Market Opportunity for Treatment of PBS
Presently, no approved products exist for treating PBS, and those that have been approved for
interstitial cystitis, a subset of PBS, are based on clinical studies which have shown the drugs to be marginally effective. According to
its website, the FDA has approved two drugs for the treatment of interstitial cystitis and neither is labeled as providing immediate
system relief. For example, at three months, the oral drug Elmiron achieved a therapeutic benefit in only 38% of patients on active
drug versus 20% on placebo. The other drug approved for interstitial cystitis, RIMSO®-50 is an intravesical treatment that was not
based on double-blind clinical trial results. According to The Interstitial Cystitis Data Base Study Experience published in the year
2000, RIMSO®-50 is widely recognized as ineffective and not included among the top ten most common physician-prescribed
treatments for urinary systems.
Consequently, there remains a significant need for new therapeutic interventions such as URG101 that can address the underlying disease process while also providing acute symptom relief. PBS is a chronic disease characterized by moderate to severe pelvic pain, urgency, urinary frequency, dyspareunia (painful intercourse) with symptoms originating from the bladder. Current epidemiology data shows that PBS may be much more prevalent than previously thought.
One theory of PBS’s pathological cause implicates a dysfunction of the bladder epithelium surface called the urothelium. The
epithelium is the inner lining of tissue organs. Normally, the urothelium is covered with a mucus layer, the glycosaminoglycan, or
GAG, layer, which is thought to protect the bladder from urinary toxins. A deficiency in the GAG layer would allow these toxins to
penetrate into the bladder wall activating pain sensing nerves and causing bladder muscle spasms. These spasms trigger responses to
urinate resulting in the symptoms of pelvic pain, urgency and frequency, the constellation of symptoms associated with this disease.
Once established, PBS can be a chronic disease, which can persist throughout life and can have a devastating impact on quality of life.
Urigen believes that the prevalence of PBS in North America is estimated to be 10.5 million, of which 3.8 million would
experience severe enough symptoms to be classified as having interstitial cystitis, a subset of PBS. This estimate was based on studies
conducted by Matt T. Rosenberg and Matthew Hazzard at the Mid-Michigan Health Centers. Each of them independently concluded
that the number of subjects with interstitial cystitis have been significantly underestimated. They evaluated over 1,000 female primary
care patients over the course of a year using a pain, urgency/frequency questionnaire to categorize subjects as symptomatic or not.
Urigen calculated its estimates based on a stringent cutoff score of 10 on the pain, urgency/frequency scale, assuming a 50% rate for
men relative to women, and a more lenient cutoff score of 13.
Clinical Trial Status
Urigen filed an IND in 2005 to initiate a Phase IIb multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of intravesical alkalinized lidocaine-heparin for the symptoms of pelvic pain and urgency of bladder origin. A Phase I study was not required because the components of URG101 are FDA-approved for other uses. The study enrolled 90 subjects randomized to drug vs. placebo in a 1:1 ratio. The study included a clinically relevant three-week treatment phase to evaluate the safety and efficacy of URG101 for the treatment of pelvic pain and/or urgency of bladder origin. While URG101 did not meet the primary endpoint in the study, the trial provided information necessary to proceed with development of the product. According to press releases issued by Acordia Therapeutics, Inc. in 2004 and 2006, there are other examples of clinical trials not achieving primary endpoints, but there are lessons learned in the study that can lead to success in Phase III trials. The rationale for continued development of URG101 was several-fold: the largest and most experienced clinical trial site met both the primary (70% drug response versus 17% placebo) and secondary endpoints of the study. Additionally, the study achieved a high level of statistical significance on improvement in urgency with just one dose over placebo and trended toward improvement in pain with just one dose. These results indicated that, in a controlled clinical trial, subjects receiving study drug experienced meaningful symptom improvement in both urgency and bladder pain over placebo.
In a subsequent Phase II multi-center, double-blind, randomized, placebo-controlled, cross-over study comparing URG101 to placebo an interim analysis of 21 completed patients demonstrated that URG101 primary and secondary efficacy measurements in the study were significantly better than placebo. Top line data analysis findings included:
- Primary Endpoint - Improvement in Average Daytime Pain (p=0.03).
