Open-label Extension Study Evaluating Long-term Safety and Efficacy of FMX103 1.5% Minocycline Topical Foam for the Treatment of Moderate-to-Severe Papulopustular Rosacea

J Clin Aesthet Dermatol. 2020;13(11):44–49

by Linda Stein Gold, MD; James Q. Del Rosso, DO; Leon Kircik, MD; Neal D. Bhatia, MD; Deirdre Hooper, MD; Walter Nahm, MD, PhD; and Iain Stuart, PhD

Dr. Stein Gold is with the Henry Ford Health System in Detroit, Michigan. Dr. Del Rosso is the Research Director at JDR Dermatology Research in Las Vegas, Nevada. Dr. Kircik is with the Icahn School of Medicine at Mount Sinai in New York, New York. Dr. Bhatia is with Therapeutics Clinical Research in San Diego, California. Dr. Hooper is with Delricht Research in New Orleans, Louisiana. Dr. Nahm is with the University of California at the San Diego School of Medicine in San Diego, California.
Dr. Stuart is with VYNE Therapeutics Inc. in Bridgewater, New Jersey.

FUNDING: This study was sponsored by Foamix Pharmaceuticals Ltd., a wholly owned subsidiary of VYNE Therapeutics Inc.

DISCLOSURES: Dr. Stein Gold is an advisor and investigator for  VYNE Therapeutics Inc, Galderma, LEO Pharma, Novartis, and Valeant and is an investigator for Janssen, AbbVie, and Solgel. Dr. Del Rosso is a consultant for Aclaris, Almirall, Athenex, Cutanea, Dermira, EPI Health, Ferndale, Galderma, Genentech, LEO Pharma, VYNE Therapeutics Inc, Novan, Ortho, Pfizer, Promius, Sanofi/Regeneron, SkinFix, and SunPharma; he has received research support from Aclaris, Almirall, Athenex, Botanix, Celgene, Cutanea, Dermira, Galderma, Genentech, LEO Pharma, VYNE Therapeutics Inc, Novan, Ortho, Promius, Regeneron, SunPharma, and Thync; he receives honoraria from Aclaris, Celgene, Galderma, Genentech, LEO Pharma, Novartis, Ortho, Pfizer, Promius, Sanofi/Regeneron, and SunPharma; and he participates in speakers bureaus for honoraria from Aclaris, Celgene, Galderma, Genentech, LEO Pharma, Novartis, Ortho, Pfizer, Promius, Sanofi/Regeneron, and SunPharma. Dr. Kircik is an investigator and consultant for VYNE Therapeutics Inc. Dr. Bhatia is an investigator and consultant for VYNE Therapeutics Inc. Dr. Deirdre Hooper served as an investigator for VYNE Therapeutics Inc; she reports personal fees from DelRicht Research during the conduct of the study; honoraria from Allergan, Almirall Aesthetics, Aqua Galderma USA, Cutera Inc., Ferndale, La Roche Posay, Pixacore, RBC Consultants (clarisonic), Revance, and Viviscal; and other financial benefits from Actavis, Dermira, GSK, Mylan, and Sol Gel. Dr. Nahm is an investigator for VYNE Therapeutics Inc. Dr. Stuart is an employee and stockholder at VYNE Therapeutics Inc.

ABSTRACT: Background. Efficacy and safety of FMX103 1.5% for papulopustular rosacea were previously demonstrated in two 12-week, Phase 3 studies.

Objective. We sought to evaluate the safety and efficacy of FMX103 1.5% foam for up to 52 weeks of treatment.

Methods. Following the completion of two 12-week, double-blind, vehicle-controlled, Phase 3 studies, subjects were invited to enter a 40-week open-label extension study in which all subjects applied FMX103 1.5% once daily. Efficacy endpoints were the reduction in inflammatory lesions and the rate of IGA treatment success from the double-blind baseline. Safety assessments included adverse events, vital signs, laboratory tests, and facial tolerability signs and symptoms.

