Lilly Targets Aduhelm With Aggressive Plans For Donanemab In Alzheimer’s
Executive Summary
Lilly plans a head-to-head study of donanemab versus Biogen’s Aduhelm to see which clears amyloid plaque better and has begun a rolling BLA toward accelerated approval of the Alzheimer’s drug.
Eli Lilly and Company placed a target on the back of recently approved and controversial Alzheimer’s drug Aduhelm (aducanumab) on 26 October, outlining plans during its third quarter earnings call to run a Phase III head-to-head clinical trial testing the company’s donanemab against Biogen, Inc./Eisai Co., Ltd.’s drug to see which antibody does a better job of clearing amyloid from the brain.
The planned head-to-head trial, slated to begin before the end of 2021 and expected to report primary endpoint data during the second half of 2022, was just one of several major research and development updates by the Indianapolis-based firm. Lilly chief scientific officer Daniel Skovronsky said the company completed enrollment in the 1,500-patient, pivotal Phase III TRAILBLAZER-ALZ 2 trial of donanemab and expects data from that study by mid-2023. It already has enrolled 300 patients in a single-arm safety addendum to the trial that will add to the safety database for donanemab, he added.
Lilly also has begun a rolling biologic licensing application (BLA) submission to the US Food and Drug Administration, seeking to complete the filing over the next few months and perhaps obtain accelerated approval of donanemab before the end of 2022. (Also see "Lilly’s Donanemab Could Be A Near-Term Aduhelm Competitor" - Scrip, 24 Jun, 2021.) With that plan, plus the head-to-head study (TRAILBLAZER-ALZ 4) and the just initiated TRAILBLAZER-ALZ 3 prevention study of donanemab in patients with Alzheimer’s brain pathology but no symptomology, Lilly is building on ambitions stated earlier this year to follow the approval pathway established by Biogen and the FDA and use it to take a leadership spot in Alzheimer’s disease. (Also see "Lilly Is Revved Up About Alzheimer's Opportunity" - Scrip, 3 Aug, 2021.)
“We're committed to facing the challenges of effectively communicating donanemab's clinical data and value proposition and to ensuring that the diagnostic and patient management ecosystems are adequately well prepared,” Skovronsky told the investor call. “Given the current environment, we think it's reasonable to have modest expectations for the scale of patient impact for anti-amyloid therapies available under accelerated approval prior to the readout of their definitive Phase III data.”
To date, Biogen has gained limited traction with Aduhelm sales in the US following the product’s accelerated approval based on its ability to clear amyloid from the brain of Alzheimer’s patients. The company reported just $300,000 in third quarter sales as it struggles to convince doctors to prescribe and payers to reimburse the therapy. It is possible that positive data from a yet-to-be-started confirmatory trial needed for full approval of Aduhelm could improve prescribing and reimbursement. (Also see "Biogen’s Q3 Aduhelm Sales Even Worse Than Expected" - Scrip, 20 Oct, 2021.)
“Assuming potential accelerated approval for donanemab in the second half of 2022, our expected TRAILBLAZER-ALZ 2 Phase III readout by mid-2023 would follow quickly, meaning the window of accelerated approval without definitive Phase III data is likely to be brief,” Skovronsky said. “Assuming positive Phase III results, we should be confident in the mid- and long-term opportunity for donanemab if approved.”
Analyst: Lilly Seeking Quick Advantage With Head-To-Head Design
In a same-day note, Evercore ISI analyst Umer Raffat called the plan for a head-to-head trial with Aduhelm interesting, but noted that with amyloid clearance as a primary endpoint, Lilly’s primary goal appears to be to measure clearance at a relatively early date on a hypothesis that its drug clears amyloid plaque more quickly. Both drugs have shown evidence of amyloid clearance to undetectable levels over longer periods of time, the analyst added.
