Evaluation of oral Ro70-0004=003, an a1A-adrenoceptor antagonist, in the treatment of male erectile dysfunction
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International Journal of Impotence Research (2001) 13, 157±161
ß 2001 Nature Publishing Group All rights reserved 0955-9930/01 $15.00
www.nature.com/ijir
Evaluation of oral Ro70-0004=003, an a1A-adrenoceptor antagonist,
in the treatment of male erectile dysfunction
A Choppin1*, DR Blue1, SS Hegde2, D Gennevois1, SA McKinnon3, A Mokatrin1, TJ Bivalacqua4 and
WJG Hellstrom4
1
Genitourinary-Systems, Neurobiology Unit, Roche Bioscience, Palo Alto, California, USA; 2Advanced Medicine, Inc., 901
Gateway Blvd, South San Francisco, California, USA; 3IntraBiotics Pharmaceuticals, Inc., 2021 Stierlin Court, Mountain
View, California, USA; and 4Tulane University, School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana, USA
a-Adrenoceptor antagonists have been used for the treatment of male erectile dysfunction (MED).
Ro70-0004=003 (Ro70-0004) is a selective and orally active a1A-adrenoceptor antagonist. The
objective of this study was to: (1) pharmacologically elucidate the a1-adrenoceptor subtype
mediating norepinephrine-induced contraction of human isolated corpus cavernosal tissue and (2)
conduct a clinical proof-of-concept study with Ro70-0004 to test the hypothesis that selective a1A-
adrenoceptor blockade would improve erectile function in patients with MED. In vitro organ bath
studies were conducted with strips of human isolated corpus cavernosal tissue obtained from
patients undergoing penile prosthesis implantation. Prazosin, cyclazosin, RS-100329 and Ro70-
0004=003 antagonized norepinephrine-induced contractile responses with af®nity estimates (pKB
or pA2) of 8.4, 7.3, 9.2 and 8.8, respectively, consistent with the singular involvement of a1A-
adrenoceptor subtype. A clinical study (single center, observer-blind, randomized, placebo-
controlled, extended period Latin-Square crossover design) was conducted in 24 male patients
(mean age 44 y) with MED of no established organic cause to evaluate the ef®cacy of a 5-mg oral
dose of Ro70-0004. The primary ef®cacy endpoint was the duration of rigidity >60% at the base
of the penis measured between 0.5 and 2.5 h post-dose. Rigidity was assessed by penile
plethysmography using the RigiScan Plus1 device during visual sexual stimulation. The safety
and ef®cacy of Ro70-0004 was also assessed. A 50-mg dose of sildena®l was included as a positive
control. For the primary ef®cacy endpoint, the mean duration of erection was 9.69 min following
administration of placebo, 8.28 min following Ro70-0004, and 22.64 min following sildena®l. Only
the difference between sildena®l and placebo reached statistical signi®cance (P < 0.05). A similar
pattern was observed when measuring a duration of rigidity > 80% at the base of the penis
(secondary endpoint). Ro70-0004 was safe and generally well tolerated (only two out of 20 patients
reported at least one adverse event). The highly selective a1A-adrenoceptor antagonist, Ro70-0004,
given at a single dose of 5 mg, did not improve erectile function when compared to
placebo. International Journal of Impotence Research (2001) 13, 157±161.