Results. The favorable safety profile of FMX103 1.5% observed in the double-blind studies was maintained over extended treatment lasting up to one year. There were no serious treatment-related adverse events. Long-term treatment with FMX103 1.5% was associated with a greater than 82-percent reduction in inflammatory lesions from baseline and with over 79 percent of subjects achieving treatment success. At the end of the open-label treatment period, over 82 percent of subjects indicated they were overall “satisfied” or “very satisfied” with FMX103 1.5%. All facial local tolerability symptoms improved through Week 52.

Limitations. Due to the nature of the open-label study, lacking a vehicle-treated control, no statistical comparisons can be made.

Conclusion. FMX103 1.5% demonstrated a favorable safety and tolerability profile for up to 52 weeks. Long-term efficacy was demonstrated by progressive reductions in inflammatory lesions and increasing IGA treatment success, suggesting that FMX103 1.5% may be a suitable option for the treatment for papulopustular rosacea.

KEYWORDS: minocycline; open-label; papulopustular rosacea; phase 3 clinical trial; safety; topical therapy

Rosacea is a chronic inflammatory dermatosis characterized by marked involvement of the central face.^1,2 Rosacea affects approximately 16 million people in the United States with a high prevalence among fair-skinned adults of Northern European descent.^2,3 Primary features of the disease often include transient or persistent erythema, inflammatory papules and/or pustules, telangiectases, or hyperplasia of the connective tissue.¹ Secondary symptoms may include itching, burning, stinging, or a dry appearance of the skin.^4,5 Numerous triggers, such as sun exposure, heat, and stress, have been associated with worsening of rosacea signs and symptoms.¹ Although the etiology of rosacea remains to be fully elucidated, these triggers are believed to activate cells, such as neutrophils, keratinocytes, mast cells, or T-helper cells to release mediators of inflammation, leading to inflammatory pain, and to promote angiogenesis.^6,7

Patients are counseled to avoid known rosacea triggers. Topical regimens are used as initial treatment for mild or moderate rosacea, while systemic therapies are often utilized as monotherapy or in combination with topicals in moderate-to-severe cases.^1,8 Current topical therapies that are approved by the United States Food and Drug Administration for inflammatory lesions of rosacea include azelaic acid, metronidazole, and ivermectin.^1,2,4,5,8 These therapies are generally effective and well tolerated by patients. Depending on disease severity, oral antibiotics may be administered either in isolation or in combination with topical treatments.⁸ The efficacy of oral antibiotics, such as the tetracycline minocycline, is believed to be due to their anti-inflammatory activity.^9–11 The anti-inflammatory action of tetracyclines involves the regulation of pro-inflammatory cytokines, as well as the inhibition of neutrophil chemotaxis, matrix metallopeptidases (MMPs), LL-37, and angiogenesis, all of which are implicated in rosacea pathogenesis.^9–11 Regardless of their exact mechanisms of action, oral tetracyclines have been used to treat inflammatory lesions of rosacea for several decades and have been associated with improvements in disease symptoms compared with placebo.^2,8 Unfortunately, long-term use of oral antibiotics can lead to adverse events, such as gastrointestinal and central nervous system side effects, photosensitivity, cutaneous hyperpigmentation, and the development of resistant bacterial strains.^1,8

FMX103 1.5% is a novel, topical foam formulation of minocycline that was developed to leverage the efficacy of minocycline in treating dermatologic conditions while minimizing the systemic adverse events that are associated with oral antibiotics.¹² The safety and efficacy of FMX103 1.5% for the treatment of papulopustular rosacea were previously demonstrated in Phase 2¹² and Phase 3¹³ randomized, double-blind, vehicle-controlled studies. Patients who were treated with FMX103 1.5% for 12 weeks exhibited significantly greater reductions in inflammatory lesions and significantly greater improvements in Investigator’s Global Assessment (IGA) treatment success than patients who received vehicle treatment, starting as early as Week 4.^12,13 Importantly, FMX103 1.5% appeared to be safe and well tolerated across these three 12-week studies.^12,13 Due to the chronic, relapsing nature of the disease, patients often require extended pharmacologic interventions. Therefore, it is essential to characterize the effects that are associated with long-term use of FMX103 1.5%. In this study, we evaluated the safety and efficacy of up to 52 weeks of once-daily topical administration of FMX103 1.5% in the treatment of moderate-to-severe papulopustular rosacea.

