EURURO Vol. 72 No. 6

988 1030

3. Evidence synthesis
3.1. Intraprostatic injectables
Intraprostatic injections for the treatment of prostatic
diseases do not represent novel concepts. Early reports of
intraprostatic injections for the management of LUTS were
documented in 1910 . Novel injectables have been
designed to address specifically key processes in the
pathophysiology of LUTS due to BPE .
[3_TD$DIFF]3.2. BoNT/A
[4_TD$DIFF]3.2.1. Basic principle
The exact mechanisms of BoNT/A still need to be
elucidated, but based on current knowledge is likely to
involve modulation of sensory neural mechanisms In
the urological field, it has been officially approved for the
treatment of idiopathic and neurogenic detrusor overac-
tivity (BOTOX; Allergan, Dublin, Ireland) and has
been explored in preliminary work for functional dis-
orders such as detrusor sphincter dyssynergia and
bladder pain syndrome/interstitial cystitis Briefly, it
was shown to modulate neurotransmission of sympathic,
parasympathic, and sensory nerve terminals in the
prostate. The chemo-denervation results in the reduction
of size and growth of the prostate and impacts contrac-
tility as the dynamic component of benign prostatic
obstruction
[5_TD$DIFF]3.2.2. Clinical outcome
Experimental evidence anticipated successful manage-
ment of LUTS due to BPE; however, results from clinical
trials have been falling short of expectations . Three
RCTs have been conducted to date . The first small
trial by Maria et al enrolled 30 individuals who were
randomly assigned to receive 200 U BOTOX or placebo via
the transperineal route. One month after treatment the
primary endpoints were met with a relevant clinical
improvement of 54% as determined by the American
Urological Association Symptom Index (p = 0.00001) and
Qmax increasing significantly from 8.1 ml/s to 14.9 ml/s
(p = 0.00001). Prostate volume was reduced by 54%
(p = 0.00001) and postvoid residual volume decreased by
60% (p = 0.00001). Clinical response was stable throughout
the follow-up period of 12 mo. No adverse events were
reported. This promising initial outcome could not be
reproduced in two further larger RCTs. Both phase 2 studies
by Marberger et al and McVary et al including
380 and 427 participants, respectively, were not able to
demonstrate a relevant benefit of BOTOX over placebo. A
recent meta-analysis failed to show the therapeutic
efficacy of BoNT/A for a meaningful therapy of male LUTS
associated with BPE in clinical practice . Therefore, no
recommendation can be made for the intraprostatic
injection of BoNT/A for the treatment of male LUTS due
to BPE.
[6_TD$DIFF]3.3. NX-1207
[7_TD$DIFF]3.3.1. Basic principle
This novel cysteine-containing linear protein of proprietary
composition with selective proapoptotic features was
suggested for the office-based administration via the
transrectal route under transrectal ultrasound guidance
for the minimally invasive treatment of male LUTS.
[8_TD$DIFF]3.3.2. Clinical outcome
After smaller clinical phase 1/2 trials had indicated efficacy
and safety of NX-1207 , the positive treatment
response after intraprostatic application was further
confirmed in two larger RCTs, with one demonstrating
noninferiority to finasteride However, both US
phase 3 pivotal studies failed to meet primary endpoints,
which prompted the sponsors to prematurely terminate the
respective European phase 3 trials. Therefore, NX-1207
failed as an intraprostatic injectable for the treatment of
male LUTS.
[9_TD$DIFF]3.4. PRX302
[10_TD$DIFF]3.4.1. Basic principle
PRX302 was designed as a first-in-class agent for the
therapy of male LUTS due to BPE. The highly toxic pore-
forming protein is originally produced as the inactive
precursor proaerolysin by the aquatic pathogen Aeromonas
hydrophila. Cleavage by furin proteases is necessary for the
activation of the precursor to its active form aerolysin,
which in turn forms stable pores in the plasma membrane,
resulting in cell death. This protein was genetically
modified to create a prostate-selective compound. The
original cleavage site was replaced with a prostate-specific
antigen-specific sequence, creating PRX302. The abundance
of active prostate-specific antigen only restricted to the
prostate confines the biologic activity of PRX302 exclusively
to prostatic tissue .
[11_TD$DIFF]3.4.2. Clinical outcome
Clinical efficacy and safety were assessed and confirmed in
a small phase 1 trial on 15 patients and a phase 2 study on
18 patients . PRX302 was injected in the transition zone
via the transperineal route under transrectal ultrasound
guidance in an office-based setting. In both studies over 60%
of treated patients experienced a 30% improvement of
clinical symptoms compared to baseline as quantified by
International Prostate Symptom Score (IPSS) after 360 d.
Only the phase 2 trial reported an increase in Qmax of 3 ml/
s in 61% of treated patients out to 12 mo. The impact of
PRX302 on prostate volume revealed a reduction of 20% in
36% of patients in the phase 1 trial and 63% of participants
enrolled in the phase 2 study for the 360-d follow-up. No
impairment of erectile function as measured by the
International Index of Erectile Function (IIEF) score was
observed in either study. Adverse events were mild to
moderate and only temporary, resolving within 72 h. A
E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 9 8 6 – 9 9 7 988