The problem of pain — can genetics help solve the opioid crisis?

Twenty-seven years ago last January, a letter in the New England Journal of Medicine concluded that: “despite widespread use of narcotic drugs in hospitals, the development of addiction is rare in medical patients with no history of addiction.”

The letter, just a single paragraph, 99 words, was sent by Hershel Jick of Boston University’s Drug Surveillance Program.

It has subsequently been blamed for legitimizing widespread and reckless use of prescription opioids, leading to an epidemic of addiction.

The missive has been referred to more than 600 times in research from pharmaceutical firms, usually to argue that opioids can safely be prescribed without risk of dependency.

This year Dr Jick told The Associated Press: "I'm essentially mortified that that letter to the editor was used as an excuse to do what these drug companies did. They used this letter to spread the word that these drugs were not very addictive."

The journal’s editors have since appended a note which warns the entry has been: “heavily and uncritically cited as evidence that addiction is rare with opioid therapy.”

Meanwhile, America has struggled with a spiralling opioid crisis that contributed to an estimated 59,000 deaths from overdose in 2016.

The problem with opioids

Opioids, as the scientist in a now infamous infomercial from Purdue Pharma explains, are among the most powerful therapeutics available for managing pain.

The promotional clip does not explain that opioids are highly addictive. Multiple pharmaceutical companies, including Purdue, are now being sued by multiple jurisdictions in the USA, including at the state level, for failing to address the risks.

Public health bodies and others blame the opioid crisis on pharmaceutical companies for promoting the overprescription of opioid painkillers.

There is a growing body of anecdotal evidence that users of heroin and other illegal narcotics develop addiction following an opioid prescription for a recognized medical condition.

Ohio attorney general Mike DeWine said: "In 2014 alone, pharmaceutical companies spent $168 million through sales reps peddling prescription opioids to win over doctors with smooth pitches and glossy brochures that downplayed the risks of the medicines.”

The problems of addiction are medical, social and economic. The American Congress has now authorized up to $800 million in spending to try to fight the problem, including money for access to treatment and recovery facilities, a plus-400% increase from the last budget.

An opportunity for innovation

An analysis from health economists at the University of Illinois at Chicago determined the annual social cost of heroin abuse, per user, to be about $51,000.

With an estimated one million heroin addicts in the USA, this puts the total social cost of heroin abuse at about $51 billion.

Given the high cost of addiction and the substantial sums now being released from the public purse to help solve the problem, analgesics developers are hotly contesting the growing market for abuse-deterrent formulations (ADFs), which the Wall Street Journal calls the “ holy grail” in painkillers.

There are three routes to misuse that an opioid candidate must address in order to be labelled by regulators as being abuse-resistant: the intranasal, the oral and the intravenous. Typically, an ADF will be designed to be hard to crush or dissolve for these purposes.

An ADF therapy may also combine an opioid with another compound which combats the euphoric effects of the drug, in order to make it less addictive, as in the case of Targiniq ER, which combines oxycodone with naloxone.

The US Food and Drug Administration has developed an Opioids Action Plan which, among other things, aims to stimulate the development of painkillers that have these properties. The FDA says it wants to “help drugmakers navigate the regulatory path to market as quickly as possible.”

The plan, and new guidance from the agency, will also create a more negative regulatory environment for opioid products that are not ADFs.

The FDA says it will use expert advisory committees to intensify scrutiny of non-ADF applications, as well as strengthen postmarketing requirements and boost warnings and safety information on labels.

Last week, Endo International (Nasdaq: ENDP) became a high-profile victim of the regulator’s more stringent approach, as the Ireland-incorporated firm opted to withdraw Opana ER (oxymorphone hydrochloride) in the USA, resulting in a  13.6% drop in share price.

There are currently 10 US FDA-approved medications, all branded drugs, with labels which describe abuse deterrent properties in line with guidance.

Texan analgesia specialist Pain Therapeutics (Nasdaq: PTIE) is also in advanced discussions with the FDA over its ADF Remoxy (oxycodone extended release).

Lack of data on ADFs

While ADFs are a rapidly growing section of the market, there is a lack of data on the long-term effectiveness of the anti-abuse characteristics they boast.

