Easing pain may have been one of the original goals of medicine, but the zeitgeist has long since moved on to harder-to-treat conditions. That makes Eli Lilly’s efforts to reinvigorate the space all the more intriguing.
With 20% of Americans suffering from debilitating chronic pain, it seems like a no-brainer for drug developers to continue to explore this area. Yet, according to Lilly Chief Scientific and Medical Officer Dan Skovronsky, M.D., Ph.D., few Big Pharmas are investing in new pain therapeutics.
“That's interesting, right?” Skovronsky told Fierce Biotech in an interview. “You have this disease that affects so many people, that's debilitating, that there aren't great therapies for, and pharma is not working on it.”
Of course, Lilly is no stranger to the pain game—the company markets the migraine drugs Reyvow and Emgality. But the deterrent to pushing further into this field isn’t that there aren’t potentially other effective drugs out there, but that they “may be a little complicated to test,” Skovronsky said. When you also consider the very high safety threshold that regulators apply to trials of new chronic pain medications, you begin to see why Big Pharma interest has dried up.
“There seems to be a lot of ideas for how we might tackle chronic pain and we realized that was actually part of the problem,” Mark Mintun, M.D., Lilly’s senior vice president of pain and neurodegeneration R&D, said in the interview. “With so many ideas … how could we do this in a really efficient way?”
That’s where Lilly’s master pain protocol comes in. Typically, companies will design a single trial for a drug and then work with sites to determine the type of patients they want and how to recruit them.
The aim of the protocol was to join up clinical trial sites to make it easier to transfer patients between pain trials or drugs rather than “have to restart from scratch each time,” Mintun said. Under the protocol, if a trial fails to hit its goal, the energy to set it up hasn’t been wasted, as the people and resources can be turned to another clinical candidate.
“[The sites] know what sort of patients to recruit—they've often pre-recruited patients who have contacted them,” he said. “The ability to have patients [and] sites committed to this effort, I think really makes this an easier, faster, more efficient overall operation.”
Since launching in 2020, the protocol has been further developed by overlapping the three major pain syndromes that Lilly is focused on—osteoarthritis, back pain and neuropathic pain—so a new drug candidate can be tested across all three indications at once “in a seamless way.”
“Not only was the thinking that we could test drugs faster because we didn't have to get up a brand new protocol, we could test more drugs, we could test drugs across different pain syndromes,” Mintun said.
This multi-indication approach has the added benefit of helping Lilly to get better at controlling placebo response, as well as using the same placebo across multiple drugs because every patient has been recruited the same way, he added.
“The concept here is that if we're going to lean in and think really hard about how to develop medicines in this really difficult space, we thought we needed to bring some really, really big ammunition,” Mintun explained. “And we feel the chronic pain master protocol fits that bill.”
The company now has trials of four molecules signed up for the program. Two of those candidates have completed phase two studies: an SSTR4 agonist for osteoarthritis pain; and a P2X7 receptor antagonist licensed from Asahi Kasei Pharma and being investigated for chronic pain. The remainder of Lilly’s clinical-stage pain pipeline consists of two candidates in phase 1 trials that are being readied to enter the protocol: a non-opioid option for neuropathic pain that Lilly licensed from Confo Therapeutics for $40 million in March, as well as one other undisclosed asset.
Lilly’s pain trials may have been bubbling away in the background for a while, but there is a potential overlap with another aspect of the company’s work that has been garnering more attention: genetic medicine. Lilly has penned RNA-focused pacts with the likes of ProQR Therapeutics and MiNA Therapeutics in recent years, and Mintun gave the example of small interfering RNA as a targeting mechanism that could also offer a way to deliver genetic medicines to nervous system tissue.
This would have the added benefit of helping overcome that “high safety bar” set by regulators for pain medicines. “If you can start guiding medicines to specifically peripheral nervous tissue, or maybe even to specific types of neurons, we could perhaps achieve a much better safety profile than just simply hitting that target across the entire body,” he explained.
With the possibility of drawing on Lilly's internal expertise in genetic medicine to deepen its pain portfolio, can the Big Pharma share what else it’s got coming down the pain pipeline?
“We have three or four that we're working very fast on and want to get into the clinic,” Mintun said. “It's premature to disclose those, but I can say broadly some of those assets are known to be very difficult targets; some are known to be targets to us.”
Lilly may be “swimming against the tide of the pharmaceutical industry” by persevering with the development of pain medicines, but Skovronsky thinks it’s a good fit for the company.
“That's where we like to be,” the CMO said. Skovronsky also referred to the company’s track record in two other research areas that at various times have fallen out of fashion with Big Pharma: obesity and Alzheimer’s—where donanemab recently scored a high-profile phase 3 success.
And while the high safety thresholds can make it tricky to get pain trials signed off by the FDA, the regulator has been sounding more supportive of the need for new drugs in this space. FDA Commissioner Robert Califf has “made promising comments about encouraging pharmacy companies to invest in pain medicines,” said Skovronsky, who pointed out that Lilly’s protocol was actually rubber-stamped by the regulator as far back as 2019.
“A lot of people in this industry just follow whatever is hot,” Skovronsky said. “But that’s 10 years too late. You need to follow what you know is going to be hot 10 years from now. The best way to do that is to make it successful, to write a future—so that's what we're trying to do here.”