Keywords: a1A-adrenoceptor; male erectile dysfunction (MED); sildena®l; plethysmography
Introduction either organic or psychogenic.3 Organic erectile
dysfunction is the result of an acute or chronic
physiological condition (80% of cases are secondary
Male erectile dysfunction (MED) is de®ned as the to organic disease, 70% of those to arterial or venous
inability to attain and maintain a penile erection for abnormalities). Psychogenic erectile dysfunction
satisfactory sexual intercourse.1 This condition may involve two mechanisms: direct inhibition
affects approximately 50% of all men 40 ± 70 y of from the brain to the spinal centers; excessive
age and occurs more often in men older than 65.2 sympathetic out¯ow and=or elevated blood catecho-
Depending on the etiology, MED can be classi®ed as lamine levels. Indicators of psychogenic erectile
dysfunction include acute onset, often related to
a speci®c event, with the most common causes
being performance anxiety, relationship con¯ict
and sexual inhibition. Male erectile dysfunction
*Correspondence: A Choppin, GU-Systems, Neurobiology
Unit, Roche Bioscience, R2-101, 3401 Hillview Avenue, represents a major clinical problem which, until
Palo Alto, CA 94304, USA. recently, was poorly treated due to the ineffective
E-mail: Agnes.Choppin@Roche.com and=or invasive treatments available. Sildena®l
Received 4 January 2001; accepted 2 February 2001 (Viagra1, P®zer), an orally active and ef®caciousEvaluation of oral Ro70-0004=003
A Choppin et al
158
type-5 phosphodiesterase (PDE-5) inhibitor
approved by the FDA in 1998, has become the
current standard therapy for MED.4 The ef®cacy of
25, 50 and 100 mg doses of sildena®l in improving
erectile function has been demonstrated in more
than 3000 patients in 21 American and European
randomized, double-blind, placebo-controlled,
phase III trials lasting up to 6 months. In these
Figure 1 Chemical structure of Ro70-0004.
studies, 59% of treated patients reported that they
were able to both achieve and maintain erections on Preliminary accounts of the ®ndings have been
most to all occasions compared to 15% of those who presented previously at the AUA 95th annual
received placebo.5 meeting.11
Penile erection is dependent, to a large extent, on
relaxation of corpus cavernosum smooth muscle of
the penis, which in turn leads to diminished venous
out¯ow and penile engorgement.6 Adequate relaxa- Methods
tion of the corpus cavernosum is mainly dependent
on release of nitric oxide (NO), a relaxant factor, and In vitro studies
also removal of contractile factors such as norepi-
nephrine (NE).6 It is known that adrenergic stimula-
tion results in contraction of the cavernosal arteries In order to characterize the a1-adrenoceptor sub-
with reduced cavernosal arterial in¯ow as well as type(s) mediating contraction of corpus cavernosum
contraction of the trabecular smooth muscle leading tissue, organ bath experiments (as described by
to collapse of the lacunar spaces. The resultant loss Choppin et al.12) were performed on biopsy speci-
of corporal veno-occlusive function leads to detu- mens of human corporal tissue obtained with
mescence. It has been suggested that the etiology of informed consent from patients undergoing penile
MED may be related to impaired corpus cavernosal prosthesis implantation for impotence. Cumulative
relaxation and=or heightened corpus cavernosal concentration ± response curves to norepinephrine,
contractile tone.7 a non-selective adrenoceptor agonist, were con-
Sildena®l potentiates NO-mediated cyclic guano- structed, in presence of an a2-adrenoceptor anta-
sine monophosphate (cGMP)-induced relaxation gonist (idazoxan), uptake blockers (cocaine and
of corpus cavernosum.4,7 The erectile process can corticosterone), an inhibitor of prostanoid synthesis
also be facilitated by antagonizing NE-induced, a1- (indomethacin), a b-adrenoceptor antagonist (pro-
adrenoceptor mediated contraction of corpus caver- pranolol) and an anti-oxidant (ascorbic acid). Strips
nosum.8 Clinically, non-selective a-adrenoceptor of tissue were incubated for 90 min in the absence or
antagonists such as phentolamine have been used presence of antagonist before a second agonist curve
for the treatment of MED.9 These drugs are mini- was constructed. The antagonists which were
mally ef®cacious because side effects such as examined were prazosin (non selective), cyclazosin
hypotension, tachycardia and nausea limit the doses (a1B-adrenoceptor selective), RS-100329 and Ro70-
which can be used clinically. It has been established 0004 (a1A-adrenoceptor selective).
