Eli Lilly & Co. is best known for its arsenal of diabetes drugs and to-date unsuccessful efforts to develop a treatment for Alzheimer's disease.

Yet over the next three years, the Indianapolis drugmaker hopes to make a mark by bringing three therapies to market for pain. Among major U.S. pharma companies, Lilly's push to develop novel non-opioid painkillers is relatively unique, with few peers looking to forge a therapeutic focus in the space.

"Large pharma completely left the pain area for quite a while," said Barry Quart, CEO of the biotech Heron Therapeutics Inc., which is developing a non-opioid drug for postoperative pain.

A handful of large drugmakers are, like Lilly, developing preventive treatments for migraine. But a look across the pharma pipeline reveals only spotty investment into pain R&D. The trade group BIO, for example, recently found only 125 programs for novel pain drugs in the clinic — a tenth of the size of the current oncology pipeline.

In place of big pharma, smaller biotechs like Heron, Vertex Pharmaceuticals Inc. and GW Pharmaceuticals plc have moved in to advance non-opioid alternatives. Success could open up a market that analysts from Cowen estimate could be worth up to $10 billion per year.

The relative dearth of novel drug development coincides with an ongoing public health crisis of opioid abuse and overdose in America. The epidemic, which claimed 42,000 lives last year, has heightened the need for non-addictive analgesics.

At the same time, the crisis has drawn scrutiny on the drug industry's role in promoting opioid use — adding a new layer of caution and regulatory oversight to drugmakers' work in the space.

Shifting to pain

Lilly's renewed focus around pain developed piecemeal. In 2013, the pharma struck a partnership with Pfizer Inc. around a drug for chronic pain known as tanezumab, buying into a clinical development program that was then stalled by safety concerns.

Deals in 2014 and 2017 to in-license compounds targeting migraines rounded out a late-stage pipeline that looks set to deliver new medicines beginning as soon as this year.

Christi Shaw, head of Lilly Bio-Medicines, characterizes the greater emphasis on R&D in pain as adaptive, reacting in the near term to setbacks in Alzheimer's research.

Yet the company also recognizes a market opportunity in the growing need for better, non-addictive treatments to help the large swathe of people who still struggle with pain.

"In the U.S., there are 100 million people — about one in three — that suffer from chronic pain," Shaw noted in an interview. "That number surpasses the incidence of people living with cardiovascular disease, diabetes or cancer."

The opioid epidemic has spurred efforts to rein in prescription of opioids, from greater risk monitoring to limiting long-term use. But Shaw pointed to patients left behind, who Lilly is betting will need new options.

"Let's not forget about the patients in pain while we try to address the opioid crisis," Shaw said. "We can go too far and swing the pendulum."

Lilly does, however, set itself up for a challenge of communication. After all, touting the promise of new drugs for pain in the midst of an epidemic spurred in part by drugmakers brings with it the prospect of greater scrutiny on safety.

Preventing migraine

Migraine will be the first proving ground of Lilly's bet on pain.

No new preventive treatment for migraine has been OK'd for sale in the U.S. since Allergan's Botox in 2010, but rapid clinical progress from four experimental antibodies could soon change that.

Galcanezumab — which Lilly acquired from Arteaus Therapeutics Inc. after originally discovering the compound — is currently under review by the Food and Drug Administration to prevent migraine. A decision on approval is expected toward the end of this year.

But galcanezumab, if approved by the FDA, will likely arrive second to market after Novartis AG and Amgen Inc.'s erenumab, which targets the same neuropeptide to reduce migraine attacks.

Competition from Teva Pharmaceutical Industries Ltd. and Alder BioPharmaceuticals Inc. looks likely to follow.

Shaw contends the company welcomes rivals, noting the large patient population for migraine in the U.S. More drugmakers in the space will mean more attention to the CGRP class, potentially driving patients to discuss treatment with their doctors (or vice versa).

"Having a couple companies in it in the beginning I think will help increase that awareness," Shaw noted.

And although opioids are usually associated with use in surgery and other acute pain settings, around 40% of migraine sufferers cycle through treatment with opioids at some point. New migraine drugs would give patients a targeted, non-addictive option to manage their headaches.

"We talk about being able to use migraine agents to alleviate pain — preventative ones to try to reduce [attacks], acute ones to try to work fast — so we can hopefully stop [patients] from having to go through an opioid," said Shaw.

Lilly touts its broader pipeline in migraine, aiming to submit its experimental drug lasmiditan for approval as an acute treatment of migraine later this year. Even so, competition will likely be fierce, potentially hinging on who's first to market, price and payer coverage

Risky bet

Lilly also hopes this year will bring positive data from the first of six Phase 3 studies testing tanezumab to treat osteoarthritic, chronic lower back and cancer pain.

Tanezumab works by blocking nerve growth factor (NGF), one of a class of drugs that initially showed promise only to have clinical development halted in 2010 and 2011 by safety concerns.

Following reports of unusual joint damage in tanezumab-treated patients with osteoarthritis, the FDA placed clinical holds on studies testing tanezumab as well as two similar drugs from Johnson & Johnson and Regeneron Pharmaceuticals Inc..

An advisory committee to the agency concluded in 2012 that further clinical study of anti-NGF agents could be acceptable provided drugmakers take steps to mitigate safety risk.

Pfizer, now partnered with Lilly, restarted trials of tanezumab in 2015. Yet the safety signals have chilled development of the drug class.

J&J, for instance, decided to discontinue work on its compound in 2016 to better prioritize other assets. That same year, Regeneron's drug was placed on another hold for joint-related adverse events, although clinical testing has since advanced.

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"We are absolutely hot on the market to look for additional assets externally.

Christi Shaw

President, Lilly Bio-Medicines

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Further deals?

No early-stage pain assets are currently listed in Lilly's development pipeline, but Shaw says the company is keen to further build its portfolio — both in pain and elsewhere.

"We are absolutely hot on the market to look for additional assets externally — if they're best-in-class or first-in-class, we are very keen to have them choose Lilly as their partner," Shaw said, while noting the company has become more willing to look at earlier, more risky drug candidates, too.

CEO Dave Ricks has said the company plans to deploy about $9 billion in the near term, raising the prospect for potential deals or collaborations across the company's therapeutic focuses.

And while development of non-opioid treatments for pain has languished in the ranks of pharma, a number of biotechs are progressing quickly.

Heron, for example, recently reported positive Phase 3 results for its drug candidate for pain following surgery. Vertex's mid-stage pain candidate recently cleared its second Phase 2 study, while GW Pharma has explored the use of cannabinoid-based drugs in pain (although a study in 2015 of one of GW's drugs failed).

The FDA, for its part, has made advancing non-opioid drug development a priority, committing to using all of its expedited review programs when appropriate to help the field advance.

"[There is] no doubt that pharma has woken up to the need," said Heron's Quart. "I think the need potentially coupled with a change in incentives would dramatically shift pharma's focus."