Market Overview
Refractory Chronic Cough (RCC) remains a large, undertreated, and globally unaddressed condition. Despite an estimated 100 million affected worldwide and ~10 million in the U.S., there are no FDA-approved therapies.
Current practice relies on off-label medicines with 31–40% adverse event rates, modest efficacy, and limited persistence. The first U.S. approval—expected no earlier than 2026—will create a new therapeutic category but will enter into a market shaped by high placebo response, demanding regulators, and increasing payer scrutiny.
Growth Drivers: Aging populations, specialist referral expansion, digital identification tools, and increasing recognition of cough hypersensitivity.
The U.S. market will likely see one winner, at most two, with meaningful time separation between market entries.
Regulatory Reset
Two Complete Response Letters (CRL) for Gefapixant (January 2022 and December 2023) materially raised the evidentiary bar:
- The FDA requires a ≥30% placebo-adjusted reduction in objective 24-hour cough frequency
- Clinically meaningful improvements in patient-reported outcomes are mandatory
- The high placebo response threatens statistical separation for all mechanisms
Without stronger Health Economics and Outcomes Research (HEOR) evidence, even efficacious therapies may see restricted access or price compression.
Mechanism Performance and Competitive Landscape
Three modalities dominate RCC development:
P2X3 Antagonists: P2X3 remains the most validated mechanism, but only highly selective, taste-sparing agents with ≥30% adjusted efficacy are viable in the U.S.
Kappa/Mu Opioid Modulators (Nalbuphine ER): Highest efficacy potential; regulatory risk tied to opioid-related concerns and need for robust Phase 3 confirmation.
Alternative Mechanisms: Includes TRPM8 agonists, sodium channel blockers, NK-1 antagonists, airway hydration. Intriguing but unproven pathways. Unlikely to deliver first-in-class approval without novel trial designs or biomarker stratification.
Digital Pathways: Meaningful potential both as standalone interventions and in combination with pharmacological drugs. Preliminary data very promising. Trajectory will depend primarily on the pace of adoption of digital therapeutics within health systems.
The Digital Inflection Point
Digital therapeutics (DTx) are emerging as central to the RCC treatment model. The field presents two distinct digital opportunities:
Standalone Digital Therapeutics
Behavioral cough suppression therapy (BCST) demonstrates 40–88% improvement in RCTs and is guideline-endorsed but bottlenecked by provider scarcity.
- Digital delivery via mobile platforms replicates BCST elements
- Early digital cohorts show ~42% reductions in cough frequency
- No drug toxicity; large addressable population
- Japan-first prescription DTx pathways (e.g., Kyorin × Hyfe) create regulatory precedent
Combination Therapy (Drug + DTx)
Digital augmentation materially strengthens the economics of pharmacologic therapy:
- Average treatment duration increases from 6–8 months to ~9 months (+20–30%)
- This yields a 20–44% increase in lifetime value (LTV) and a 7–8× ROI for manufacturers
- Objective monitoring provides regulators and payers with real-world evidence on durability
- Combination approaches may offer differentiation where efficacy deltas are narrow
The drug+DTx model is a high-leverage commercial tool and could become a requirement for payers evaluating chronic symptom management therapies.
Outlook 2026–2035
Three structural forces will shape the market this decade:
1. Regulatory interpretation of placebo-adjusted efficacy: Only agents demonstrating clear improvement in objective and subjective cough frequency are likely to be approved in the U.S.
2. Durability and HEOR evidence: Therapies demonstrating long-term symptom control with measurable QoL and cost offsets will capture payer support.
3. Digital integration: Objective monitoring and behavioral therapeutics—either standalone or integrated—will expand the market, improve clinical outcomes, and protect persistence-driven revenue.