doi:10.1111/codi.12540

Editorial

Faecal incontinence: the ‘Cinderella’ disorder Colorectal surgeons may not be generally familiar with the process by which a new drug progresses from concept to clinical use, and may wonder why such developments seem so laborious. In general, drug therapy is not a mainstay of the armamentarium for colorectal surgeons although there are several examples of drugs that are now widely used in clinical practice by colorectal surgeons. Perhaps the best example of this is topical glyceryl trinitrate used for the treatment of anal fissures; other examples include nifedipine and phenylephrine. This article sets the scene for a series of papers charting the development of a topical agent, the 1R,2S isomer of methoxamine (NRL001), which aims to increases anal sphincter pressure to treat mild to moderate faecal (or bowel) incontinence and explains the process from concept to clinical use. The mechanisms of continence in the bowel are complex; when they go wrong faecal incontinence often results. Faecal incontinence is often viewed as the ‘Cinderella’ disorder in comparison with urinary incontinence. Faecal incontinence is becoming increasingly common as the population ages, with a generally accepted prevalence of up to 8% in the general community [1–4] and almost 50% among nursing home residents [5]. There is greater prevalence in females, with an overall risk factor of 1.51 [95% confidence interval (CI) 1.10–2.11] [6]. Faecal incontinence may be caused by anatomical damage to the internal and external anal sphincters resulting from trauma (congenital, obstetric, surgical, accidental or iatrogenic) [7]. However, in many cases there is no distinct structural damage and faecal incontinence appears to result from a degenerative disorder affecting the smooth muscle of the internal anal sphincter (IAS). Symptoms of faecal incontinence range from mild difficulty with gas control to severe loss of control over liquid and formed stools [8]. Currently available treatments often have limited success in treating these symptoms. Despite the widely recognised unmet medical need, the numbers of well-controlled clinical trials in faecal incontinence are relatively small. Furthermore, of those clinical trials ongoing, medical devices such as bulking agents (e.g. injectable gels) and neuromodulation [e.g. sacral nerve stimulation (SNS), percutaneous tibial nerve stimulation (PTNS), transcutaneous tibial nerve stimulation (TTNS)] or surgical techniques are being tested rather than pharmaceutical preparations [9]. The current symptomatic treatments for faecal incontinence range from lifestyle adaptations, dietary manipu-

lation, coping strategies (e.g. pads, self-medication, etc.), biofeedback or physiotherapy [10], through to surgical sphincter repair or replacement (such as the magnetic anal sphincter [11]) or other procedures such as SNS [12–14], injectable bulking agents [15], PTNS or TTNS [16–18]. For many patients, due to perceived embarrassment, self-consciousness and lack of awareness of options, consultation with healthcare practitioners is often delayed until the disorder has become more severe [7]. A survey found that although episodes of faecal incontinence were self-reported by 36.2% of primary care patients, only 2.7% of these patients had a documented medical diagnosis [19]. Patient entry into treatment pathways is thus highly variable. Young patients, often female with faecal incontinence caused by obstetric trauma, may be suitable for surgical repair [20]. Elderly patients may find similar solutions suitable, but for those with no obvious evidence of repairable damage upon investigation via anal ultrasound, surgery may not be an appropriate option and alternative interventions need to be considered [20]. Many faecal incontinence patients try coping strategies such as evacuation prior to journeys and/or holding a route map indicating potential toilet stops (a variety of mobile phone apps are available). The use of sanitary pads or incontinence pads and/or the taking of constipating agents such as loperamide or codeine-containing preparations may be seen as a low profile self-treatment solution, and are also common first line treatments for those that do consult healthcare practitioners. In a recent survey of community-based patients, 45% of respondents said they used absorbent products to manage their faecal incontinence [21]. Some patients may be eligible for bowel retraining and biofeedback; success with these modalities can be high, but is also variable from hospital to hospital, or physician to physician. Neuromodulatory intervention can provide relief and SNS, PTNS or TTNS have helped some patients [12–14,16–18]. The number of peer reviewed clinical research papers are much greater for SNS than either PTNS or TTNS; however, a number of studies are on-going that may increase the number of reports for the latter over the coming years. Despite the fact that the precise mechanism of action of these technologies is poorly understood and that their long term success rates are uncertain, they have become widely accepted in Europe. SNS is now first line surgical treatment for most severe cases of faecal incontinence, even superseding