Methods

Study design. FX2016-13 (Study 13) was an open-label, multicenter, 40-week extension study that was conducted at 70 sites in the United States. Subjects were eligible to enter this study upon successful completion of one of two pivotal, double-blind, vehicle-controlled, Phase 3 studies, FX2016-11 (Study 11) and FX2016-12 (Study 12). Eligible subjects included males and females 18 years of age or older with moderate-to-severe facial papulopustular rosacea at the start of the double-blind study. At Week 12, eligible subjects were invited to continue into the open-label extension study, provided their rosacea had not worsened relative to their baseline IGA assessment. All subjects applied FMX103 1.5% to the full face once daily for up to 40 weeks. Treatment was guided by each subjects’ clinical response. Study investigators were permitted to suspend treatment if there was clinical improvement or resolution of rosacea. However, subjects were encouraged to continue in the study and attend all scheduled clinic visits. In the event of rosacea recurrence or worsening, treatment could be resumed. Concomitant use of prescription or over-the-counter medications or any change in dosage during the study was permitted and recorded.

These studies were conducted in accordance with the principles of the Declaration of Helsinki and the principles of Good Clinical Practice. The study protocol was approved by an institutional review board at each site, and all patients provided written informed consent.

Safety and efficacy endpoints. Safety and efficacy evaluations occurred during visits at Weeks 16, 22, 28, 34, 40, 46, and 52 of the open-label extension study, relative to the baseline visit of the preceding double-blind study. Safety assessments included treatment-emergent adverse events (TEAEs), laboratory tests, vital signs, physical examinations, and local skin tolerability assessments. The coprimary efficacy endpoints were the absolute change in inflammatory lesion count at Week 52 compared to the baseline of the preceding double-blind study, and the IGA treatment success rate at Week 52, where success was defined as an IGA score of 0 or 1, and at least a two-grade improvement (reduction) from baseline. The absolute and percent change from baseline in inflammatory lesions and the dichotomized IGA treatment success rate at each visit were among the secondary efficacy endpoints. The Subject Satisfaction Questionnaire (SSQ) was administered at Week 52 as an additional efficacy endpoint.

Statistical analysis. Safety parameters were assessed for all subjects who entered the open-label safety extension phase of either study and used at least one dose of the study product (all-treated population). Safety assessments were based on descriptive statistics; no statistical tests were performed. No comparator statistical testing was performed for the open-label efficacy data, and all data are presented from observed cases only, with no imputation for missing data.

Results

Baseline characteristics and subject disposition. A total of 504 subjects were included in the all-treated population: 332 had received FMX103 1.5% during the double-blind study and 172 received vehicle foam (Figure 1). Of these 504 subjects, 217 were from Study 11, and 287 were from Study 12. A total of 410 (81.3%) subjects completed the open-label phase. Overall, 94 subjects discontinued the study, with five subjects discontinuing due to a TEAE (Figure 1).

No major differences were observed in baseline demographics and disease characteristics between the two treatment groups from the double-blind study who entered the open-label extension (Table 1). Overall, subjects ranged between 18 and 85 years of age, with the majority being white (96.2%) and female (69.6%). The overall inflammatory lesion count at the double-blind baseline was 28.8, and there was a similar distribution of subjects between treatment groups who had either moderate (IGA=3) or severe (IGA=4) rosacea at double-blind baseline (FMX103/FMX103 group vs. vehicle/FMX103 group: for moderate, 90.7% vs. 86.6%; for severe, 9.3% vs. 13.4%).

Concomitant use of other medications was permitted, with 81.3 percent of subjects using any other medication during the open-label extension period (Table 1). Vitamins, lipid-modifying agents, and agents acting on the angiotensin system were the most commonly used concomitant classes of drugs. Notably, concomitant use of medications for dermatologic purposes was relatively low across all subjects in the pooled population, including the use of antibiotics and chemotherapeutics (2.0%), antifungals (1.4%), and other dermatologic preparations (1.2%) (Table 1).

