madman
Super Moderator
Abstract
Background Oral finasteride is a well-established treatment for men with androgenetic alopecia (AGA), but long-term therapy is not always acceptable to patients. A topical finasteride formulation has been developed to minimize systemic exposure by acting specifically on hair follicles
Objectives To evaluate the efficacy and safety of topical finasteride compared with placebo , and to analyze systemic exposure and overall benefit compared with oral finasteride .
Methods This randomized, double-blind, double-dummy, parallel-group, 24 -week study was conducted in adult male outpatients with AGA at 45 sites in Europe. Efficacy and safety were evaluated. Finasteride, testosterone, and dihydrotestosterone (DHT) concentrations were measured .
Results Of 458 randomized patients, 323 completed the study, and 446 were evaluated for safety. Change from baseline in target area hair count (TAHC ) at Week 24 (primary efficacy endpoint) was significantly greater with topical finasteride than placebo (adjusted mean change 20.2 vs 6.7 hairs; p < 0.001), and numerically similar between topical and oral finasteride. Statistically, significant differences favoring topical finasteride over placebo were observed for change from baseline in TAHC at Week 12, and investigator-assessed change from baseline in patient hair growth/loss at Week 24. Incidence and type of adverse events, and cause of discontinuation, did not differ meaningfully between topical finasteride and placebo. No serious adverse events were considered treatment-related. As maximum plasma finasteride concentrations were >100 times lower, and reduction from baseline in mean serum DHT concentration was lower (34.5 vs 55. 6 % ), with topical versus oral finasteride, there is less likelihood of systemic adverse reactions of a sexual nature related to a decrease in DHT with topical finasteride.
Conclusion Topical finasteride significantly improves hair count compared to placebo and is well tolerated. Its effect is similar to that of oral finasteride, but with markedly lower systemic exposure and less impact on serum DHT concentrations
Introduction
Androgenetic alopecia (AGA), or male pattern baldness, is a genetically determined disorder caused by susceptibility of hair follicles to androgenic miniaturization, occurring most commonly at the scalp vertex. 1 The condition affects more than half of men under 50 years of age . 2 Even clinically imperceptible hair loss has been correlated with decreased quality of life. 3 Men predisposed to AGA have an increased rate of conversion of testosterone to dihydrotestosterone (DHT ) within the hair follicle, a process involving type II 5α -reductase . 4 Finasteride, a synthetic anti-androgen that inhibits type II 5α -reductase, was approved initially in tablet form for the treatment of male AGA . 5
The clinical efficacy of oral finasteride for treating AGA is well established. Long-term studies of oral finasteride 1 mg in men with AGA demonstrated slower progression of hair loss or enhanced hair growth, compared with baseline and/or placebo, as early as 3 months after treatment start and extending for 5 -10 years. 6 -10 Although oral finasteride is generally well tolerated, 5 in some patients 5α -reductase inhibition is associated with sexual adverse effects (erectile dysfunction, ejaculation problems, decreased libido),11 and increased risk of depression,12 prompting health authorities in some countries to include warnings in the product labeling. 13. Topical administration of finasteride offers the potential to reduce systemic effects related to its mechanism of action by preferentially inhibiting 5 -α reductase in the scalp, as has been suggested in recent years. 14
Preliminary results regarding topical application of finasteride for the treatment of AGA were promising. In testosterone -induced alopecia albino mouse model, higher follicular density and anagen: telogen ratios were observed in the group treated with topical finasteride 2% solution. 15 In humans, topical finasteride application for the treatment of AGA was first explored by Mazarella and colleagues in a study involving 52 patients (28 males) with AGA. Beginning from six months, a progressive and significant decrease in the rate of hair loss was observed in the topical finasteride versus the placebo group, with no significant changes in plasma levels of total testosterone, free testosterone, and DHT between treatment groups.16
*The current phase III study aimed to evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of topical finasteride (0.25% solution applied once daily in a volume between 50 µ L and 200 µ L) compared with placebo and to assess the overall patient benefit of topical finasteride relative to oral finasteride at 24 weeks.
Efficacy analyses
At Week 24, the adjusted mean change from baseline in TAHC was significantly greater with topical finasteride than with placebo (20.2 vs 6.7 hairs; p < 0.001), and was numerically similar to that with oral finasteride ( 21.1 hairs) (Figure 3 ). The post hoc sensitivity analysis produced robust results with the same conclusion: the adjusted mean change from baseline in TAHC at Week 24 was significantly greater with topical finasteride than placebo (16.3 vs 6.3 hairs; p = 0.012) and numerically similar to that with oral finasteride (18.7 hairs) (Figure 4).