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primary sphincter repair in patients with an identified sphincter defect [22]. A fascinating area of development with huge promise for those at the more severe end of the disease spectrum is that of human tissue re-engineering [23]. Research interests in methods that may repair the internal and external anal sphincter are ongoing, some of which are in Phase II clinical development. Against this backdrop of treatments for faecal incontinence, there is a place for novel, well tolerated pharmaceutical preparations that could help provide relief of symptoms for some patients with faecal incontinence, or supplement existing partial relief (including neuromodulation techniques) for others. For some years, the concept of a1-adrenoceptor agonism to increase IAS tone has been described in scientific literature. To date, clinical investigations using phenylephrine have reported a mixed success [24]. NRL001 (1R,2S-methoxamine hydrochloride) is being developed for the treatment of passive faecal incontinence caused by low IAS tone. The success of treatment is expected to depend on the extent and duration of the increase in mean anal resting pressure (MARP) together with the minimum of systemic aadrenergic effects. A number of formulations of NRL001 were considered and tested, with the most favourable option being a suppository formulation with slow release characteristics, thereby providing the desired local pharmacological action whilst avoiding sudden, sharp peaks of NRL001 plasma concentrations that may lead to undesirable side effects. The route from concept to prescription drug is complex and involves multiple experts with skills ranging from the physical sciences such as chemistry or pharmaceutics; preclinical sciences for example pharmacology and toxicology; through to clinical scientists and physicians who collaborate to test the potential of the product in patient groups. It takes around 10 years, often longer, to progress from the research laboratory to the patient and only 10% of the new chemical entities (NCEs) that start in preclinical testing make it to the clinical stage. There are three key stages of clinical testing prior to a marketing authorisation application (MAA); Phase I, Phase II and Phase III. In Phase I trials an Investigational Medicinal Product (IMP) is administered to c. 25 50 healthy volunteers, or in some special cases patient volunteers, to study its safety, tolerability and pharmacokinetics and also to seek any surrogate markers that may indicate that the desired therapeutic effect may be possible. Phase II trials test the IMP in 100–500 patients with the target disease, with the objective of exploring the detailed actions of the therapeutic intervention (over a range of doses)

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compared to placebo in order to gain adequate confidence in the benefit/risk profile of the selected dose(s) to proceed to confirmatory Phase III studies. This is the third stage of clinical testing and may involve anywhere from 1000 patients upwards in large scale, multicentre, randomised clinical trials that seek to confirm the efficacy hypotheses generated in Phase II and provide more information on the safety and tolerability of the IMP. Phase III clinical testing will usually employ the final formulation of the intended marketed product and in parallel to the Phase III clinical studies, the quality parameters for the physical product that define manufacturing requirements and product shelf life will be finalised. After all three phases of clinical development, and all physical product characterisation are completed, a company can file a MAA in those countries in which the product is intended to be used. Review and approval of this application typically takes over 12 months and the issue of national licences, pricing and reimbursement requirements are additional steps to navigate prior to full market access. Trials do not cease once the pharmaceutical product has been put on sale; they continue throughout its marketing lifecycle. Post authorisation Phase IV clinical studies (as a combination of further controlled clinical trials and observational studies seeking data on real world clinical outcomes, i.e. conditions close to usual medical care in a specific local environment) and also global pharmacovigilance, all serve to provide additional, longitudinal information on both efficacy and tolerability with specific targets to detect any possible rare undesirable side effects which had escaped attention in the previous phases and to define conditions of use for certain groups of patients either at-risk of adverse events or who might particularly benefit from the medication. NRL001 is undertaking its journey through this complex process and this supplement describes the early Phase I work together with a meta-analysis of the cardiovascular data from these studies; see Table 1 for a list of the studies reported [25–29]. In addition, the Phase II clinical study design is presented [30]. In the SUM study [25], healthy subjects received three single doses of 1 g rectal suppositories (containing 5 or 10 mg NRL001 or matching placebo) or 2 g rectal suppositories (containing 10 or 15 mg NRL001 or matching placebo) on three separate dosing days. A clear increase in MARP following administration of NRL001 was established, supporting a potential therapeutic use in faecal incontinence. There was no evidence against dose proportionality for the pharmacokinetic variables AUCt, AUC0–∞ and Cmax in this study. SUSD was a dose escalation study [26]. Two cohorts of healthy subjects (Group 1) received four single doses