that a1, but not a2, adrenoceptors mediate contrac- Contractions were recorded as changes in tension
tion of human erectile tissue.6,7 Molecular and from baseline and were expressed as a percentage
pharmacological studies have indicated the exis- of the maximum response of the ®rst agonist
tence of at least three a1-adrenoceptor subtypes (a1A, concentration ± effect curve. Agonist concentration
a1B and a1D). Although human corpus cavernosal ± response curves were ®tted using a nonlinear
tissue is endowed with a1A-adrenoceptors,10 func- iterative ®tting program (Origin, Microcal Software,
tional evidence for their involvement in contractile Inc., Northampton, MA) to estimate agonist potency
responses is lacking. It is conceivable that this (pEC50). Antagonist af®nities (pKB or pA2 values)
avenue of research could lead to the development of were determined using one or several concentra-
more ef®cacious and safer drugs for the treatment tion(s) of each antagonist, as described by Arunlak-
of MED. shana and Schild.13
The aim of this study was two-fold: (1) to pharma-
cologically characterize the a1-adrenoceptor subtype
mediating contraction of human corpus cavernosum Clinical study
in vitro; and (2) to evaluate the clinical hypothesis that
Ro70-0004 (3-(3-{4-[¯uoro-2-(2,2,2-tri¯uoroethoxy)-
phenyl]-piperazin-1-yl}-propyl)-5-methyl-1H-pypi- This clinical study design was an observer-blind,
midine-2,4-dione mono hydrochloride monohydrate, randomized, placebo-controlled, extended period
Figure 1), a selective a1A-adrenoceptor antagonist, will Latin-Square study design that was performed at
improve erectile function in patients with MED. one research center. Twenty-four male MED patients
International Journal of Impotence ResearchEvaluation of oral Ro70-0004=003
A Choppin et al
159
(41.7% black, 58.3% Caucasian), 18 ± 65 y of age cavernosal tissue (pEC50 5.80 0.13, n 4). Prazo-
(mean age 44 y), with MED of a continual duration of sin, cyclazosin, RS-100329 and Ro70-0004 produced
at least 6 months which had no established organic parallel dextral shifts of the concentration-effect
cause based on clinical evaluation and blood tests curve to NE with no change in the maximum
were enrolled to evaluate the effect of a single dose response (ie Ð consistent with competitive antagon-
of Ro70-0004 on erectile function. The safety and ism). The antagonist af®nity estimates obtained in
tolerability of the study drug was also assessed. The human corpus cavernosum are shown in Table 1.
study consisted of four dosing periods at 7-day Binding af®nities at human cloned a1-adrenoceptor
intervals. On each dosing day, patients were subtypes are shown for comparison. These results
admitted to the research center where they received suggest that the a1A-adrenoceptor subtype mediates
a single oral dose of either 5 mg of Ro70-0004, 50 mg contraction of human corpus cavernosum.
of sildena®l, or placebo, and the last treatment was
repeated on the last dosing day. Patients remained
in the research center until all of the 4 h post-
dose=discharge study activities had been completed. Clinical study
Penile rigidity was assessed at the base and the Safety results. Single 5 mg doses of Ro70-0004 were
tip of the penis using the RigiScan Plus1 device safe and generally well tolerated without clinically
from 30 min pre-dose to 2.5 h post-dose. Visual signi®cant changes in vital signs or laboratory test
sexual stimulation (eg sexually explicit videotapes) results. Two out of 20 patients reported at least one
occurred from 30 min post-dose to 2.5 h post-dose. adverse effect after receiving a single 5 mg oral dose
Safety data, including adverse effects, study with- of Ro70-0004 (Table 2). Ro70-0004 was as well
drawal reasons, laboratory data, electrocardiograms, tolerated as sildena®l in this study. There were
and concomitant medications were recorded for minimal differences of adverse effects for patients
each patient. The study termination visit occurred dosed with either Ro70-0004 or sildena®l.
1 week following the last dose of study drug.
RigiScan Plus1 measurements exhibit large inter-
patient variability, therefore a crossover study Ef®cacy results. Rigidity at the base of the penis:
design was chosen to allow for a within-patient Following visual sexual stimulation, the mean
comparison between Ro70-0004 and placebo. duration of rigidity >60% at the base of the penis
Sildena®l was included in each treatment se- was 9.69 min following administration of placebo,
quence as an active control to validate the study 8.28 min following 5 mg of Ro70-0004, and
results.
