The biopharmaceutical industry, recognizing the role of prescription opioids in the epidemic of addiction gripping the US, has launched efforts to address the crisis by developing non-opioid alternatives for pain. However, experts contend companies will need help if they are to succeed in weaning the health care system off its stash of inexpensive narcotics.
Biopharma companies face a multifaceted problem. The challenge goes beyond understanding of the science of pain, discovering new biological targets and identifying biomarkers to serve as clinical endpoints for efficacy.
Solving the problem, experts say, will also involve support from other key sectors of the health care system: such as a recognition from regulators for changes in clinical trial design to improve the chances for success of new pain medicines; and a willingness of health care providers and insurers to pay for the opioid alternatives once they reach the market.
“The track record for developing new drugs in this area has been relatively poor,” observes Jeremy Levin, Chairman and CEO of Ovid Therapeutics. An experienced pharmaceutical executive, Levin is leading the Biotechnology Innovation Organization’s opioid working group, which is charged with devising public policy initiatives to foster new drug alternatives to prescription opioids.
“If you look at clinical drug development, the ability to get a drug approved in new pain indications, which are non-opioid, is low,” Levin says. “It’s about five times less likely than the normal 10% approval rate (for all drugs). In fact there are only two instances of new pain drugs being developed in the past 10 years.”
Among the reasons for this high failure rate, says Corey Davis, managing director of Seaport Global Securities, is “that pain, unlike other disease endpoints, is completely subjective. It’s completely dependent on patients’ rating of their own pain.”
Exacerbating the dilemma, Davis adds, “Payers and insurance companies have very little incentive to prioritize any new drug that would come with a premium price over cheap generic opioids,” which are proven painkillers.
As a result, Davis says, “Despite the fact that (pain) is the single largest pharmaceutical volume market out there, there just has not been the type of volume influx you would imagine for new pain drugs. I think that’s changing, but it’s still going to be years before we get there.”
The change, Levin says, is driven by the enormous suffering and cost associated with the opioid epidemic: tens of thousands of lives lost each year combined with an annual economic burden of more than $1 trillion.
Algomedix President and CEO Jeffrey Herz, whose emerging company is targeting transient receptor potential (TRP) ion channels as a non-opioid alternative for pain, describes in personal terms his commitment and the sense of urgency.
“I knew the tragic story of a young man who was a medical student and became a victim of an opioid overdose,” says Herz. “As the scientific founder (of Algomedix), with over 20 years’ experience working in the field of drug discovery and development for pain and inflammation, I realized that no major advances had been made in the field for almost two decades.”
WuXi AppTec – a leading global pharmaceutical and biopharmaceutical open access capability and technology platform – assists biotech and pharmaceutical companies from discovery to manufacturing and beyond. An important element of this support involves offering a communications platform to facilitate the exchange of ideas among the most innovative companies and the creative people behind them.
In this installment of WuXi’s new communications platform on the future of drug discovery and development, leading experts in non-opioid, non-addictive drug research and development discuss the opioid epidemic, its origins and the scientific and political challenges they face in providing patients with effective non-opioid alternatives for pain. They include Corey Davis, Hydra Biosciences President and CEO Russell Herndon, Jeffrey Herz, Kineta CEO Shawn Iadonato, and Jeremy Levin. Their complete interviews also are available on this website.
“The origin of the opioid epidemic is complex and multifactorial and deadly in its result,” says Ovid Therapeutics’ Jeremy Levin, who chairs the opioid working group of more than 30 biopharma CEOs assembled by BIO to confront the public health crisis of opioid addiction.
In addition to the illegal trade in opioids, such as heroin, which has been consistent throughout America’s history, Levin says “something different” happened in the 1980s and 1990s – “the entrance of industrial players. During that period, recognizing the benefit that certain opioid derivatives had in pain relief, a number of companies started to produce pills that provided pain relief and they were very, very successful. The only problem is that patients who weren’t addicts became addicted to those pills.”
The US National Institute on Drug Abuse quantifies the problem this way:
Levin says, “While the sources of this crisis come from a variety of different parts, in large measure, the opioid crisis is now sustained and growing as the result of illegally supplied drugs.”
Opioid medications, however, are still the most commonly prescribed drugs for acute and chronic pain, which explains why Levin and his BIO colleagues consider support for development of non-opioid, non-addictive alternatives as one of the principles guiding their recommendations for addressing the crisis.
“The first principle,” Levin says, “is that we advance our understanding of the biology of pain and addiction to enable the development of innovative treatments. There are circumstances where opioids can be used effectively and there are times where patients will be better suited to have access to novel, non-addictive treatments.”