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Table 1 Studies reported in this supplement. Study

Title

SUM [25]

A randomised, controlled, crossover study to investigate the safety and response of 1R,2S-methoxamine hydrochloride (NRL001) on anal function in healthy volunteers Randomised clinical trial: study of escalating doses of NRL001 given in rectal suppositories of different weights A randomised, controlled, crossover study to investigate the pharmacodynamics, pharmacokinetics and safety of 1R,2S-methoxamine hydrochloride (NRL001) in healthy elderly subjects A double-blind, placebo-controlled, randomised, parallel-group, doseescalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days Meta-analysis for cardiovascular effects of NRL001 after rectal application in healthy volunteers

SUSD [26]

SAGE [27]

SURD [28]

Meta-analysis [29]

of 1 g or 2 g rectal suppository containing 5, 7.5 or 10 mg NRL001, or matching placebo. A further two cohorts of healthy subjects (Group 2) received four single doses of 1 g or 2 g rectal suppository containing 10, 12.5 or 15 mg NRL001, or matching placebo. The results showed that suppository size (1 g vs 2 g) did not affect the pharmacokinetic variables AUC0–tz, AUC0–∞ or Cmax, and all variables were dose proportional. In the SAGE study [27], healthy elderly subjects received a single 2 g suppository of 10 mg NRL001 and a matching placebo in two separate treatment periods. They did not show significantly different biological responses to NRL001 than seen in younger healthy volunteers in the earlier studies. In the repeat dose study (SURD [28]), healthy subjects received single daily doses of 2 g rectal suppositories containing 7.5 mg, 10 mg, 12.5 mg or 15 mg NRL001, or matching placebo, for 14 days. The pharmacokinetic results and analysis showed that AUC and Cmax broadly increased with increasing NRL001 doses, and there was no evidence against dose proportionality. NRL001 did not accumulate over time. All the studies monitored safety, including close monitoring for clinically relevant alterations in blood pressure and heart rate as systemically circulating race-

mic methoxamine is known to raise blood pressure and cause bradycardia with peripheral vasoconstriction. NRL001 was well tolerated in single and repeat doses up to 15 mg, in both 1 g and 2 g suppositories. A decrease in heart rate was observed with administration of NRL001 suppositories compared with placebo in all studies. A meta-analysis of the cardiovascular data from the four studies concluded that there was a dose-dependent effect of NRL001 on heart rate [29]. QT intervals were affected by changes in heart rate; however, QTC trends were dependent on the correction factor used. A thorough QTC study for NRL001 will therefore be required. The overall conclusions from this body of work shows that NRL001 increases MARP in healthy volunteers and is well tolerated in a young and elderly population. This suggests that NRL001 is worthy of clinical investigation in Phase II patient populations with passive faecal incontinence.

Conflicts of interest J.H. Scholefield, Chair of Safety and Data monitoring Committee for Libertas trial (funded by Norgine). D. Walker is employed by Norgine Limited.