The primary variable was the cumulative dura- Table 1 Af®nity estimates for adrenocepor antagonists in human
tion of rigidity greater than or equal to 60% at the corpus cavernosum and at cloned a1-adrenoceptors (CHO-K1 cells)
base of the penis as measured by RigiScan Plus1 Human corpus Human cloned
from 30 min post-dose to 2.5 h post-dose. The Antagonist cavernosum a1-AR subtypes
secondary variables were the cumulative duration (concentration) pKB or pA2a pK1b
of rigidity greater than 60% at the tip and greater
a1a a1b a1d
than 80% at the base and tip of the penis. Only Prazosin (0.1 mM) 8.4 9.0 0.1 9.9 0.1 9.5 0.1
penile erections during the 2 h of visual sexual Cyclazosin (0.1 mM) 7.3 7.9 0.2c 9.9 0.0c 8.5 0.1c
stimulation were included. RS-100329 (3 nM) 9.2 9.6 0.1 7.5 0.1 7.9 0.1
Per protocol analyses included complete squares Ro70-0004=003 8.8a 8.9 0.1 7.1 0.1 7.2 0.1
(10, 30 and 100 nM)
of patients with available RigiScan Plus1 data from
all four treatment periods. The primary and second- b
Data from Williams et al14, except c, data from Giardina et al15.
ary variables were analyzed using an analysis of
variance (ANOVA) model with terms for sequence,
Table 2 Adverse events following a single oral dose of placebo,
patient within sequence, treatment, period and 5 mg Ro 70-0004 or 50 mg sildena®l
carry-over. An intent-to-treat analysis was per-
formed on all available RigiScan Plus1 data using Ro70-0004 Sildena®l
the same ANOVA model. Placebo 5 mg 50 mg
Total number of patients 21 20 22
Any adverse event 1 (4.8%) 2 (10.0%) 2 (9.1%)
General disorders
Results Dizziness (excluding vertigo) 1 (5.0%) 1 (4.5%)
Sedation 1 (4.5%)
Vascular disorders
In vitro studies Haematoma nose 1 (4.5%)
Hypotensive episode 1 (5.0%)
Thrombophlebetitis 1 (4.8%)
Gastrointestinal disorders
Norepinephrine (NE) produced concentration- Nausea 1 (5.0%)
dependent contraction of the human isolated corpus
International Journal of Impotence ResearchEvaluation of oral Ro70-0004=003
A Choppin et al
160
22.64 min following 50 mg of sildena®l. The mean erection8 and is used for diagnostic and therapeutic
duration of rigidity >80% at the base of the penis purposes, whilst a-adrenoceptor agonists such as
was 0.67 min following administration of placebo, metaraminol may be used to reverse this effect.
0.45 min following Ro70-0004, and 5.26 min follow- Furthermore, non selective a-adrenoceptor subtype
ing sildena®l. Only the difference between sildena®l antagonists such as phentolamine,19 selective a1-
and placebo reached statistical signi®cance adrenoceptor antagonists (eg prazosin and moxisy-
(P 0.05). lyte)20 have been evaluated in clinical trials as
Rigidity at the tip of the penis: The mean duration possible treatments for MED although the systemic
of rigidity >60% at the tip of the penis was 5.33 min adverse effects of these drugs limits their therapeu-
following administration of placebo, 5.52 min fol- tic value. Given the known heterogeneity of a1-
lowing 5 mg of Ro70-0004, and 9.21 min following adrenoceptor subtypes, efforts to elucidate the
50 mg of sildena®l. The mean duration of rigidity functional a1-adrenoceptor subtype in human erec-
> 80% at the tip of the penis was 1.23 min following tile tissue and develop selective drugs for this target
administration of placebo, 1.20 min following Ro70- may be therapeutically rewarding. Ro70-0004 is a
0004, and 3.18 min following sildena®l. Ro70-0004 selective a1A-adrenoceptor antagonist. The selectiv-
and sildena®l did not produce a signi®cant effect ity of Ro70-0004 has been demonstrated in contrac-
(P > 0.05 vs placebo). tile assays in native tissues (including human lower
The ef®cacy data with placebo, Ro70-0004 and urinary tract tissues) and at recombinant a1-adreno-
sildena®l is summarized in Table 3. ceptor subtypes using both binding (Table 1) and
functional assays.14 In the present study, we have
characterized the a1-adrenoceptor subtype mediat-
ing contraction of human corpus cavernosum using
Discussion a range of selective pharmacological probes. The
af®nity estimates of prazosin (non-selective), cycla-
zosin (a1B-selective), Ro70-0004 and RS-100329
For most patients with erectile dysfunction, oral (a1A-selective) suggest that the a1-adrenoceptor
agents are a preferred treatment over using vacuum mediating contraction of human erectile tissue
pumps,16 penile prosthesis17 or injection of vasodi- equates with the a1A-adrenoceptor subtype.
