Lilly’s Donanemab Set For Broad Indication, No Tau PET Imaging Condition Following US FDA Panel Nod

Eli Lilly and Company’s Alzheimer’s treatment donanemab appears primed for US approval with a broad indication and without requirements for tau PET imaging after a smooth US Food and Drug Administration advisory committee review.

However, the anti-amyloid agent comes with clinical practice questions inherent with the dosing-to-clearance strategy that was used in the Phase III trial, including when to stop treatment, how frequently to assess amyloid plaque levels through PET, and when and whether to restart donanemab therapy.

The Peripheral and Central Nervous System Drugs Advisory Committee voted unanimously on 10 June that donanemab’s efficacy had been demonstrated, and the risk-benefit assessment was positive, in Alzheimer’s disease patients with mild cognitive impairment and mild dementia.

The panel gave a strong endorsement to a drug that has faced a host of regulatory hiccups in its path to market, including an initial complete response letter for an insufficient safety database, a second-cycle review extension, and a late-review-cycle announcement of an advisory committee meeting that led to a missed user fee goal date. (Also see "Lilly’s Donanemab Delay: Labeling, Real-World Operationalization May Be Reason For Adcomm" - Pink Sheet, 9 March, 2024.)

Should Tau PET Imaging Be Required?

The Phase III TRAILBAZER-ALZ 2 trial (also known as Study AACI) contained two design features that distinguished it from other anti-amyloid clinical programs, but also created complexities for labeling and implementation in clinical practice. (Also see "Lilly’s Donanemab: US FDA's Questions Focus On Patient Selection, Dose Cessation" - Pink Sheet, 6 June, 2024.)

The FDA asked the panel whether the clinical efficacy results seen in Study AACI extended to the entire population of patients, including those with no or very low levels of tau.

Patients with low/medium tau levels and high tau levels were enrolled into the study. Subjects with no or very low tau levels were excluded from the placebo-controlled trial, but were eligible to enroll in the Study AACI Safety Addendum.

Most advisory committee members said they would be comfortable with an indication spanning the tau spectrum.

Despite no direct clinical evidence in individuals with no or very low tau levels, committee members generally said they could extrapolate efficacy to that subgroup, in part because biomarker data in the safety addendum demonstrated target engagement in those patients. The reductions in amyloid, plasma p-tau 217 and glial fibrillary acidic protein (GFAP) in patients with no and very low levels of tau were similar to those seen in Study AACI.

“The Phase III, as well as the Phase II, provide robust evidence of effectiveness, and the Phase III hitting on the primary and the key secondaries, that is all good,” said Merit Cudkowicz, neurology chair and director of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital. “I think for the no or the very low, all we have is really the biomarker effect and the safety from the extension study, but there is precedent from other studies that lowering amyloid is associated with clinical effect as well.”

Panelists said it would be impractical to require that patients undergo tau PET imaging prior to treatment and that such a mandate would impede access.

Tau PET is more challenging to assess than amyloid PET, said Kathleen Poston, a neurologist and director of the Stanford Movement Disorders Center.

“Amyloid positivity/negativity is a fairly commonplace thing that somebody is able to do, whether it be in CSF or PET, soon likely in plasma as well, but the degree of tau abnormality can only be determined via tau PET and it’s not just a visual read that can be done,” she said. “This requires very sophisticated, higher … academic centers that have imaging capabilities in many cases.”

“From a very practical perspective, I think this would be not a wise thing to have as a barrier,” Poston said. “If there had been no biomarker data available in that low group, I would have much more pause. But with the biomarker data there both in amyloid PET and in two plasma markers, I am comfortable with that both from a data perspective and from a pragmatic perspective.”

“The practical question is should tau PET be stipulated, should it be required?,” said Nilufer Ertekin-Taner, chair of the neuroscience department at Mayo Clinic in Jacksonville, FL. “From a practical standpoint, it is my impression that it should not be.”

“Getting amyloid PET is already hard enough and already these types of studies and inclusion in these types of trials are easier for patients of certain social and ethno/racial groups and geographical location,” she said. “Inclusion of requirements for a PET tau will further limit the number of patients who can have access to these types of medications.”

Dose Cessation Innovative But More Data Needed

Study AACI also was novel because a treatment stopping rule was included allowing cessation of donanemab dosing guided by amyloid PET levels measured at 24, 52 and 76 weeks after the start of treatment. If the amyloid plaque level was <11 Centiloids on a single PET scan, or 11 to <25 Centiloids on two consecutive PET scans, the subject was eligible to switch to placebo.

David Hyman, Lilly’s group VP and chief medical officer, was asked how doctors would know when to stop therapy, and when or if to restart it.

“When we look at what could be a reasonable time point to repeat an amyloid PET scan to determine clearance, about one year seems like a pretty good time point to do that,” Hyman said. “We predict that at one year, approximately two-thirds of patients would have a visually negative PET scan and be able to discontinue should they want to do that.”

“Exactly what you’re optimizing for, if you’re a health care system looking to absolutely minimize the use of the product, you might bring that a little bit earlier or a little bit later, but I think in general about a year … represents the optimal time point for most patients,” Hyman said.

Several committee members said the dose cessation approach was an innovative trial design that, when adapted to clinical practice, could reduce patient, caregiver and health care system burden. However, more long-term data are needed on the duration of amyloid clearance, how frequently patients should be monitored, when to re-start donanemab treatment, and the potential adverse effects of stopping, then restarting therapy.

“I am very encouraged by the model here of looking at a biomarker or evidence of target engagement and target clearance, which was the goal of the therapy, and being able to come up with a conceptual time when that therapy does not need to be continued,” Poston said.

But she also said when and how many times to retest amyloid if levels have not cleared after one year and when to consider restarting treatment after stopping remains unclear.

“Neither of these questions were answered by the data presented to us today, and I think as a provider those are questions I would eventually want to have an answer to, to practically implement this in clinic,” Poston said.

“We predict that at one year, approximately two-thirds of patients would have a visually negative PET scan and be able to discontinue should they want to do that.” – Eli Lilly’s David Hyman

The ability to stop treatment could benefit patient compliance, said Sarah Dolan, a consultant to the Critical Path Institute and the panel’s acting consumer representative.

“The fact that we can discontinue potentially this medicine at some point when amyloid’s been cleared could actually be a motivational factor for patients to stay compliant with testing, with their infusions,” Dolan said.

However, patient and caregiver education would be needed if treatment is stopped because amyloid has cleared, she said.

“Patients that have been discontinued because they’ve cleared amyloid can celebrate that, but there always is going to be that concern in the back of their heads, ‘Is it coming back?’ ‘Am I getting worse?’ I do think it would be beneficial for the applicant to consider tools to give to patients that are no longer being treated, but are being monitored and their care partners to watch them at home because potentially you could have symptoms come back before your next PET scan,” Dolan said.

Daniel Press, chief of the cognitive neurology unit at Beth Israel Deaconess Medical Center, said the treatment cessation paradigm could help increase access. He said infusion capacity is a rate-limiting step at many hospitals.

Donanemab's once-a-month administration and 30-minute infusion, with the potential to stop therapy when amyloid is negative, will allow more patients to get treated, Press said.