As the FDA admits: “Because opioid medications must in the end be able to deliver the opioid to the patient, there may always be some potential for abuse of these products.”

The US regulator also states in its guidance that: “The science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving.”

A recent report from US non-profit organization the Institute for Clinical and Economic Review (ICER) found little evidence to demonstrate that ADFs reduce opioid abuse.

Meanwhile, cost-benefit analyses found that use of such formulations, in place of regular opioids, would result in an additional $533 million in costs.

A genetic pathway to pain management?

Concerns over the viability of ADFs as a safe alternative to conventional opioids has fuelled interest in alternative therapeutic approaches, such as a vaccine, currently under development at the the Scripps Research Institute (TSRI) in California.

In a trial on primates, researchers were able to train the immune system to produce antibodies which neutralize heroin molecules, checking the feeling of euphoria produced by opioids.

Another solution would be to find an alternative to opioids that was equally effective at managing pain.

One radical approach, still in early stages of development, is the use of genetic engineering to modulate the body’s response to inflammation, preventing tissue damage and pain.

Researchers at the University of Utah used CRISPR techniques to: “stop cell death and keep the cells from producing molecules that damage tissue and result in chronic pain.”

An intriguing and more profound therapeutic option is hinted at through the study of conditions such as congenital analgesia, a rare genetic disorder which results in generalized insensitivity to pain, and genetic erythromelalgia, in which patients experience excessive sensitivity to temperature, resulting in chronic incurable pain.

In both cases, researchers have discovered an association with a mutation in a sodium channel pathway, known as Nav1.7, which seems to transmit pain messages to the brain, and is encoded by the gene SCN9A.

Nav1.7 clinical development

In 2011 and 2014, US-based Xenon Pharmaceuticals (Nasdaq: XENE) entered into co-development deals with Swiss pharma major Roche (ROG: SIX), to explore ways of manipulating this channel to produce selective analgesic effects.

The companies are looking to initiate a Phase II trial this year for GDC-0310.

Xenon has also been working with Teva Pharmaceutical to develop a non-selective pain management therapy, TV-45070, which recently completed a Phase IIb study.

"Results from Phase II trial with 29 patients showed a 50% reduction in pain intensity scores for the test group."

While topline results announced at the end of last month showed the trial did not meet the primary endpoint of pain reduction, the company has not given up on the candidate, saying it will continue to analyze the data.

Other major companies have shown an interest in this nascent therapeutic approach. US-based biotech giant Amgen (Nasdaq: AMGN) signed an agreement earlier this year with Montanian startup SiteOne Therapeutics, which is using technology from Stanford University.

Commenting on the deal, SiteOne chief executive Stan Abel said: "The opioid crisis in the USA has created a critical need for safe and effective non-opioid solutions for managing pain.”

“This agreement will allow us to accelerate the development of our Nav1.7 therapeutic candidates for managing acute and chronic pain without the addiction potential of existing therapies," he added.

A relative veteran, Amgen has an arsenal of biopharmaceutical technology platforms it can bring to bear. The company is said to be testing “up to 10,000 molecules against Nav1.7 each week” as it explores the potential of this therapeutic approach.

New York-based Pfizer, after buying and then spinning out pain specialist Icagen, has also built up a Nav1.7 program based around PF-05089771, which is in Phase II trials at the moment.

But perhaps the most advanced clinical program exploring the pathway is BIIB074, which biotech major Biogen (Nasdaq: BIIB) brought on board when it bought UK-based Convergence Pharmaceuticals for up to $675 million in 2015.

Biogen is now developing the candidate at its research site in Maidenhead, UK, and it has shown promise. Results from Phase II trial with 29 patients showed a 50% reduction in pain intensity scores for the test group.

At this point, the science behind the sodium channel is incomplete. Researchers are not able to map out precisely its mechanism, its connection with genetic expression and with the experience of pain.

Nonetheless, the interest shown by the industry is a reflection, not just of the urgent need for an alternative to opioids, but of the inherent promise this therapeutic approach seems to contain.

For now, for patients suffering from a wide range of conditions, there is hope we may finally have an answer to one of mankind’s most profound concerns, the problem of pain.