At Week 12, a statistically significant increase from baseline in TAHC relative to placebo was observed with topical finasteride (Figure 3). Changes from baseline in other secondary efficacy outcomes in the ITT population are summarised in Table 2. The adjusted mean change from baseline to Week 24 in TAHW indicated negligible changes with any study treatment. At Week 24, the patient-assessed MHGQ score for the item ‘overall assessment’ was similar across treatment groups. The investigator-assessed adjusted mean change from baseline to Week 24 in patient hair growth/loss at the vertex was statistically significantly greater with topical finasteride than placebo (0.8 vs 0. 3, p < 0.0 0 1) and was numerically similar to that with oral finasteride (0. 7 ). Blinded -assessor evaluation of patient hair growth/loss at the vertex indicated no to minimal change from baseline in any group at Week 24
To assist in interpreting the clinical relevance of the findings, a post hoc sensitivity analysis was performed on the mITT/safety population. For MHGQ and investigator and blinded-assessor evaluations of the change in patient hair growth/loss, results were dichotomized into ‘responder’ and ‘non -responder’ categories, where the response for each item was defined as showing any degree of improvement. The percentage of responders with respect to investigator assessment, blinded-assessor assessment, and three items of the MHGQ were significantly greater with topical finasteride than placebo (Table 3).
PK and PD analyses Mean
Mean ± SD maximum plasma finasteride concentrations were 36.5 ± 45.9 pg/mL with topical finasteride and 7166 ± 12,744 pg/mL with oral finasteride at Week 12; and were 48.0 ± 87.2 pg/mL and 5029 ± 4182 pg/mL, respectively, at Week 24.
Mean serum DHT concentrations in the placebo group remained unaffected during the study (range: 38.5 to 39.8 ng/dL). Mean serum DHT concentrations at Week 24 were 34.6% lower than at baseline in the topical finasteride group (25.75 vs. 39.32 ng/dL, respectively), and were 55.6% lower than at baseline in the oral finasteride group (15.75 vs. 35.50 ng/d L, respectively). The adjusted mean difference in the change from baseline in serum DHT concentrations was statistically significant between topical finasteride and placebo (p < 0.05), and between topical finasteride and oral finasteride (p < 0.05), at each of Weeks 4, 8, 12, and 24 (Figure 5 ).
The lower impact of topical finasteride on DHT levels was not accompanied by any shift from normal to high plasma testosterone concentrations for patients in this group; this was also the case for the placebo group. In the oral finasteride group, this shift occurred in four (6.7%) patients
*Some patients treated with oral finasteride may experience adverse effects potentially related to the circulating plasma concentration of drug required to achieve effective concentrations at the scalp. There is an ongoing debate whether, in some cases, the use of oral finasteride 1 mg/day to treat male pattern hair loss may be associated with irreversible sexual dysfunction and severe depression. 26-29 As demonstrated in the current study, maximum mean plasma finasteride concentrations were more than 100 -fold lower with the topical versus oral formulation, and the impact on serum DHT concentrations after 24 weeks’ treatment was statistically significantly lower with topical versus oral finasteride (reductions of 34.6% and 55.6%, respectively). While this does not exclude the possibility of systemic adverse events related to decreased DHT in both groups, the probability is lower with topical than oral finasteride. A trend was evident for fewer treatment-related sexual adverse events, and associated treatment discontinuations, in the topical versus oral finasteride group
The main finding of the study was that the change from baseline in hair count was significantly greater with topical finasteride than placebo and similar to that observed with oral finasteride. This result was achieved with markedly lower systemic exposure to finasteride and less impact on serum DHT concentrations compared with oral finasteride. Topical finasteride was well tolerated and had a safety profile not meaningfully different from that of placebo. As such, topical finasteride appears to be a useful option for the treatment of AGA in men. Further studies would be useful to demonstrate the long-term efficacy of topical finasteride. Understanding the reasons for the relatively high number of treatment discontinuations and negligible changes from baseline to end of treatment in certain subjective measures such as patient-assessed MHGQ score for ‘overall assessment’ and blinded -assessor evaluation of patient hair growth/loss may assist in designing future studies.