Treatment duration and study drug exposure. Across both the double-blind and open-label study periods, the mean (standard deviation [SD]) treatment duration on FMX103 1.5% was 340.7 (61.14) days for subjects in the FMX103/FMX103 group (range: 87–387 days) and 246.2 (74.23) days for subjects in the vehicle/FMX103 group (range: 15–329 days). The percentages of subjects exposed to FMX103 1.5% for at least six months, and at least one year, were 96.1 percent and 81.9 percent, respectively, for the FMX103/FMX103 group and 84.9 percent and 0 percent for the vehicle/FMX103 group. Overall, the mean (SD) treatment duration during the combination of the double-blind and open-label studies was 308.5 (79.67) days (range: 15–387 days), with 465 subjects (92.3%) exposed to FMX103 1.5% for at least six months and 272 subjects (54.0%) exposed for at least one year. Overall, there were high rates of study drug adherence in both treatment groups (mean adherence, 98.5% for FMX103/FMX103 and 98.4% for vehicle/FMX103).

Long-term safety and tolerability. Long-term use of FMX103 1.5% minocycline foam was generally safe and well tolerated (Tables 2 and 3). The reported incidence of TEAEs in the double-blind FMX103 1.5% group (FMX103/FMX103) and in the double-blind vehicle group (vehicle/FMX103) was 137 subjects (41.3%) and 64 subjects (37.2%), respectively. The TEAEs reported with the greatest incidence were upper and viral upper respiratory tract infection, each reported in 14 subjects (4.2%) in the FMX103/FMX103 group, and sinusitis, reported in nine subjects (5.2%) in the vehicle/ FMX103 group. All other TEAEs were reported in less than three percent of subjects from either group. The reported incidence of treatment-related TEAEs was low: five (1.5%) in the FMX103/FMX103 group and eight (4.7%) in the vehicle/FMX103 group. There were few serious TEAEs: nine events in six subjects (1.8%) in the FMX103/FMX103 group and four events in four subjects (2.3%) in the vehicle/FMX103 group; none were considered treatment related. The majority of reported TEAEs were classified by the investigator to be mild or moderate in severity. Among the severe TEAEs, only one case of pruritus in the vehicle/FMX103 group was considered to have a probable relation to treatment. Acne was the only treatment-related TEAE reported in less than one subject from either group (2 subjects [1.2%] in the vehicle/FMX103 group).

Evaluation of local signs and symptoms was based on the investigators’ evaluation of erythema, telangiectasia, burning/stinging, flushing/blushing, dryness/xerosis, peeling/desquamation, and hyperpigmentation of the application sites. Itching was self reported by the subjects. All signs and symptoms, with the exception of erythema, were graded using a four-point scale (none to severe), while erythema was graded using a five-point scale (clear skin to severe). At Week 52, the majority of subjects in the pooled population (>57%) had no signs of burning/stinging, flushing/blushing, dryness/xerosis, itching, peeling/desquamation, or postinflammatory hyperpigmentation. Among those subjects who did show signs or symptoms, the majority were mild in severity (Table 3). No appreciable difference was observed between the two groups as defined by treatment in the double-blind studies; thus, local facial tolerability data were pooled across all subjects (Table 3). All facial local tolerability assessments at Week 52 improved relative to the facial assessments at the double-blind baseline (Table 3), with a more pronounced improvement in erythema. Overall in the pooled population, the percentage of patients with clear and almost clear erythema at the double-blind baseline improved, from 4.0 percent to 59.3 percent by the end of the open-label study.

Long-term efficacy. Long-term treatment with FMX103 1.5% was associated with a progressive decrease in inflammatory lesions and a parallel increase in the proportion of subjects achieving IGA treatment success (Figure 2). The mean absolute change from double-blind baseline in inflammatory lesions to Week 52 in the pooled population was –22.8 lesions, with comparable decreases observed in subjects from both groups (Figure 2A): for FMX103/FMX103, the mean change was –23.0 lesions, and for vehicle/FMX103, the mean change was –22.5 lesions). The percentage change in inflammatory lesions at Week 52 pooled across all subjects corresponded with an 82.3-percent decrease relative to the double-blind baseline, with comparable decreases in both groups (Figure 2B): for FMX103/FMX103, the mean percent change was –83.01%, and for vehicle/FMX103, the mean percent change was –80.91%). Overall, the proportion of subjects achieving IGA treatment success at Week 52 was 79.8 percent in the pooled population, with comparable rates of success regardless of prior treatment (Figure 2C).

