Updated Comprehensive DED Treatment Pipeline Chart: And Why Was Diquafosol & Rebamipide not FDA approved?

The exact reasons for FDA non-approval of diquafosol and rebamipide are not publicly documented in the medical literature. Neither drug appears to have been formally rejected by the FDA; rather, they were never submitted for FDA approval or the applications were withdrawn before completion.[1][2][3][4][5] The available evidence suggests these were business/regulatory strategy decisions rather than safety or efficacy failures, as both drugs demonstrated positive clinical trial results and are successfully marketed in Asia.[1][6][7]  

For diquafosol, early U.S. clinical development occurred in the 2000s under the designation INS365, with Phase 2 trials showing promise.[3] However, no Phase 3 U.S. trials or New Drug Application (NDA) submission to the FDA are documented in the literature. The drug was subsequently developed and approved in Japan (2010) and South Korea, where it has been widely used with demonstrated efficacy and safety.[1][2] The lack of FDA pursuit may reflect the high regulatory bar for dry eye trials in the U.S., where demonstrating statistical significance in both sign and symptom endpoints has proven challenging for multiple products.[5]    

For rebamipide, Phase 2 and Phase 3 trials were conducted and published, showing superiority over placebo and sodium hyaluronate in improving both objective signs and subjective symptoms.[6][7] Despite these positive results, the drug was approved only in Japan (2012) and has not been submitted to the FDA.[4][8] Again, no formal rejection is documented—the manufacturer (Otsuka Pharmaceutical) appears to have chosen not to pursue U.S. approval, possibly due to market considerations, regulatory complexity, or strategic prioritization of Asian markets where the drug has been commercially successful.[8]  

Updated Comprehensive DED Treatment Pipeline Chart

  

  

Treatment / Drug	Mechanism of Action	Primary Indication	Regulatory Status	Notes
MGD / EVAPORATIVE DRY EYE
Perfluorohexyloctane (MIEBO)	Anti‑evaporative barrier	MGD / Evaporative	FDA Approved 2023	Prescription eye drop
AZR‑MD‑001	Selenium sulfide keratolytic / lipogenic	MGD	Phase 3 Active	Improves meibum quality/quantity
LipiFlow	Thermal pulsation	MGD	FDA Approved Device	In‑office treatment
TearCare	Thermal therapy	MGD	FDA Approved Device	In‑office treatment
OptiLight IPL	Intense pulsed light	MGD	FDA Approved Device	In‑office treatment
Topical azithromycin / doxycycline	Anti‑inflammatory / antimicrobial	MGD / Blepharitis	Available (off‑label)	Oral or topical formulations
AQUEOUS DEFICIENCY
Cyclosporine 0.05% (RESTASIS)	T‑cell immunomodulator	Aqueous deficiency	FDA Approved 2003	BID dosing
Cyclosporine 0.09% (CEQUA)	T‑cell immunomodulator	Aqueous deficiency	FDA Approved	Nanomicellar formulation
Cyclosporine 0.1% (VEVYE)	T‑cell immunomodulator	Aqueous deficiency	FDA Approved	Water‑free formulation
Lifitegrast 5% (XIIDRA)	LFA‑1 / ICAM‑1 antagonist	Aqueous deficiency / inflammation	FDA Approved	Reduces inflammatory signaling
Varenicline nasal spray (TYRVAYA)	Cholinergic agonist	Aqueous deficiency	FDA Approved	Stimulates trigeminal parasympathetic pathway
Loteprednol 0.25% (EYSUVIS)	Corticosteroid	Aqueous deficiency / inflammation	FDA Approved	Short‑term flare therapy
TJO‑087	Cyclosporine	Aqueous deficiency	Investigational	Phase unclear
SCAI‑001	Cyclosporine	Aqueous deficiency	Investigational	Phase unclear
Reproxalap	Reactive aldehyde species inhibitor	Aqueous deficiency / inflammation	Investigational	Phase 3 data published
HBM9036 (Tanfanercept)	TNF‑alpha inhibitor	Aqueous deficiency / inflammation	Investigational	Biologic anti‑inflammatory
OCS‑02 (Licaminlimab)	Anti‑inflammatory agent	Aqueous deficiency	Investigational	Topical biologic
Cenegermin (OXERVATE)	Nerve growth factor	Neurotrophic keratitis / severe DED overlap	FDA Approved	Biologic tear film restoration
Autologous serum tears	Biologic tear substitute	Severe aqueous deficiency	Available (compounded)	Contains growth factors and cytokines
Punctal plugs	Tear retention	Aqueous deficiency	FDA Approved	Increases tear volume
MUCIN DEFICIENCY
Diquafosol 3%	P2Y2 receptor agonist	Mucin deficiency / short TBUT	Approved in Japan & Korea	No FDA submission; strong RCT data
Rebamipide 2%	Mucin secretagogue	Mucin deficiency	Approved in Japan	No FDA submission; strong Phase 2/3 data
SYL1001 (Tivanisiran)	siRNA therapy	Mucin deficiency / neuropathic pain	Investigational	RNA interference mechanism
MIM‑D3 (Tavilermide 5%)	Muscarinic agonist	Mucin deficiency	Investigational	Promotes goblet cell activity
Recombinant human lubricin	Biolubrication	Mucin deficiency / friction syndrome	Investigational	Phase unclear
IC‑265	Unknown mechanism	Mucin deficiency	Investigational	Phase unclear
OK‑101	Unknown mechanism	Mucin deficiency	Investigational	Phase unclear
PL9643	Unknown mechanism	Mucin deficiency	Investigational	Phase unclear
SHJ002	Unknown mechanism	Mucin deficiency	Investigational	Phase unclear
AR‑15512	Unknown mechanism	Mucin deficiency	Investigational	Phase unclear
BRM421	Unknown mechanism	Mucin deficiency	Investigational	Phase unclear