Background Oral finasteride is a well-established treatment for men with androgenetic alopecia (AGA), but long-term therapy is not always acceptable to patients. A topical finasteride formulation has been developed to minimize systemic exposure by acting specifically on hair follicles
Objectives To evaluate the efficacy and safety of topical finasteride compared with placebo , and to analyze systemic exposure and overall benefit compared with oral finasteride .
Methods This randomized, double-blind, double-dummy, parallel-group, 24 -week study was conducted in adult male outpatients with AGA at 45 sites in Europe. Efficacy and safety were evaluated. Finasteride, testosterone, and dihydrotestosterone (DHT) concentrations were measured .
Results Of 458 randomized patients, 323 completed the study, and 446 were evaluated for safety. Change from baseline in target area hair count (TAHC ) at Week 24 (primary efficacy endpoint) was significantly greater with topical finasteride than placebo (adjusted mean change 20.2 vs 6.7 hairs; p < 0.001), and numerically similar between topical and oral finasteride. Statistically, significant differences favoring topical finasteride over placebo were observed for change from baseline in TAHC at Week 12, and investigator-assessed change from baseline in patient hair growth/loss at Week 24. Incidence and type of adverse events, and cause of discontinuation, did not differ meaningfully between topical finasteride and placebo. No serious adverse events were considered treatment-related. As maximum plasma finasteride concentrations were >100 times lower, and reduction from baseline in mean serum DHT concentration was lower (34.5 vs 55. 6 % ), with topical versus oral finasteride, there is less likelihood of systemic adverse reactions of a sexual nature related to a decrease in DHT with topical finasteride.
Conclusion Topical finasteride significantly improves hair count compared to placebo and is well tolerated. Its effect is similar to that of oral finasteride, but with markedly lower systemic exposure and less impact on serum DHT concentrations
Introduction
Androgenetic alopecia (AGA), or male pattern baldness, is a genetically determined disorder caused by susceptibility of hair follicles to androgenic miniaturization, occurring most commonly at the scalp vertex. 1 The condition affects more than half of men under 50 years of age . 2 Even clinically imperceptible hair loss has been correlated with decreased quality of life. 3 Men predisposed to AGA have an increased rate of conversion of testosterone to dihydrotestosterone (DHT ) within the hair follicle, a process involving type II 5α -reductase . 4 Finasteride, a synthetic anti-androgen that inhibits type II 5α -reductase, was approved initially in tablet form for the treatment of male AGA . 5
The clinical efficacy of oral finasteride for treating AGA is well established. Long-term studies of oral finasteride 1 mg in men with AGA demonstrated slower progression of hair loss or enhanced hair growth, compared with baseline and/or placebo, as early as 3 months after treatment start and extending for 5 -10 years. 6 -10 Although oral finasteride is generally well tolerated, 5 in some patients 5α -reductase inhibition is associated with sexual adverse effects (erectile dysfunction, ejaculation problems, decreased libido),11 and increased risk of depression,12 prompting health authorities in some countries to include warnings in the product labeling. 13. Topical administration of finasteride offers the potential to reduce systemic effects related to its mechanism of action by preferentially inhibiting 5 -α reductase in the scalp, as has been suggested in recent years. 14
Preliminary results regarding topical application of finasteride for the treatment of AGA were promising. In testosterone -induced alopecia albino mouse model, higher follicular density and anagen: telogen ratios were observed in the group treated with topical finasteride 2% solution. 15 In humans, topical finasteride application for the treatment of AGA was first explored by Mazarella and colleagues in a study involving 52 patients (28 males) with AGA. Beginning from six months, a progressive and significant decrease in the rate of hair loss was observed in the topical finasteride versus the placebo group, with no significant changes in plasma levels of total testosterone, free testosterone, and DHT between treatment groups.16
*The current phase III study aimed to evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of topical finasteride (0.25% solution applied once daily in a volume between 50 µ L and 200 µ L) compared with placebo and to assess the overall patient benefit of topical finasteride relative to oral finasteride at 24 weeks.
Efficacy analyses
At Week 24, the adjusted mean change from baseline in TAHC was significantly greater with topical finasteride than with placebo (20.2 vs 6.7 hairs; p < 0.001), and was numerically similar to that with oral finasteride ( 21.1 hairs) (Figure 3 ). The post hoc sensitivity analysis produced robust results with the same conclusion: the adjusted mean change from baseline in TAHC at Week 24 was significantly greater with topical finasteride than placebo (16.3 vs 6.3 hairs; p = 0.012) and numerically similar to that with oral finasteride (18.7 hairs) (Figure 4).