The combined societal impact of chronic pain and narcotics abuse is staggering. According to a February 2018 report from BIO on non-opioid drug development, as many as 100 million people in the US suffer from chronic pain, which costs the health care system more than $600 billion a year. More than 23 million people are addicted to drugs and alcohol, which translates into another $700 billion in annual economic and health care costs. Each year, more people die from opioid-related overdoses than are killed in motor vehicle crashes.
In describing why he agreed to chair BIO’s opioid working group, Levin says, “I could not stand by in the face of an opioid epidemic which every year is taking 63,000 people, devastating communities, and costing us as a nation $1.3 trillion.”
The pace of non-opioid drug development will depend not only on biotech and pharmaceutical scientific breakthroughs, but also on the support of the entire health care system, according to Seaport Global Securities’ Corey Davis.
“Until recently there hasn’t been an ultra-sense of urgency to develop alternatives (to opioids); by recently, I mean in the last five years or so,” Davis says. “The opioid epidemic has taken the spotlight in all of the media news outlets and it is a huge problem. But drugs don’t get developed unless there is financial incentive to do so, and that’s improving.”
Where are we now?
While progress is being made on the research and clinical development fronts, the amount of private investment does not match the scale of the problem and pales in comparison to other diseases, such as cancer.
BIO’s report reveals that venture capital investment in companies focused on pain is 3.6% of total drug company funding and is 17 times less than the amount of venture investment for cancer companies in the past decade.
Kineta, Algomedix, and Hydra Biosciences are among the biotech companies that have taken on the challenges of developing non-opioid, non-addictive pain medicines whose mechanism of action does not involve opioid receptors in the brain.
Opioid receptors are the destinations for opioid drugs, such as oxycodone, hydrocodone, codeine, morphine and fentanyl; and while they are effective in blocking pain, the interaction also produces pleasurable responses, which can lead to abuse and addiction.
Kineta is targeting the α9/α10 nicotinic acetylcholine receptor (nAChR) found on neurons in the peripheral nervous system for treatment.
“Our α9/α10 nAChR antagonists are derived from the venom of the Conus regius, a small cone snail native to the Caribbean Sea,” he says. “Because the receptor is only found in the peripheral nervous system, not the brain and spinal cord, drugs that target it likely won’t have the same severe side effects as opioids.”
Iadonato says the α9/α10 nAChR antagonists have “demonstrated analgesic properties in several pre-clinical animal models. But what truly differentiates them are the anti-inflammatory and neuro-protective effects that we’ve also seen in the studies. We believe that combination may offer a disease modifying therapy that can slow or hold the progression of chronic pain.”
Algomedix and Hydra are developing small molecule inhibitors that target a member of the transient receptor potential (TRP) ion channel family, TRPA1, which triggers a pain response in neurons when tissue damage and inflammation occur.
Hydra Biosciences’ Russell Herndon explains, “TRPA1 acts as a rheostat in pain sensing neurons, dialing up or down their activity without blocking their ability to fire as compared to novocaine, which simply turns off the neuron. TRPA1 is also a peripheral target. Even local delivery of a TRPA1 blocked can be analgesic, showing activity in the brain is not required.”
Herndon adds, “We believe that by decreasing the activity of the channel in pain sensing neurons that we can treat chronic pain such as diabetic peripheral neuropathies, chemotherapy induced neuropathies as well as others.”
Algomedix’s Jeffrey Herz says his company is pursuing treatments for acute and chronic pain with its TRPA1 small molecule inhibitor.
“This target is located in the peripheral nervous system on the endings of specialized nociceptor (pain sensing) nerve fibers,” he explains “This means that we can specifically block pain signals without having any other effect on sensory modalities.”
In addition to ion channels and nicotinic acetylcholine receptors, Davis says other non-opioid drugs in development are targeting cannabinoid receptors, nerve growth factor (NGF) receptors, G-protein coupled receptors (GPCRs) and calcitonin gene-related peptides (CGRPs).
Pacira Pharmaceuticals, Davis observes, “has reformulated an old short acting drug, bupivacaine, to create a longer acting version called Exparel,” which is already on the market and could be used for post-surgical pain as a substitute for morphine, an opioid that is highly addictive.
Among the big pharma companies, he says, Pfizer and Eli Lilly and Co. are developing tanezumab, a monoclonal antibody that blocks NGF from triggering pain-sensing neurons. The drug is being developed for osteoarthritis as well as chronic back and cancer pain.