Drug	Clinical Evidence	Safety Profile	Approval Status (U.S. vs Asia)	Reason for No FDA Approval
Diquafosol (INS365 / Diquas)	• Multiple RCTs show superiority to placebo and non‑inferiority to sodium hyaluronate • Significant improvements in corneal staining, rose bengal staining, TBUT, Schirmer • 75% of trials show improvement in both signs and symptoms	• Well‑tolerated • Mild eye irritation most common adverse event • Long‑term safety confirmed in real‑world studies	• Japan: Approved (2010) • South Korea: Approved • United States: No FDA submission documented	• No evidence of FDA rejection • U.S. Phase 2 completed, but no Phase 3 or NDA filed • Likely business/regulatory strategy decision • U.S. dry eye trials require dual sign‑and‑symptom endpoints, historically difficult to meet
Rebamipide (OPC‑12759 / Mucosta)	• Phase 2 and 3 trials show dose‑dependent efficacy • 2% formulation superior to placebo and sodium hyaluronate • Improves fluorescein staining, lissamine green staining, TBUT, and symptoms • 64.5% of patients rated “improved or markedly improved”	• No serious adverse events reported in trials • Excellent tolerability profile	• Japan: Approved (2012) • United States: Never submitted for FDA review	• No evidence of FDA rejection • Manufacturer (Otsuka) did not pursue U.S. approval • Likely due to market strategy, regulatory complexity, and strong Asian market performance

  

  

  

  

Key Points on Diquafosol and Rebamipide Non-Approval

  

  

Diquafosol (INS365/Diquas):  

  

- Demonstrated efficacy in multiple RCTs showing superiority to placebo and non-inferiority to sodium hyaluronate for corneal staining, with superiority for rose bengal staining[1]  

  

- Improved tear film breakup time, Schirmer test, and subjective symptoms in 75% of trials[9]  

  

- Well-tolerated with only mild eye irritation as the most common adverse event[1][10]  

  

- Successfully marketed in Japan and South Korea since 2010[2]  

  

- No FDA submission documented—appears to be a business decision rather than regulatory rejection[3][11]  

  

Rebamipide (OPC-12759/Mucosta):  

  

- Phase 2 and 3 trials showed dose-dependent efficacy with 2% formulation superior to placebo and 0.1% sodium hyaluronate[6][7]  

  

- Improved both objective signs (fluorescein staining, lissamine green staining, TBUT) and subjective symptoms[6][7]  

  

- 64.5% of patients rated treatment as "improved or markedly improved" vs. 34.7% for sodium hyaluronate[7]  

  

- No serious adverse events in clinical trials[6][7]  

  