lator agents directly into the corpora cavernosa Clinically, Ro70-0004 has been evaluated in
(agents commonly used include papaverine, phen- patients for the treatment of benign prostatic
tolamine and PGE1 which have been used singly or hyperplasia (BPH; this data has not been published).
in combination.18 The recent introduction of oral In humans, Ro70-0004 is rapidly absorbed after oral
sildena®l, a drug which facilitates the NO=c-GMP administration (tmax 1 ± 2 h) with an elimination
relaxant mechanism in erectile tissue, has offered half-life of 5 ± 7 h. An oral dose of 5 mg Ro70-
MED patients with a new therapeutic option. An 0004 yielded plasma drug levels suf®cient to
alternative therapeutic strategy is to antagonize the produce selective and long-lasting a1A-adrenoceptor
a1-adrenoceptor contractile pathway. Indeed, caver- blockade.
nosal a-adrenoceptor blockade is known to produce The present study was undertaken to determine
whether Ro70-0004 could improve erectile function
Table 3 Summary of rigidity at the base and tip of the penis as in MED patients. This study demonstrated unequi-
measured by RigiScan Plus1 vocally that a 5 mg dose of Ro70-0004 was ineffec-
Ro70-0004 Sildena®l tive in improving erectile activity as measured by
Placebo 5 mg 50 mg RigiScan Plus1 in patients with erectile dysfunction
with no established organic cause. The clinical
Rigidity (base)
> 80% (base)
study design was validated using sildena®l which
Number of periods 25 26 27 did increase penile rigidity at the base of the penis.
Duration of erection (min) 0.67 1.69 0.45 1.69 5.26 1.63 However, the 5.26 min duration of rigidity > 80% at
P-value (vs placebo) 0.926 0.05 the base of the penis obtained in this study was
> 60% (base) lower than what has been reported previously.21 It
Number of periods 25 26 27
Duration of erection (min) 9.69 3.71 8.28 3.70 22.64 3.57 should be noted that both Ro70-0004 and sildena®l
P-value (vs placebo) 0.784 0.013 were safe and well tolerated in this study.
Rigidity (tip) It is well known that the sympathetic nervous
> 80% (tip) system is involved in erectile function. Possible
Number of periods 25 26 27
Duration of erection (min) 1.23 1.21 1.20 1.20 3.18 1.16
explanations for the failure of an a1A-adrenoceptor
P-value (vs placebo) 0.988 0.239 antagonist to produce ef®cacy in this study include
> 60% (tip) (1) a redundancy of contractile mechanisms, (2) the
Number of periods 25 26 27 involvement of a1A-adrenoceptors in cavernosal
Duration of erection (min) 5.33 2.85 5.52 2.84 9.21 2.75 smooth muscle but not in penile vascular smooth
P-value (vs placebo) 0.962 0.318
muscle contraction. It is possible, however, that
Total number of patients is 20. The durations are means s.e. selective antagonism of the a1A-adrenoceptor
International Journal of Impotence ResearchEvaluation of oral Ro70-0004=003
A Choppin et al
161
subtype may have synergistic effects when adminis- 9 Becker AJ et al. Oral phentolamine as treatment for erectile
tered with other pro-erectogenic compounds (eg dysfunction. J Urol 1998; 159: 1214 ± 1216.
