues that are familiar to Lilly’s monoclonal antibody competitors Biogen and Eisai. Leqembi holds a black box warning of amyloid-related imaging abnormalities (ARIA), which is the chief concern of this class of medicines. ARIA can suggest a risk of brain bleeds or swelling, and several deaths have occurred across the class due to this adverse event, including at least three from the donanemab group in Lilly’s Study AACI.

There are two types of ARIA, edema (ARIA-E) and hemosiderin deposition (ARIA-H), which are swelling and bleeding in the brain, respectively. ARIA is usually asymptomatic and goes away over time, however, in rare cases, it can be severe and lead to death.

Leqembi’s warning specifically describes a risk of ARIA and intracerebral hemorrhage greater than 1 cm, with an increased risk in patients who are ApoE ε4 homozygotes, which is a genetic form of Alzheimer’s. The warning recommends testing for ApoE ε4 status.

Lilly reported an adverse event rate of 5% in the patient population, with 25% experiencing ARIA-H microhemorrhage, 24% ARIA-E, 15% ARIA-H superficial siderosis (a complication of a brain bleed) and 13% headache.

“Overall, in AACI there was an imbalance in mortality that was primarily driven by ARIA-related deaths,” the FDA said.

While ARIA is a known risk, the FDA said that there was limited exposure to non-aspirin antithrombotic medications during Lilly’s trial, which means a conclusion cannot be drawn as to the actual risk of these events associated with donanemab.

Medications in the monoclonal antibody class already have a warning to take caution when co-prescribing Alzheimer’s meds and anticoagulants or a thrombolytic agent.

Since ARIA-E can mimic neurologic deficits just like a stroke, the FDA said prescribers should use caution to determine whether the symptoms might be due to the Alzheimer’s med before administering an anticoagulant.

Lilly has vigorously defended the safety of donanemab and did so again in the lengthy FDA rebuttal. Specifically, the company said that the ARIA results are consistent with the monoclonal antibody class. Donanemab has been tested in 2,802 patients across Lilly’s program, which is the largest safety database for any amyloid-targeting therapy.

“Beyond the known class-risk of ARIA with a low frequency of fatal events (0.3%), there is no evidence of an increase in risk of mortality or excess death related to donanemab,” Lilly wrote.


The questions

The matter is now in the committee’s hands. The FDA has asked the advisors to consider the following questions:

  • Whether the available data provide evidence of the effectiveness of donanemab for the treatment of Alzheimer’s disease and whether there is support for effectiveness across the subgroups based on tau PET imaging.
  • The dosing regimen used in the clinical studies that completed treatment based on reduction of amyloid plaques on PET imaging and are there scientific and/or clinical considerations that may factor into a decision to stop or continue dosing with donanemab if approved?
  • The overall benefit-risk assessment of donanemab for the treatment of Alzheimer’s disease and are there subgroups of patients for whom the benefit-risk assessment may be more or less favorable?

The meeting begins Monday at 9 a.m. ET.