Interstitial cystitis (IC) or “painful bladder syndrome” (PBS), is a chronic inflammatory condition affecting the bladder which is most common among women. It is characterised by urinary frequency, urgency and bladder pain without an identifiable cause.
IC predominantly affects young and middle-aged women, although its prevalence in males is probably under-estimated. Onset can be gradual or abrupt and duration of symptoms is variable. Graduation of intensity ranges from inconvenience to all pervasive and socially debilitating condition. Episodic exacerbations add to the difficulty of managing this chronic disease. It is poorly understood, poorly characterised and treatment is mostly empirical and unsatisfactory.
The reported prevalence of IC/PBS varies due to the use of different diagnostic criteria and is believed to be widely under-reported. A survey of American households suggests that at least 900,000 women have received a diagnosis of IC or PBS. IC/PBS symptoms are similar to those of other uro-gynaecological conditions and many women receive inappropriate medical treatments, including hormone therapy and hysterectomy.
There are currently only a few approved specific drug treatments for IC/PBS. These treatments have limited clinical efficacy and may take several months to provide symptomatic relief. Off-label treatments include antidepressants, antihistamines, electrical nerve stimulation and heparin bladder instillation.
PSD597 is a novel formulation of a marketed analgesic agent, based on intellectual property developed by Dr Richard Henry of Queen’s University in Kingston, Ontario, Canada. It is instilled into the bladder using a technique that will be suitable for both out-patient clinics and home administration. Plethora Solutions, following approval from the FDA to start Phase II clinical trials, has initiated these trials in North America in two indications: Interstitial Cystitis, where recruitment was completed in June 2007 and in Painful Bladder procedures. It is also conducting additional work in parallel using micelle nanotechnology in-licensed from Maelor pharmaceuticals in order to improve the drug profile.
The phase II study in interstitial cystitis was a randomised, double-blind, placebo controlled trial into which 102 patients were recruited in 22 centres in the USA and Canada. The immediate and prolonged effects of a course of PSD597 treatment were investigated.
Patients who received PSD597 showed clear and substantial improvements in the primary endpoint measure, Global Response Assessment (GRA), a patient-rated scale of improvement in bladder symptoms which is now an international standard in IC/PBS trials. At Day 8, 15 patients (30%) in the ‘intent-to-treat’ population reported moderate or marked improvement after PSD597 treatment compared with only 5 patients (10%) randomized to placebo (p=0.012); improvements in the two groups at Day 15 were 24% and 12% respectively (p=0.102). Analysing the response across all GRA categories, the difference with PSD597 treatment at Day 15 was highly significantly different from placebo (p=0.005). These positive results were replicated across all secondary endpoints with improvements reported in bladder pain, urinary frequency and urgency, whether assessed as individual symptoms or combined into widely-accepted symptom and problem indices. The O’Leary-Sant Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index each improved following treatment with PSD597 (p=0.041, p<0.001 at Day 8, respectively, comparing PSD597 and placebo treatment groups; p=0.12, p=0.038 comparing the two treatments at Day 15). PSD597 was well tolerated, appeared safe, and was devoid of systemic side effects often experienced with oral drugs.
The drug effect was confirmed in an extension to the study. In this voluntary part of the trial, patients who completed the double-blind placebo controlled phase were offered the choice of open label treatment with PSD597 for 5 days from Day 15. Notably, 86% of patients elected to receive a second treatment. This provides direct evidence of treatment acceptability and the lack of alternative treatment options. Treatment was again well tolerated and safe. At Day 22, 63% of those patients who had received PSD597 in the double-blind study phase reported moderate or marked improvement in Global Response Assessment after the second treatment; of the patients who previously were randomized to placebo, 44% now responded to active treatment. By Day 29, GRA response rates were still maintained at 56% and 39% in the two groups.
The results complement those seen in the initial double-blind study phase and, together, they suggest that the benefits of PSD597 are sustained for a considerable period after treatment and, secondly, confirm that clinical benefit can be increased with repeated administration of PSD597 [please click on title to view].
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