- Successfully marketed in Japan since 2012[8]  

  

- No FDA submission documented—manufacturer (Otsuka) chose not to pursue U.S. approval despite positive trial results[4][8]  

  

The absence of these mucin secretagogues from the U.S. market represents a significant therapeutic gap, particularly for patients with mucin-deficient dry eye or short tear breakup time.[2][5][11] Both drugs address mechanisms not targeted by currently FDA-approved treatments and have demonstrated clinical benefit in Asian populations.[12]  

  

Would you like me to provide more detail on the comparative efficacy between diquafosol and rebamipide, or explore the regulatory challenges specific to dry eye drug development in the United States?  

  

References

1. Diquafosol Ophthalmic Solution 3 %: A Review of Its Use in Dry Eye. Keating GM. Drugs. 2015;75(8):911-22. doi:10.1007/s40265-015-0409-7.

2. Clinical Utility of 3% Diquafosol Ophthalmic Solution in the Treatment of Dry Eyes. Koh S. Clinical Ophthalmology (Auckland, N.Z.). 2015;9:865-72. doi:10.2147/OPTH.S69486.

3. Diquafosol Tetrasodium: A Novel Dry Eye Therapy. Nichols KK, Yerxa B, Kellerman DJ. Expert Opinion on Investigational Drugs. 2004;13(1):47-54. doi:10.1517/13543784.13.1.47.

4. The Efficacy and Safety of Rebamipide Ophthalmic Suspension (OPC-12759) in Patients With Dry Eye Disease: A Systematic Review of Randomized Controlled Trials. Ballesteros-Sánchez A, Sánchez-González MC, De-Hita-Cantalejo C, et al. Journal of Clinical Medicine. 2023;12(22):7155. doi:10.3390/jcm12227155.

5. Efficacy of Topical Ophthalmic Drugs in the Treatment of Dry Eye Disease: A Systematic Literature Review. Holland EJ, Darvish M, Nichols KK, Jones L, Karpecki PM. The Ocular Surface. 2019;17(3):412-423. doi:10.1016/j.jtos.2019.02.012.

6. Rebamipide (OPC-12759) in the Treatment of Dry Eye: A Randomized, Double-Masked, Multicenter, Placebo-Controlled Phase II Study. Kinoshita S, Awamura S, Oshiden K, et al. Ophthalmology. 2012;119(12):2471-8. doi:10.1016/j.ophtha.2012.06.052.

7. A Randomized, Multicenter Phase 3 Study Comparing 2% Rebamipide (OPC-12759) With 0.1% Sodium Hyaluronate in the Treatment of Dry Eye. Kinoshita S, Oshiden K, Awamura S, et al. Ophthalmology. 2013;120(6):1158-65. doi:10.1016/j.ophtha.2012.12.022.

8. Rebamipide Ophthalmic Suspension for the Treatment of Dry Eye Syndrome: A Critical Appraisal. Kashima T, Itakura H, Akiyama H, Kishi S. Clinical Ophthalmology (Auckland, N.Z.). 2014;8:1003-10. doi:10.2147/OPTH.S40798.

9. Efficacy and Safety of Topical Diquafosol Ophthalmic Solution for Treatment of Dry Eye: A Systematic Review of Randomized Clinical Trials. Wu D, Chen WQ, Li R, Wang Y. Cornea. 2015;34(6):644-50. doi:10.1097/ICO.0000000000000429.

10. Long-Term Safety and Effectiveness of Diquafosol for the Treatment of Dry Eye in a Real-World Setting: A Prospective Observational Study. Ohashi Y, Munesue M, Shimazaki J, et al. Advances in Therapy. 2020;37(2):707-717. doi:10.1007/s12325-019-01188-x.

11. P2Y2 Receptor Agonists for the Treatment of Dry Eye Disease: A Review. Lau OC, Samarawickrama C, Skalicky SE. Clinical Ophthalmology (Auckland, N.Z.). 2014;8:327-34. doi:10.2147/OPTH.S39699.

12. Comparing Two Mucin Secretagogues for the Treatment of Dry Eye Disease: A Prospective Randomized Crossover Trial. Jin Y, Seo KY, Kim SW. Scientific Reports. 2024;14(1):13306. doi:10.1038/s41598-024-63784-4.