10 Dausse J-P, Leriche A, Yablonsky F. Patterns of messenger
sildena®l). Thus the role, if any, of the a1A- RNA expression for a1-adrenoceptor subtypes in human
adrenoceptor subtype in erectile dysfunction corpus cavernosum. J Urol 1998; 160: 597 ± 600.
requires further investigation. 11 Choppin A et al. Evaluation of oral Ro 70-0004=003, an a1A
adrenoceptor antagonist, in the treatment of male erectile
dysfunction. J Urol 2000; 163: 900P, 2000.
12 Choppin A, Eglen RM, Hegde SS. Pharmacological character-
Acknowledgements ization of muscarinic receptors in rabbit isolated iris sphincter
Roche Bioscience provided drugs and ®nancial muscle and urinary bladder smooth muscle. Br J Pharmacol
support for this study. 1998; 124: 883 ± 888.
13 Arunlakshana O, Schild HO. Some quantitative uses of drug
antagonists. Br J Pharmacol Chemother 1959; 14: 48 ± 58.
14 Williams TJ et al. In vitro alpha 1-adrenoceptor pharmacology
References of Ro 70-0004 and RS-100329, novel alpha1A-adrenoceptor
selective antagonists. Br J Pharmacol 1999; 127: 252 ± 258.
15 Giardina D et al. Synthesis and biological pro®le of the
1 NIH Consensus Development Panel on Impotence. Impotence. enantiomers of [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-cis-
JAMA 1993; 270: 83 ± 90. octahydroquinoxalin-1-y1]furan-2-ylmethanone (cyclazosin),
2 Feldman HA et al. Impotence and its medical and psycho- a potent competitive alpha 1B-adrenoceptor antagonist.
social correlates: results of the Massachusetts Male Aging J Med Chem 1996; 39: 4602 ± 4607.
Study. J Urol 1994; 151: 54 ± 61. 16 Lewis RW, Witherington R. External vacuum therapy for
3 Davis-Joseph B, Tiefer L, Melman A. Accuracy of the initial erectile dysfunction: use and results. World J Urol 1997; 15:
history and physical examination to establish the etiology of 78 ± 82.
erectile dysfunction. Urology 1995; 45: 498 ± 502. 17 Montague DK. Penile prostheses. An overview. Urol Clin N
4 Goldstein I et al. Oral sildena®l in the treatment of erectile Amer 1989; 16: 7 ± 12.
dysfunction. New Engl J Med 1998; 338: 1397 ± 1404. 18 Levine SB et al. Side effects of self-administration of
5 Padman-Nathan H, Steers WD, Wicker, PA. Ef®cacy and safety intracavernous papaverine and phentolamine for the treatment
of oral sildena®l in the treatment of erectile dysfunction: a of impotence. J Urol 1989; 141: 54 ± 57.
double-blind, placebo-controlled study of 329 patients. Int J 19 Goldstein I. Oral phentolamine: an alpha-1, alpha-2 adrener-
Clin Prac 1998; 52: 375 ± 380. gic antagonist for the treatment of erectile dysfunction. Int J
6 Andersson K-E, Wagner G. Physiology of penile erection. Impot Res 2000; 12(Suppl 1): S75 ± S80.
Physiol Rev 1995; 75: 191 ± 236. 20 Marquer C, Bressolle F. Moxisylyte: a review of its pharma-
7 Andersson K-E, Stief CG. Neurotransmission and the contrac- codynamic and pharmacokinetic properties, and its therapeu-
tion and relaxation of penile erectile tissues. World J Urol tic use in impotence. Fundam Clin Pharmacol 1998; 12: 377 ±
1997; 15: 14 ± 20. 387.
8 Brindley GS. Cavernosal alpha-blockade: a new technique for 21 Boolell M, Gepi-Attee S, Gingell JC, Allen, MJ. Sildena®l, a
investigating and treating erectile impotence. Br J Psychiat novel effective oral therapy for male erectile dysfunction. Br J
1983; 143: 332 ± 337. Urol 1996; 78: 257 ± 261.
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