“Is Lilly hoping to have an earlier timepoint from this trial read out shortly into the [expected] launch,” Raffat pondered. The planned primary endpoint is not a clinical endpoint, he said; amyloid clearance is a surrogate endpoint that was accepted by the FDA for the accelerated approval of Aduhelm, a controversial decision that contradicted the recommendations of an FDA advisory panel. (Also see "Biogen/Eisai Win On Aduhelm Approval Bet And Wager Next On Price" - Scrip, 7 Jun, 2021.) Lilly has pointed to garnering data from its pivotal TRAILBLAZER-ALZ 2 study by mid-2023, whereas Biogen has nine years to complete its confirmatory post-marketing study of Aduhelm’s benefit. (Also see "Accelerated Approval Of Lilly’s Alzheimer’s Drug Could Last About 15 Months, CEO Says" - Pink Sheet, 14 Jul, 2021.)
Raffat said an unanswered question coming out of the Lilly call is whether the head-to-head TRAILBLAZER-ALZ 4 study will assess clinical efficacy as well as amyloid plaque clearance, perhaps with a secondary endpoint using a longer time interval. He also wondered whether the study will use a 12-month endpoint of Clinical Dementia Rating-Sum of Boxes (CDR-SB).
Bernstein analyst Ronny Gal said Lilly is “seeking to bury Aduhelm post-2023 given it will not have efficacy data, and with the head-to-head study reading out even before the Lilly pivotal (late 2022), Lilly will have a strong argument for efficacy superiority.”
“I would say by clearing plaque faster and deeper, we believe that as well as identifying the right patients, we've optimized the chances for showing compelling benefits in the Phase III, which, as we've said, is what was going to show significant uptake in the class,” Lilly Neuroscience president Anne White said. “We continue to see the same opportunity for donanemab in the mid to long term once these challenges are addressed and the confirmatory data is available.”
R&D Updates Beyond Donanemab Offer A Mixed Bag
Beyond its donanemab updates, Lilly execs also noted during the company’s call that it is pulling the plug on Pfizer Inc.-partnered tanezumab in osteoarthritis pain after the NGF inhibitor drew an FDA complete response letter. (Also see "Tirzepatide’s Glowing Obesity Data Steal Show On Lilly’s Earnings Call" - Scrip, 28 Apr, 2022.) Lilly also is ending development of its tau-targeting Alzheimer’s candidate zagotenemab after it failed to meet the primary endpoint in a Phase II study. Evercore ISI’s Raffat said neither decision was a surprise and that the call on tanezumab was a “long time coming.” (Also see "Pfizer/Lilly Had Big Ambitions For Tanezumab; Are They Finally Dashed?" - Scrip, 25 Mar, 2021.)
On a more positive note, Lilly revealed that it has filed a new drug application for the dual glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide for approval in type 2 diabetes and used a priority review voucher with the filing, which should set an FDA action date during June 2022. (Also see "Lilly's Tirzepatide Shows Up Novo's Ozempic In Head-To-Head Diabetes Trial" - Scrip, 4 Mar, 2021.) Skovronsky said Lilly is optimistic about the drug’s prospects due to the findings of the SURPASS-4 study for hemoglobin A1c control and weight loss, with benefit seen past the trial’s 52-week treatment period and out to two years.
Solid Financial Quarter Boosted By COVID-19 Revenues
Overall, Lilly reported 18% worldwide year-over-year sales growth for the quarter, to more than $6.77bn, driven 17% by volume and 1% by benefits from foreign exchange. In the US, revenue rose 26% year-over-year to $3.99bn – with 22% of that due to volume and 4% attributed to higher realized prices. When excluding $393m realized from sales of COVID-19 therapies including Olumiant (baricitinib), domestic revenue was up 14%, the company said. Ex-US revenue of $2.78bn rose 8% year-over-year, with lower realized prices creating a 4% headwind to that business.
The pharma’s key growth products – Trulicity (dulaglutide), Taltz (ixekizumab), Verzenio (abemaciclib), Jardiance (empagliflozin), Emgality (galcanezumab), Olumiant, Tyvyt (sintilimab), Retevmo (selpercatinib) and Cyramza (ramucirumab) – grew by 17% and accounted for 58% of the quarterly revenue, Lilly pointed out. “Revenue attributable to our newer medicines … now represents nearly 60% of our core business this quarter, an important indicator for our long-term growth potential,” CEO David Ricks said.