Clinical studies with finasteride in men with androgenetic alopecia

As in the development program in men with BPH, initial clinical studies with finasteride in men with male pattern hair loss (androgenetic alopecia, AGA) were directed toward demonstration ofbiochemical efficacy (Kaufman 1996). Androgen receptor number, DHT content and 5aR activity were all reported to be higher in balding than non-balding scalp from subjects with AGA, lending further support to the hypothesis that lowering DHT content in the scalp would be useful in the treatment of patients with AGA (Dallob et al. 1994; Price 1975; Randall et al. 1991; Sawaya 1991). Subsequent immunolocalization and enzyme inhibitor studies demonstrated that type 2 5aR protein was expressed in structures within the hair follicle (Bayne et al. 1999; Hoffmann and Happle 1999). The early studies with finasteride in men with AGA demonstrated that daily oral administration reduced the DHT content ofthe affected scalp in a dose-dependent manner, based on analysis of scalp biopsies, and suggested that the dose range from 0.2 to 5 mg be evaluated for assessment of clinical benefit (Dallob etal. 1994; Drake etal. 1999).

18.5.1 Efficacy based on hair count, hair weight, clinical photography, patient assessment

Several controlled clinical studies established the efficacy of finasteride 1 mg in the treatment of men with AGA (Kaufman and Dawber 1999; Shapiro and Kaufman 2003). A placebo-controlled, proof-of-concept pilot study with finasteride 5 mg confirmed the utility of the mechanism of 5aR inhibition and suppression of DHT formation in the treatment of men with AGA (Roberts etal. 1999). Subsequent clinical dose-ranging studies established 1 mg as the optimal daily dose for treatment of this disorder, consistent with the results of earlier studies evaluating the biochemical efficacy of finasteride in this patient population (Roberts et al. 1999). Definitive multicenter placebo-controlled studies established the beneficial effect of finasteride 1 mg on scalp hair growth in both the vertex and frontal (anterior mid-scalp) areas of the scalp, using a comprehensive set of endpoints in men with AGA (Kaufman et al. 1998; Leyden et al. 1999). Summarizing a body of evidence, the benefit of finasteride treatment was consistently demonstrated using a variety of evaluation techniques across multiple studies. These included: (1) macropho-tographic hair count, obtained from a defined area of the vertex or frontal scalp (Canfield 1996; Kaufman et al. 1998; Leyden et al. 1999); (2) phototrichogram analysis, obtained from a defined area of the vertex scalp (Van Neste et al. 2000);

(3) hair weight, obtained from a defined area of the frontal scalp (Price etal. 2002);

(4) scalp biopsy, obtained from a defined area of the vertex scalp adjacent to the area used for macrophotographic hair count (Whiting 1990; 1993; Whiting et al. 1999); (5) standardized 'global' clinical photography of the vertex or frontal scalp, which also provides a measure of change in the degree of scalp coverage (Canfield 1996) (6) investigator clinical assessment of scalp hair growth; and (7) patient self-assessment of scalp hair growth and satisfaction with scalp hair appearance (Barber et al. 1998). Each of these evaluation techniques supports, and the consistency of the results confirms, that, by reducing perifollicular DHT through suppression of DHT formation, finasteride treatment leads to improvement in scalp hair growth in men with AGA. Finasteride 1 mg (PropeciaTM) was first approved for marketing in 1997 and is currently approved for the treatment of men with AGA in over 60 countries.

18.5.2 Study in monozygotic twins

Stough etal. (2002) reported results from a randomized, placebo-controlled study evaluating the effects of finasteride 1 mg vs. placebo in nine male monozygotic (identical) twin pairs with AGA over one year of observation, with each twin pair randomized to either finasteride 1 mg or matching placebo. While the sample of subjects available for such a study is necessarily limited in size, the results observed in these identical twin pairs were consistent with results from other clinical trials enrolling larger numbers of subjects, supporting the conclusions regarding the benefits of finasteride treatment in this unique and rare patient population studied.

18.5.3 Long-term follow-up

The two definitive, placebo-controlled studies in men with predominantly vertex hair loss were initially conducted over two years, with cohorts of patients randomized to active (finasteride 1 mg) or placebo treatment continuously or switched to

Month

Fig. 18.5 Effects of finasteride 1 mg and placebo on men with AGA: hair count in a defined area of the vertex scalp over two years (Kaufman etal. 1998).

Month

Fig. 18.5 Effects of finasteride 1 mg and placebo on men with AGA: hair count in a defined area of the vertex scalp over two years (Kaufman etal. 1998).

the alternate treatment after the first year (Kaufman et al. 1998). Fig. 18.5 shows the effect of treatment allocation on the primary efficacy endpoint of these studies, macrophotographic hair count obtained in a defined, 1-inch diameter circular area (5.1 cm2) of scalp hair at the anterior leading edge of the vertex bald spot (baseline hair count = 876 hairs). These studies were continued as controlled clinical trials over five years for determination of the long-term efficacy and safety profile of finasteride 1 mg in the treatment of men with AGA (Finasteride Male Pattern Hair Loss Study Group 2002; Shapiro and Kaufman 2003). The results of the five-year controlled extensions to the two definitive studies in men with predominantly vertex hair loss demonstrated that treatment with finasteride produced durable improvements in scalp hair growth, with the separation between the treatment groups (finasteride vs. placebo) increasing over time. These long-term studies also demonstrated that the incidences of newly-reported side-effects declined with long-term use.

Most of the reviewed studies enrolled men with mild to moderately severe AGA (Norwood-Hamilton scale Il-Vhairlosspatterns) (Hamilton 1951;Norwood 1975) who were between the ages of 18 and 41 years at the time of initial randomization. A separate study evaluating men with more severe AGA was recently concluded but results have not yet been released. In older men (ages 41 to 60 years) with AGA, Whiting and co-workers reported on the results of a two-year placebo-controlled study with finasteride 1 mg in this patient population (Whiting et al. 2003). As in the younger population, results in this population of men with AGA demonstrated improvement in scalp hair growth over the two years of observation, although men ages 41-50 had numerically greater scores of improvement compared to those aged 51-60 based on the primary efficacy endpoint (standardized clinical photography).

18.5.4 Safety

In studies of finasteride 1 mg in young men with AGA, side-effects related to finasteride treatment were confined to transient impairment of sexual function (decreased libido, erectile dysfunction, and decreased ejaculate volume) in a small number of men. In aggregate, in studies in younger men, 3.8% of patients receiving finasteride compared to 2.1% receiving placebo reported these side-effects, yielding a treatment group difference of < 2% (US Product Circular for Propecia® 2002). In the two-year placebo-controlled study of finasteride 1 mg in older men with AGA, more patients reported side-effects related to sexual function in each treatment group, as expected: 8.7% for finasteride and 5.1% for placebo, yielding a treatment group difference of 3.6% (Whiting etal. 2003). Few patients discontinued the studies because of these side-effects, and the incidence of reported side-effects declined with continued treatment.

Hair Loss Prevention

Hair Loss Prevention

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