Subject satisfaction. Overall, there was a high rate of subject satisfaction with FMX103 1.5%. At the end of the study, the majority of subjects (82.4%) reported being overall “satisfied” or “very satisfied” with FMX103 1.5% in treating their rosacea. The majority of subjects (83.2%) were also satisfied or very satisfied with how FMX103 1.5% compared with other products, as well as with its ease of use (92.9%). Most subjects (83.2%) reported being “likely” or “very likely” to recommend FMX103 1.5% to a friend.

Discussion

The efficacy, safety, and tolerability of FMX103 1.5% topical minocycline foam for the short-term treatment of moderate-to-severe papulopustular rosacea have previously been demonstrated in 12-week, double-blind, placebo-controlled Phase 2¹² and Phase 3¹³ studies. Here, we report that once-daily topical application of FMX103 1.5% minocycline foam for up to one year maintained the favorable safety profile established in the double-blind studies. Additionally, the long-term efficacy data demonstrated that FMX103 1.5% continued to be associated with a progressive decrease in the number of inflammatory lesions, as well as an improvement in overall IGA treatment success.

The safety results during the open-label study reported here are similar to those observed during the two preceding, 12-week, double-blind studies. As in the double-blind studies, the majority of the TEAEs were considered mild or moderate, and the frequency of TEAEs observed in all patients in the open-label study was similar to that observed in the double-blind studies, with upper respiratory tract infection and viral upper respiratory tract infection being among the most common TEAEs across studies. This suggests that the favorable safety profile of FMX103 1.5% was maintained over the extended treatment period lasting for up to one year.

An important outcome was that the most concerning events that are typically associated with oral minocycline were not observed with extended use of FMX103 1.5%. TEAEs have been reported in up to 56 percent of patients being treated with oral minocycline, and have included fatigue, dizziness, and lupus-like syndrome.^14,15 Additionally, pseudotumor cerebri has been associated with oral minocycline use, manifesting clinically with headache and blurred vision.¹⁴ In this open-label extension study with topical minocycline foam, 10 subjects (2.0%) reported headaches, and none of these events were deemed to be related to treatment with FMX103 1.5%. None resulted in study discontinuation, and none were determined to be related to the development of pseudotumor cerebri. Furthermore, the hyperpigmentation reported during local facial tolerability assessments (Table 3) was focal post-inflammatory hyperpigmentation resulting from acne itself, and not minocycline-induced hyperpigmentation commonly associated with oral minocycline use (e.g, blue-gray discoloration, brown patches on legs, blue scars).

Patient adherence is often a limiting factor in rosacea therapy.¹⁶ Patient frustration due to lack of clinical response, a delayed response, the occurrence of adverse events, or general dissatisfaction with the treatment experience can be contributing factors that compromise patient adherence to dermatologic interventions.^17,18 In the current study, FMX103 1.5% treatment was associated with ongoing improvements in rosacea outcomes during the 40-week open-label extension study. Consistent with these long-term treatment benefits, patients reported high levels of satisfaction with their use of FMX103 1.5%. Together, the positive efficacy outcomes, favorable 52-week safety profile, and patient satisfaction with FMX103 1.5% may foster patients’ adherence to therapy. A positive effect on treatment adherence would likely result in increased rates of treatment success among rosacea patients, suggesting that FMX103 1.5% topical minocycline foam could be a promising new therapy for the management of rosacea.

Limitations. Because of the nature of the open-label study, no statistical inference can be made on comparability due to the absence of a control group. Therefore, no comparator analysis of efficacy was carried out for data from the 40-week open-label extension study. Additionally, the data that are presented here correspond to observed cases from each study visit without imputation for missing data. Specifically, subjects who discontinued the open-label study due to lack of effect, TEAE, or other reasons are not included in the descriptive statistics.