“All the CGRP companies – Amgen, Teva Pharmaceuticals, Allergan and Lilly – are developing drugs for migraine pain,” Davis observes. These drugs are monoclonal antibodies designed to block CGRPs, which are neurotransmitters involved in triggering migraine headaches.
Other potential targets, Levin observes, include those involving the biology associated with fatty acids, nitric oxide, chemokines, corticoid receptors and IL-10 receptors. “There are 26 different mechanisms under investigation and we need to insure that we can secure adequate basic research funding and begin to tease out the critical pathways and mechanisms.”
Despite the current non-opioid drug development efforts, BIO’s report reveals that by comparison the oncology pipeline has roughly 2,700 drug candidates, which is 10 times the total in the pain area.
“With that level of disparity,” Levin says “I don’t believe we can honestly say that as an industry we’ve explored even a fraction of all the avenues of how best to treat pain.”
Where are we headed?
Many experts acknowledge the biopharmaceutical industry has been slow to develop non-opioid, non-addictive alternatives for pain, and the reasons range from lack of sufficient basic scientific understanding about pain to doubts about marketplace acceptance of new drugs.
“There’s probably 10 different reasons,” Davis observes. “Number one is opioids are pretty good at relieving pain from an efficacy standpoint. They’re terrible on the safety side. But it’s hard to compete with the efficacy of an opioid.”
The opioid epidemic has altered that thinking, but many challenges lie ahead. BIO’s opioid working group is focusing on legislation to increase funding for basic research into pain and addiction, improve access to non-opioid pain alternatives and treatments for opioid abuse, and expedite the regulatory review process for new drugs.
“The regulatory hurdles and past failures of other treatment modalities focused on pain have driven investment away from this space,” Herndon contends. He suggests the FDA should adopt a program for non-addictive pain medications similar to the fast track designation for cancer drugs.
To stimulate more private sector investment, Iadonato suggests the government could provide R&D tax credits and subsidies, and extend market exclusivity for new drugs.
Herz says the magnitude of the opioid epidemic requires a Cancer Moonshot approach from the federal government for accelerating non-opioid pain drug development. He also calls on the major pharmaceutical companies to explore more partnerships with small biotechs.
“It has become clear,” Herz observes, “that although a novel non-opioid pain medicine, which is easy to use and addresses a large patient population, can be a blockbuster, large pharmaceutical companies are not providing the innovation needed to create these medicines.”
Davis says better clinical trial design with surrogate biomarkers to measure pain also is a priority. For example, success in clinical studies relies on patients judging the level of pain relief, making it difficult to assess the difference between placebo and drug treatment groups.
“There’s a very high placebo rate,” Davis says. “The placebo rate in pain trials has been creeping up over the last 10 years whereas the drug effect arm in pain trials is staying the same.”
In addition, he observes, abnormal physiological causes vary significantly from one pain condition to another. “Whether you’re thinking about cancer pain, pain caused by inflammation or tissue injury, or neurological pain, migraine pain, irritable bowel syndrome pain or fibromyalgia,” Davis says, “each of those carries a different pathophysiology, so it’s not necessarily a one size fits all when you’re trying to conduct a clinical trial for pain.”
Another significant hurdle is market reimbursement. There are no guarantees hospitals and insurers will favor non-opioids over inexpensive opioids.
“That makes securing reimbursement for a new branded therapy a challenge for payers,” Iadonato explains. “They require seeing demonstrated clinical differentiation and/or better safety profile compared to the standard of care and lower cost generics.”
Convincing payers of the value of more expensive non-opioid medicines will require proving not only their clinical effectiveness, but also their cost effectiveness.
Davis contends non-opioid, non-addictive medicines represent tremendous savings for the health care system by eliminating treatment for opioid side effects, not only abuse and addiction, but also adverse events such as constipation, respiratory depression, sedation and falls.
“There will absolutely be substantial cost savings (with non-opioid drugs), but it needs to be viewed in a holistic way on the entire system,” he explains.
When asked what scientific and technological advances are required to achieve more progress in development of non-opioid drugs, Levin says the industry needs “to go back to basics” and apply “the tools of big data analysis, genomic analysis and clinical records, and thereby insure a deeper understanding of the link between addiction, physiology and pain.”
The overall goal is not to eliminate use of opioids, but to provide non-addictive alternatives to reduce mass consumption of opioids.
“One very true statement about treating individuals in pain is that there is no ‘magic bullet,’” Herndon says. “Doctors need multiple options in their armamentarium so that they can identify the best treatment for that specific patient.”