At Week 12, a statistically significant increase from baseline in TAHC relative to placebo was observed with topical finasteride (Figure 3). Changes from baseline in other secondary efficacy outcomes in the ITT population are summarised in Table 2. The adjusted mean change from baseline to Week 24 in TAHW indicated negligible changes with any study treatment. At Week 24, the patient-assessed MHGQ score for the item ‘overall assessment’ was similar across treatment groups. The investigator-assessed adjusted mean change from baseline to Week 24 in patient hair growth/loss at the vertex was statistically significantly greater with topical finasteride than placebo (0.8 vs 0. 3, p < 0.0 0 1) and was numerically similar to that with oral finasteride (0. 7 ). Blinded -assessor evaluation of patient hair growth/loss at the vertex indicated no to minimal change from baseline in any group at Week 24
To assist in interpreting the clinical relevance of the findings, a post hoc sensitivity analysis was performed on the mITT/safety population. For MHGQ and investigator and blinded-assessor evaluations of the change in patient hair growth/loss, results were dichotomized into ‘responder’ and ‘non -responder’ categories, where the response for each item was defined as showing any degree of improvement. The percentage of responders with respect to investigator assessment, blinded-assessor assessment, and three items of the MHGQ were significantly greater with topical finasteride than placebo (Table 3).
PK and PD analyses Mean
Mean ± SD maximum plasma finasteride concentrations were 36.5 ± 45.9 pg/mL with topical finasteride and 7166 ± 12,744 pg/mL with oral finasteride at Week 12; and were 48.0 ± 87.2 pg/mL and 5029 ± 4182 pg/mL, respectively, at Week 24.
Mean serum DHT concentrations in the placebo group remained unaffected during the study (range: 38.5 to 39.8 ng/dL). Mean serum DHT concentrations at Week 24 were 34.6% lower than at baseline in the topical finasteride group (25.75 vs. 39.32 ng/dL, respectively), and were 55.6% lower than at baseline in the oral finasteride group (15.75 vs. 35.50 ng/d L, respectively). The adjusted mean difference in the change from baseline in serum DHT concentrations was statistically significant between topical finasteride and placebo (p < 0.05), and between topical finasteride and oral finasteride (p < 0.05), at each of Weeks 4, 8, 12, and 24 (Figure 5 ).
The lower impact of topical finasteride on DHT levels was not accompanied by any shift from normal to high plasma testosterone concentrations for patients in this group; this was also the case for the placebo group. In the oral finasteride group, this shift occurred in four (6.7%) patients
*Some patients treated with oral finasteride may experience adverse effects potentially related to the circulating plasma concentration of drug required to achieve effective concentrations at the scalp. There is an ongoing debate whether, in some cases, the use of oral finasteride 1 mg/day to treat male pattern hair loss may be associated with irreversible sexual dysfunction and severe depression. 26-29 As demonstrated in the current study, maximum mean plasma finasteride concentrations were more than 100 -fold lower with the topical versus oral formulation, and the impact on serum DHT concentrations after 24 weeks’ treatment was statistically significantly lower with topical versus oral finasteride (reductions of 34.6% and 55.6%, respectively). While this does not exclude the possibility of systemic adverse events related to decreased DHT in both groups, the probability is lower with topical than oral finasteride. A trend was evident for fewer treatment-related sexual adverse events, and associated treatment discontinuations, in the topical versus oral finasteride group
The main finding of the study was that the change from baseline in hair count was significantly greater with topical finasteride than placebo and similar to that observed with oral finasteride. This result was achieved with markedly lower systemic exposure to finasteride and less impact on serum DHT concentrations compared with oral finasteride. Topical finasteride was well tolerated and had a safety profile not meaningfully different from that of placebo. As such, topical finasteride appears to be a useful option for the treatment of AGA in men. Further studies would be useful to demonstrate the long-term efficacy of topical finasteride. Understanding the reasons for the relatively high number of treatment discontinuations and negligible changes from baseline to end of treatment in certain subjective measures such as patient-assessed MHGQ score for ‘overall assessment’ and blinded -assessor evaluation of patient hair growth/loss may assist in designing future studies.
