Opioid-induced constipation, tardive dyskinesia, and other medication-induced syndromes present worthwhile revenue opportunities for pharmaceutical R&D.
In the 1960s, researchers discovered that the loss of motor control from Parkinson’s disease (PD) was tied to a deficiency of dopamine in a part of the brain involved in the coordination of movement.
Evidence soon established that administration of levodopa, a dopamine precursor molecule, dramatically improved PD symptoms. Here’s the catch: relief of symptoms was accompanied by severe nausea and vomiting. Levodopa was not only being converted to dopamine in the brain but also in the bloodstream, activating dopamine receptors in the peripheral nervous system and causing the adverse side effects.
In order for levodopa treatment to become useful, it had to first be well-tolerated by patients. Scientists began exploring co-administration of levodopa with inhibitors of DOPA decarboxylase, the enzyme responsible for levodopa conversion. The most effective of these was carbidopa, which was shown by a Merck scientist in 1971 to prevent nausea induced by levodopa.
Four years later, the company launched the first carbidopa/levodopa combination product under the brand name Sinemet (from sin emitos, literally “without vomiting”). The drug combination remains the gold standard treatment of PD today and represents over 1/3 of the $4 billion global market.
The process of minimizing the unintended consequences of vital medications is not over. Gaps in treatment present a revenue growth opportunity for both large and small firms.
Identifying unmet need
Carbidopa/levodopa combination therapy is a classic example of a second medication undoing the damage of a first. Treatments to counteract the adverse effects of chemotherapy – nausea, vomiting, weakened immune system – are another historical precedent. Amgen’s Neulasta, a bone marrow stimulant used to raise neutrophil counts lowered by cancer medication (chemotherapy-induced neutropenia) has been on the market so long that it’s facing biosimilar competition.
Given the increasing challenges and dramatically rising costs of developing the next blockbuster for a primary indication, medication-induced syndromes are an opportunity to take a look at existing markets in a new light. Perhaps there are greater depths (adverse effects that have gone untreated) in existing indications than previously realized. Greater depths offer greater profits.
While it’s not a revolutionary concept, treatments for medication-induced syndromes are a growing area of focus. Complementary medications can improve adherence to therapy regimens, prevent life-saving treatments from disrupting patient quality of life, and increase use of drugs with narrow therapeutic indices that currently present challenges to providers.
Highlighting this emerging strategic trend, several therapies targeting medication-induced syndromes are moving through the pipeline or have recently entered the market:
- Valeant’s oral Relistor was approved on July 19th for opioid-induced constipation (OIC). The company anticipates as much as $1 billion in peak sales. Relistor subcutaneous injection has been approved since 2008 to treat OIC in patients with advanced illness who are receiving palliative care, and was approved in 2014 for the treatment of OIC in patients with chronic non-cancer pain. AstraZeneca’s Movantik, also an oral therapy, was approved for OIC in 2014. Between 41% and 81% of patients receiving opioids for non-cancer pain experience constipation. The global OIC market continues to grow significantly and is estimated to hit $2.78 billion by 2022.
- In October 2015, the FDA granted accelerated approval for Boehringer Ingelheim’s Praxbind, an anticoagulant reversal agent specifically tailored to reverse the effects of BI’s Pradaxa. Patients taking anticoagulants require quick reversal of the blood thinning effects during major bleeding episodes or emergency surgery. Two other oral anticoagulant reversal agents are in development. In February 2016, the FDA accepted a BLA with priority review for Portola Pharmaceuticals’ andexanet alfa, which targets factor Xa inhibitors. Portola is expecting an FDA decision on August 17th. Perosphere’s Ciraparantag, a nonspecific agent that antagonizes multiple anticoagulants, is currently in Phase 2 trials and has received fast track status from the FDA. Oral anticoagulants are forecast to have global sales of $12 billion in 2020; 1% to 4% of patients taking oral anticoagulants are likely to experience major bleeding episodes and another 1% will undergo emergency surgery.
- Teva Pharmaceuticals’ SD-809 (deutetrabenazine) received breakthrough status from the FDA in November 2015 for tardive dyskinesia, a movement disorder caused by long-term or high-dose use of antipsychotics. Currently in Phase 3 trials, the treatment would be the first approved for tardive dyskinesia in the US but faces potential competition from Neurocrine’s Valbenazine, which recently completed Phase 3 trials. The average prevalence rate of tardive dyskinesia for individuals taking antipsychotic medication is estimated to be about 30%. The global market for dyskinesia therapeutics (including both levodopa-induced dyskinesia and tardive dyskinesia) is expected to reach $480 million by 2019.
Bringing complementary treatments to market
AstraZeneca’s “OIC is Different” campaign includes a general awareness push for opioid-induced constipation.
Targeting medication-induced therapies as part of R&D strategy is not without competitive considerations. Most of the time, means exist to partially address the issue. Even if existing treatments (e.g. generic laxatives in the case of OIC) are known to be less effective for the niche application, it’s necessary to run comparison trials. Then, it’s time to carve out market share from popular, broader application drugs. The right messaging must communicate how tailored the drug is for the medication-induced condition, without overemphasizing the drawbacks of the primary medication.
Relistor’s messaging focuses on OIC as a “distinct type of constipation” and frequently highlights the method of action as directly reversing the unintended effects of the culprit medication (blocking opioid binding in tissues of the gastrointestinal tract). AstraZeneca’s “OIC is Different” campaign drew raised eyebrows last year, but it was a clear move to help Movantik compete with both OTC laxatives and non-specific therapies like Takeda’s Amitiza by raising OIC awareness.
Keeping patients first
Recent scandals of 5,000% price hikes and other short-sighted efforts to maximize profits at the expense of patients and the broader healthcare system have rattled the public’s perception of the entire pharmaceutical industry, which at its core is founded on compassion and care. In a time where negative press dominates the conversation, pharmaceutical companies have an opportunity to stand out from the milieu by positioning themselves as patient-centric. Demonstrating a commitment to patients by improving overall care quality can be an especially potent business strategy.
There are also financial benefits to consider. Many therapy-related illnesses are treated off-label with products designed for other indications. Due to the generally under-developed market for therapy-related illnesses, there is arguably greater possibility to develop a small-molecule solution than for a primary indication for which several generations of increasingly complex products have already been developed. With the costs of R&D rapidly increasingly as a result of more advanced products, there is potential to create multiple market-leading drugs for secondary conditions with smaller levels of investment in areas absent of approved therapies. In addition, available science could provide a head start.
It’s a profitable and sustainable strategy that both small and large players in the industry should consider. Competing in today’s market does not require going “all-in” on expensive pipeline assets in hopes of creating the next blockbuster drug for a large-market indication. Alone or as a complement to higher investment (and higher risk) projects, there are many opportunities to demonstrate loyalty to patients and shareholders alike by remaining attentive to unmet needs.