When the FDA approved an Alzheimer’s disease therapy on the basis of its ability to reduce a known hallmark of the disease in June, a lightbulb lit up at Eli Lilly.
The Indianapolis-based drugmaker had a therapy that could do the same, with clinical data showing it did so quickly and consistently. But the drug had been put on the backburner—with research slowly plugging away—without a regulatory path forward in the near future. Now, not only had a window opened, but Lilly's neuroscience team figured they might even be able to beat their competitor to the punch with a golden ticket: proof that their drug actually slows the progression of the disease.
That approval was, of course, for Biogen’s Aduhelm, which won a green light based on its ability to clear amyloid plaques from the brain, rather than clinical efficacy. This is known as a biomarker, which is a measurable hallmark of a disease that can be used as a surrogate endpoint to reasonably predict whether a drug works. Biomarker evidence can be used to support an accelerated approval at the FDA.
Lilly had always hoped to file donanemab for an accelerated approval, but found little interest at the FDA without further research. The company designed its phase 2 Trailblazer-ALZ clinical study as a registrational trial, just in case, with multiple biomarkers surrounding the two main theories behind Alzheimer’s: amyloid and tau. Weeks before the Aduhelm decision, though, one executive said Lilly expected to need to conduct at least two more studies before filing donanemab at the FDA.
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“We had not seen a lot of pickup by the FDA and in the field for any one of those becoming a pathway for accelerated approval, until early June,” said Mark Mintun, M.D., Sr. VP of Neuroscience R&D for Lilly. He’s also the president of Lilly unit Avid Radiopharmaceuticals.
Alzheimer’s disease is not well understood, but the current thinking is that abnormal proteins called beta amyloid clump together in the brain and disrupt cell function. Another protein, called tau, strings together in the part of the brain involved in memory and forms tangles inside neurons, blocking the communication between the cells. When amyloid builds up into plaques, it pushes the tau throughout the brain.
Once the FDA signaled that a reduction of amyloid was a suitable surrogate endpoint for Alzheimer’s, Lilly went full-bore behind the effort to push donanemab forward. The pharma giant also consolidated neuroscience into one unit in August, to be helmed by Anne White, who was serving as senior vice president and president of Lilly Oncology.
“Our direction is the same, it's just that the progress and some of the success has led into this new phase that makes sense for us to establish a business unit,” Mintun said in an interview.
Now, Lilly has a concentrated group of people to focus on all the issues that come up as new Alzheimer’s treatments come to market.
Show me the data
Getting a therapy across the FDA finish line based on a biomarker is great, but where’s the efficacy data? Mintun said that as fast as Lilly is moving to get an accelerated approval for donanemab, they are also working behind the scenes to collect data on the looming question: Do these new Alzheimer’s drugs actually work?
Lilly began the phase 3 portion of donanemab’s clinical development, Trailblazer-ALZ 2, at risk with 1,500 patients. That program kicked into gear after a positive readout in January. The study has now closed to new patients, and 18 months after the last patient starts dosing, the world will get the data. That puts a readout sometime in the first half of 2023, Mintun said.
“That’s for us the next big step, in 2023. That's not that far away, the way things go in Alzheimer's disease,” he said.
Lilly is preparing for an accelerated approval to arrive as early as next year as long as the submission is in by the end of 2021. If the efficacy data is strong in 2023, that could support a full approval.
“We don't feel like there is going to be a huge lag between the biomarker and the clinical data,” Mintun said.
That’s key because the FDA gave Biogen nine years to complete a phase 4 study to prove Aduhelm actually works. So based on Mintun’s timeline, Lilly could have the data to back up donanemab well before Biogen gets the same for Aduhelm.
Even after approval, Mintun said the phase 3 program has a second long-term follow-up phase planned after the 2023 readout.
“That's probably one of the more powerful things that pharmaceutical companies can do is to take the patients who we have a lot of data on when they entered the trial … and then look at that continued arc of whether they go downhill or whether they stabilize,” Mintun said. The company also wants to collect real-world data on donanemab’s use.
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Mintun admits that the pharmaceutical industry has not done a great job of preparing the market for a breakthrough medicine that has a massive unmet need, or the follow-up data that is needed to boost confidence in the new therapies.
“The field needs to come together and say what's the best way to do this,” Mintun said. “Maybe people haven't felt compelled to figure this out but I think we all feel a little differently about it right now and I hope that translates into action.”
Biogen has run into myriad problems trying to get onto the market: the original label for the therapy would cover 6 million Americans. While Biogen has priced Aduhlem at $56,000 per year, payers have balked at the estimated total cost that could be as high as $100,000 per patient. The FDA ultimately walked back the label.
Lilly, on the other hand, is already having conversations about reimbursement and access issues that will face donanemab should it be approved. The company is preparing information for coverage decisions by agencies such as the Centers for Medicare and Medicaid Services. Before the Aduhelm label change, estimates placed the cost to Medicare at $29 billion.
Mintun also believes that Lilly and the industry need to step up diagnostic efforts to get patients into trials well before they start to see symptoms to ensure the best outcomes.
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“We feel that combining both early and accurate diagnosis with therapy is going to be a key to being able to make a difference in this disease,” Mintun said.
Picking a horse
Lilly has more than donanemab in the Alzheimer’s pipeline that will now be under the purview of the new neuroscience unit. The most advanced is zagotenemab, a large molecule anti-tau antibody that has a phase 2 readout expected later this year. Mintun knows all too well that anti-tau therapies have not had much success in the clinic, but Lilly is hoping zagotenemab, a more selective antibody, will break through.
A separate candidate, solanezumab, has been slowly moving through a phase 3 trial in preclinical Alzheimer’s, the first trial of its kind to try to slow the disease before patients start to see the devastating neurological effects, according to Mintun.
It's not solanezumab's first try, though. The therapy has struggled in previous trials, failing to spur an improvement in patients with mild disease and in an early-onset, inherited form of Alzheimer’s. Lilly responded by boosting dosing in later studies to try to find an effect. Results are due in a couple years.
Another therapy in the pipeline is a phase 1 O-GlcNAcase inhibitor which is believed to make tau less likely to misfold. Lilly is also researching another biologic drug N3pG-4 in early symptomatic Alzheimer’s.
And then there are the outside partnerships, including an RNA pact with Dicerna, and science that is even further out. Mintun wouldn’t say which theories Lilly is chasing just yet.
“I'm not so sure I want to name which horse we're backing at this exact moment,” he said. “I can assure you that we're looking at a wide variety and feel like we have the scientific basis to move on many of them simultaneously.”
Editor's note: This story was updated at 8:30 a.m. ET on Sept. 9, 2021, to reflect Mark Mintun's new title.