This article is a Clarivate Analytics Market Insight report, an ongoing series featuring expert reviews of hot topics in the pharma/biotech field, with analysis and discussion on the factors currently affecting the industry. Data leveraged for this analysis was gathered from Clarivate Analytics Cortellis.
The pain market
Due to the significant healthcare and economic costs of pain, analgesia represents a promising market for pharmaceutical companies. In the U.S., estimates suggest that about 100 million adults experience chronic pain conditions, and globally the International Association for the Study of Pain (IASP) and the European Pain Federation (EFIC) statistics indicate that one in five individuals suffers from moderate-to-severe chronic pain. Key demographic trends, including the aging population and improved cancer survival, suggest that the demand for prescription pain management products will increase. Treatment options range from non-prescription medications such as non-steroidal anti-inflammatory drugs and acetaminophen for mild to moderate pain, to opioids for moderate to severe pain.
Opioids: a healthcare crisis
Opioids provide an important treatment option in pain management that has a history dating back thousands of years. Since the 1990s, the use of opioids in the treatment of pain has expanded significantly, fueled by the recognition that pain was being undertreated and by the implementation of policies to ensure appropriate pain management. In 1996, Purdue Pharma’s extended-release, high-dose formulation of oxycodone, OxyContin, entered the U.S. market and soon achieved blockbuster status; annual sales of $2.977 billion were reported in 2009 (source Thomson Reuters I/B/E/S). Healthcare providers in the U.S. began using opioids such as OxyContin to treat chronic pain, resulting in more individuals taking opioids for longer periods of time or at higher doses. However, the abuse potential of opioids is very high, and controversy surrounds the U.S. marketing of OxyContin, which by 2004 had become the most prevalently abused prescription opioid in the U.S. Stating that the risk of addiction for OxyContin was less that 1%, with claims that the product was less addictive and less open to abuse and diversion compared with other opioids, resulted in Purdue facing fines of $634 million for misbranding.
In 2016 more than one third of adult Americans were prescribed opioids, according to a National Survey on Drug Use and Health (NSDUH) report, and 230 million opioid prescriptions were written that year in the U.S. The increased medical use of opioids has been accompanied by an increase in the abuse and misuse of prescription opioids. According to the Centers for Disease Control and Prevention (CDC), almost 2 million individuals abused or were dependent on prescription opioids in 2014. CDC figures show that the number of opioid-related overdose deaths has quadrupled since 1999, and currently 40% of opioid overdose deaths in the U.S. involve a prescription opioid. This increase in prescription opioid-related deaths in the U.S. prompted President Trump to declare the opioid crisis a national Public Health Emergency in October 2017.
Three FDA-approved drugs (methadone, buprenorphine and naltrexone) are used in medication-assisted treatment (MAT) programs to treat opioid use disorder. However, the standard of care, daily oral buprenorphine, requires regular visits to the pharmacy. Indivior’s Sublocade is the first and only once-monthly injection of buprenorphine available in the U.S., and represents a new approach that could prove beneficial in a population who may find complying with a daily regimen particularly challenging. According to Cortellis Consensus Forecast data (source Thomson Reuters I/B/E/S), 2023 sales of $1.464 billion are anticipated for Sublocade, surpassing peak sales achieved by current market leader Suboxone. Sublocade and its potential impact on the MAT therapy market were discussed in more depth in this January 2018 Market Insight report by Ulrike Jahnke on Life Sciences Connect: Sublocade approval likely to be a game changer in the U.S. fight against opioid addiction.
Reducing the risk: abuse-deterrent opioids
Opioid abuse is estimated to have cost the U.S. economy around $504 billion in 2015, according to the White House Council of Economic Advisers. Several measures have been introduced in recent years to reduce the risk of opioid abuse. For example, the FDA’s revisions to its regulation of opioids, including enhanced labeling and re-examining of the risk-benefit paradigm for their use. FDA action has included a request for voluntary market withdrawal of Endo Pharmaceuticals’ Opana ER, which was withdrawn in July 2017.
As part of the FDA’s response to the opioid crisis, it has committed to driving the use of tamper-resistant/abuse-deterrent opioids. This move creates opportunities for pharmaceutical companies to deliver branded products into an increasingly generic pain market. The FDA lists seven categories of abuse-deterrent technologies, selected examples of which are listed in Table 1.
| Category | Examples |
| Physical/chemical barrier formulations | OxyContin TR, Hysigla ER, Opana ER, Nucynta, Xtampza and Arymo |
| Agonist/antagonist combination | Embeda, Targiniq ER |
| Aversion | Oxaydo |
| Delivery system | Exalgo, Zalviso |
| NCEs and prodrugs | NKTR-181, difelikefalin |
| Combination | Rexista, Apadaz |
Table 1: Examples of drugs using various categories of abuse-deterrent technologies. Source: Cortellis, Clarivate Analytics
As of March 2018, the FDA had approved nine extended-release and one immediate-release opioids with abuse-deterrent claims (Table 2). The first opioid to be approved with abuse-deterrent claims was Purdue’s OxyContin Neo, which is a reformulated version of the company’s original OxyContin, designed to resist abuse via crushing or inhalation. The original formulation of OxyContin was discontinued in the U.S. in April 2013 in favor of the tamper-resistant formulation, following a decision by the FDA that the benefits of original OxyContin no longer outweighed its risks. This decision also means that the FDA will not approve any generic versions of the original OxyContin, allowing OxyContin Neo to maintain high pricing. In just over one year following market entry, OxyContin Neo achieved blockbuster status, with annual sales of $2.100 billion in the U.S. in 2011.