John H. Scholefield* and David Walker† *Division of Surgery, Queen’s Medical Centre, University Hospital Nottingham, Nottingham, UK and †Norgine Limited, Uxbridge, UK

References 1 National Institute for Health and Clinical Excellence. Faecal Incontinence: The Management of Faecal Incontinence in Adults. NICE clinical guideline 49. 2007. http://www. nice.org.uk/CG049 (accessed 25 September 2013). 2 Whitehead WE, Borrud L, Goode PS et al. Fecal incontinence in US adults: epidemiology and risk factors. Gastroenterology 2009; 137: 512–7. 3 Melville JL, Fan MY, Newton K, Fenner D. Fecal incontinence in US women: a population-based study. Am J Obstet Gynecol 2005; 193: 2071–6. 4 Perry S, Shaw C, McGrother C et al. Prevalence of faecal incontinence in adults aged 40 years or more living in the community. Gut 2002; 50: 480–4. 5 Leung FW, Schnelle JF. Urinary and fecal incontinence in nursing home residents. Gastroenterol Clin North Am 2008; 37: 697–707. 6 Nelson RL. Epidemiology of fecal incontinence. Gastroenterology 2004; 126: S3–7. 7 Hayden DM, Weiss EG. Fecal incontinence: etiology, evaluation, and treatment. Clin Colon Rectal Surg 2011; 24: 64–70. 8 Rome III. Diagnostic Criteria for Functional Gastrointestinal Disorders. http://www.romecriteria.org/assets/pdf/

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19_RomeIII_apA_885-898.pdf (accessed 25 September 2013). ClinicalTrials.gov. http://clinicaltrials.gov/ (accessed 5 August 2013). Bols EM, Berghmans BC, Hendriks EJ et al. A randomized physiotherapy trial in patients with fecal incontinence: design of the PhysioFIT-study. BMC Public Health 2007; 7: 355. Wong MT, Meurette G, Wyart V, Lehur PA. Does the magnetic anal sphincter device compare favourably with sacral nerve stimulation in the management of faecal incontinence? Colorectal Dis 2012; 14: e323–9. Duelund-Jakobsen J, van Wunnik B, Buntzen S, Lundby L, Baeten C, Laurberg S. Functional results and patient satisfaction with sacral nerve stimulation for idiopathic faecal incontinence. Colorectal Dis 2012; 14: 753–9. Ratto C, Litta F, Parello A, Donisi L, De Simone V, Zaccone G. Sacral nerve stimulation in faecal incontinence associated with an anal sphincter lesion: a systematic review. Colorectal Dis 2012; 14: e297–304. Griffin KM, Pickering M, O’Herlihy C, O’Connell PR, Jones JF. Sacral nerve stimulation increases activation of the primary somatosensory cortex by anal canal stimulation in an experimental model. Br J Surg 2011; 98: 1160–9. Hoy SM. Dextranomer in stabilized sodium hyaluronate (Solesta): in adults with faecal incontinence. Drugs 2012; 72: 1671–8. Hotouras A, Murphy J, Walsh U et al. Outcome of Percutaneous Tibial Nerve Stimulation (PTNS) for fecal incontinence: a prospective cohort study. Ann Surg 2013; 00: 1–5. Aug 23. [Epub ahead of print]. George AT, Kalmar K, Sala S et al. Randomized controlled trial of percutaneous versus transcutaneous posterior tibial nerve stimulation in faecal incontinence. Br J Surg 2013; 100: 330–8. Thomas GP, Dudding TC, Rahbour G, Nicholls RJ, Vaizey CJ. A review of posterior tibial nerve stimulation for faecal incontinence. Colorectal Dis 2013; 15: 519–26. Dunivan GC, Heymen S, Palsson OS et al. Fecal incontinence in primary care: prevalence, diagnosis, and health care utilization. Am J Obstet Gynecol 2010; 202: 493. e1–6. Kamm MA. Faecal incontinence: many treatment options now exist for this embarrassing condition. BMJ 2003; 327: 1299–300. Bliss DZ, Lewis J, Hasselman K, Savik K, Lowry A, Whitebird R. Use and evaluation of disposable absorbent prod-

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Faecal incontinence: the 'Cinderella' disorder.

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