Subjects were permitted to use either prescription or over-the-counter concomitant medications throughout the open-label period and were able to discontinue or recommence the study at any time during the 40-week extension period. Concomitant medications used at any time during the study and either indicated for rosacea, or known to have a therapeutic benefit in rosacea, were clindamycin (0.6%), doxycycline (0.8%), erythromycin (0.2%), metronidazole (0.4%), and ivermectin (0.2%). Thus, while these data may not provide an accurate representation of the safety and efficacy of patients solely using FMX103 1.5% for 40 consecutive weeks, they may be representative of a real-world setting in which patients use concomitant medications and have varying rates of adherence to their individualized treatment plans.

Conclusion

Overall, FMX103 1.5% appeared to be safe, well tolerated, and effective for the long-term treatment of papulopustular rosacea. The long-term safety profile after 52 weeks of daily application was similar to that seen after the 12 weeks of use in the double-blind Phase 3 studies. During the additional 40 weeks of treatment, continuous improvement in lesion reduction and IGA treatment success was demonstrated by the subjects treated with FMX103 1.5%. Taken together with data from the double-blind studies, which demonstrated significant improvements as compared with vehicle foam, the current results provide further evidence supporting the potential of FMX103 1.5% to be a suitable option for the treatment for moderate-to-severe papulopustular rosacea.^12,13

Acknowledgments

Writing assistance for this manuscript was provided by Scient Healthcare Communications.

References

1. Oge LK, Muncie HL, Phillips-Savoy AR. Rosacea: diagnosis and treatment. Am Fam Physician. 2015;92:187–196.
2. Rainer BM, Kang S, Chien AL. Rosacea: epidemiology, pathogenesis, and treatment. Dermatoendocrinol. 2017;9:e1361574.
3. Li WQ, Cho E, Khalili H, et al. Rosacea, use of tetracycline, and risk of incident inflammatory bowel disease in women. Clin Gastroenterol Hepatol. 2016;14:220-5 e1–3.
4. Schaller M, Schofer H, Homey B, et al. Rosacea management: update on general measures and topical treatment options. Journal der Deutschen Dermatologischen Gesellschaft (Journal of the German Society of Dermatology: JDDG). 2016;14(suppl 6):17–27.
5. Taieb A, Stein Gold L, Feldman SR, et al. Cost-effectiveness of ivermectin 1% cream in adults with papulopustular rosacea in the United States. J Manag Care Spec Pharm. 2016;22:654–665.
6. Ahn CS , Huang WW. Rosacea pathogenesis. Dermatol Clin. 2018;36:81–86.
7. Yamasaki K, Kanada K, Macleod DT, et al. TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes. J Invest Dermatol. 2011;131: 688–697.
8. Goldgar C, Keahey DJ, Houchins J. Treatment options for acne rosacea. Am Fam Physician. 2009;80:461–468.
9. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 3: a status report on systemic therapies. Cutis. 2014;93:18–28.
10. Garrido-Mesa N, Zarzuelo A, Galvez J. Minocycline: far beyond an antibiotic. Br J Pharmacol. 2013;169:337–352.
11. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006;54: 258–265.
12. Mrowietz U, Kedem TH, Keynan R, et al. A Phase II, randomized, double-blind clinical study evaluating the safety, tolerability, and efficacy of a topical minocycline foam, FMX103, for the treatment of facial papulopustular rosacea. Am J Clin Dermatol. 2018;19:427–436.
13. Stein Gold L, del Rosso J, Kircik L, et al. Minocycline 1.5% foam for the topical treatment of moderate-to-severe papulopustular rosacea: Results of two phase 3, randomized, clinical trials. J Am Acad Dermatol. 2020;82:1166–1173.
14. Solodyn [package insert]. Scottsdale, AZ: Medicis; March 2011.
15. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74:945-973 e33.
16. Wolf JE, Jr. Medication adherence: a key factor in effective management of rosacea. Adv Ther. 2001;18:272–281.
17. Dreno B, Thiboutot D, Gollnick H, et al. Large-scale worldwide observational study of adherence with acne therapy. Int J Dermatol. 2010;49:448–456.
18. Snyder S, Crandell I, Davis SA, et al. Medical adherence to acne therapy: a systematic review. Am J Clin Dermatol. 2014;15:87–94.