| Drug | Company | Active ingredients | Immediate/extended release | U.S. market status |
| Embeda | Pfizer | Morphine + naltrexone | Extended release | Launched in September 2009 |
| OxyContin Neo | Purdue Pharma | Oxycodone | Extended release | Launched in August 2010 |
| Hysingla ER | Purdue Pharma | Hydrocodone | Extended release | Launched in January 2015 |
| Xtampza ER | Collegium Pharma | Oxycodone | Extended release | Launched in June 2016 |
| Arymo | Egalet | Morphine | Extended release | Launched in March 2017 |
| MorphaBond | Daiichi Sankyo/Inspirion | Morphine | Extended release | Launched in October 2017 |
| Targiniq ER | Mundipharma | Oxycodone + naloxone | Extended release | Approved in July 2014 |
| RoxyBond | Inspirion | Oxycodone | Immediate release | Launch expected in 2018 |
| Troxyca ER | Pfizer | Oxycodone + naloxone | Extended release | Approved in August 2016, but Pfizer stated in November 2017 that there were no plans to launch the drug |
| Vantrela ER | Cephalon | Hydrocodone | Extended release | Approved in January 2017, but Teva stated in February 2018 that commercial opportunities for the drug were not being pursued |
Table 2: Approved abuse-deterrent opioid drugs in the U.S.. Source: Cortellis, Clarivate Analytics
Opinions mixed on the success of abuse-deterrent opioids
Postmarketing assessments on the effect of introducing OxyContin Neo have shown reductions in abuse, doctor shopping and overdose fatalities. However, a report from the Institute of Clinical and Economic Review (ICER) concluded that while OxyContin Neo has reduced the abuse risk among individual patients and decreased diversion of the drug to illicit supply and use, there is insufficient evidence to demonstrate effectiveness on a population level. The report also raises concerns that abuse-deterrent formulations can lead individuals to seek non-tamper-resistant, potentially more dangerous drugs that can be abused, such as fentanyl and heroin. Caution is also urged regarding policies mandating replacement of all non-abuse-deterrent opioids with abuse-deterrent formulations, because of the lack of data on the effects of doing so.
Novel abuse-deterrent approaches
Development of opioids formulated with abuse-deterrent properties has been demonstrated to reduce “drug liking” and make abuse more challenging, although it is still possible to abuse such drugs by injection and intranasal routes, as well as orally. Nektar’s NKTR-181 is a novel mu-opioid agonist created using Nektar’s proprietary polymer conjugate technology. The drug’s abuse-deterrent properties are inherent to its novel molecular structure and are not reliant on a formulation approach to prevent conversion into a more abusable form. NKTR-181 crosses the blood-brain barrier slowly, and has shown reduced euphoria and sleepiness scores compared with oxycodone. Moreover, the drug elicited significantly lower “drug-liking” and “feeling-high” scores compared with oxycodone at all doses tested in a phase III human abuse liability (HAL) study. In terms of efficacy, NKTR-181 has also proven effective in reducing chronic low back pain. The drug has Fast Track status in the U.S. for the treatment of moderate-to-severe chronic pain and a regulatory filing in this setting is anticipated by April 2018. NKTR-181 is expected to enter the market in 2020, and to achieve sales of $55 million by 2023.
An alternative approach has been used by Cara Therapeutics for difelikefalin, which targets peripheral kappa-opioid receptors, providing pain relief without stimulating mu-opioid receptors and so aiming to avoid abuse and addiction issues. As difelikefalin has low blood-brain-barrier permeability, the side effect of hallucinations caused by stimulation of kappa-opioid receptors in the brain is also limited. Oral and intravenous formulations of difelikefalin are in development, with the intravenous formulation being the most advanced, having entered phase III development for post-operative pain in September 2015. Data from a HAL study has demonstrated significant reductions in “drug-liking” and “feeling- high” scores for therapeutic (5 microg/mg) and supratherapeutic (15 microg/mg) doses of difelikefalin compared with the Schedule IV analgesic pentazocine. In addition, both doses were equivalent to placebo in overall “drug-liking” and “take-drug-again” measures. The drug has also demonstrated significant pain relief in three phase II trials in patients with acute postoperative pain, and was shown to decrease patient-controlled morphine analgesia use. Intravenous difelikefalin is anticipated to enter the market in 2020, and achieve sales of $521 million by 2023.
Summary
The opioid pain market is a lucrative one, but is experiencing significant challenges in the U.S. as the country grapples with prescription opioid addiction, overdose and fatalities. The situation has been declared a national Public Health Emergency and the FDA has introduced several measures intended to reduce opioid abuse. The development of abuse-deterrent prescription opioids is one such measure, but although abuse-deterrent formulations of opioids reduce drug liking and abuse, concerns have been highlighted by an ICER report regarding the insufficiency of currently available data to determine the effects of these formulations at the population level. However, the low abuse liability but effective analgesic efficacy reported for drugs such as NKTR-181 and difelikefalin highlight the potential of novel abuse-deterrent opioids.
2018 is on track to see a record number of new blockbuster drugs scheduled to launch across a wide range of therapeutic areas, according to the newly released Drugs to Watch 2018. The report is compiled from data within the Cortellis database, from Clarivate Analytics, and features profiles of 12 new game-changing drugs – including Sublocade – that are predicted to achieve annual sales of >$1 billion by 2022.
Learn more by downloading the report here!