- Secondary Endpoints - Improvement in Daytime Urgency (p=0.03) and Total Symptom Score (p=0.03). In addition, patients reported improved symptom relief with URG101 as measured by PORIS (p=0.01).
Market Opportunity for Treatment of Radiation Cystitis
Urigen estimates that the incidence of radiation cystitis in the United States is more than 34,000 cases per year. This estimate is
based on a comprehensive review of more than 40 peer-reviewed articles on specific pelvic irradiation treatments, such as
brachytherapy and external beam radiation therapy, and the frequency of adverse urogenital side effects. The annual incidence was
then calculated by the annual incidence of pelvic cancer, which can be found at www.cancer.gov, its estimated radiation rate and
adverse urinary symptom rate. Although the symptoms of radiation cystitis are similar to those of interstitial cystitis, the clinical
etiology or underlying cause, can be differentiated based on the mechanism of disease. In fact, clinical studies of products in
development for interstitial cystitis typically exclude patients suffering from radiation cystitis. According to a search of the FDA’s
website, currently, there are no FDA-approved or licensed treatments of these symptoms that are caused by pelvic irradiation.
Pelvic irradiation, both external beam and brachytherapy, represents one of the cornerstones of cancer therapy for a variety of local cancers including: prostate, ovarian, cervical, bladder, and colorectal cancers. Radiation cystitis, or pelvic pain and/or urgency of bladder origin secondary to pelvic irradiation, is a well-recognized side effect of pelvic irradiation.
Based on extensive review of literature, Urigen has calculated that radiation cystitis is observed in 6-15% of patients receiving
pelvic radiotherapy, and that for prostate cancer this rate is higher and ranges from 25-30%, or about 1 out of 3-4 men treated. The
average time from the beginning of radiation therapy to initial symptoms can be several months to several years. The acute symptoms
of radiation cystitis may be so painful as to disrupt the radiation treatment regimen. In most cases, acute symptoms are reversible
several weeks after cessation of therapy. However there is a subset of patients that develop chronic radiation cystitis in which these
symptoms remain indefinitely, possibly due to irreversible damage an/or improper healing of the bladder wall.
Clinical Trial Status
Several patients with radiation cystitis have been treated by Urigen’s scientific founder with URG101. Urigen believes that these
treatments, coupled with Urigen’s clinical experience with URG101 for PBS, warrant further testing for radiation cystitis.
Consequently, Urigen has expanded its IND to include the evaluation of URG101 in a Phase II multi-center, randomized, doubleblind,
placebo-controlled crossover to open-label study to evaluate the safety and efficacy of URG101 in patients exhibiting symptoms
of pelvic pain and /or urgency of bladder origin secondary to pelvic irradiation.
Market Opportunity for Treatment of Dyspareunia
Dyspareunia is sexual dysfunction manifested as painful or difficult sexual intercourse. The disorder is recurrent and associated with a disruption of normal functioning. Dyspareunia is most frequently in females; however, incidence has also been reported among males.
The actual incidence of dyspareunia is difficult to determine, since the majority of cases are unreported by patients. In a survey
conducted by Edward O. Laumann, Anthony Paik and Raymond C. Rosen on sexual experience and dyspareunia, 24% of respondents
stated that dyspareunia was “frequent” or “constant,” 47% reported that they had less frequent intercourse because of dyspareunia, and
33% reported that their dyspareunia had an adverse effect on their relationship with a sexual partner.
Clinical Trial Status
An unpublished clinical study by Dr. Joel M.H. Teichman and Dr. Blayne Welk demonstrates that administration of URG101
relieves symptoms of dyspareunia in women suffering from the disorder. Dr. Teichman and Dr. Welk, each of Vancouver, Canada,
studied twelve consecutive Interstitial Cystitis/Painful Bladder Syndrome patients that were sexually active, diagnosed with
dyspareunia and treated with an intravesical therapeutic solution. The patients were treated with intravesical instillations three times
per week for three weeks, and re-evaluated three weeks later. Eleven of the twelve patients reported improvements of greater than
50%. Eight patients reported no dyspareunia after instillations. Drs. Teichman and Welk concluded intravesical therapeutic solution
provides relief of voiding symptoms, pain, and dyspareunia in IC/PBS patients. Based on these anecdotal results, Urigen is collaborating with a leading academic center to explore the potential of URG101 to effectively treat women diagnosed with dyspareunia.
