Aes-210 is a novel formulation of an existing drug known as clotrimazole (CLT). CLT is widely known to have potent anti-inflammatory effects. Aes-210 presents CLT in a viscous, muco-adhesive gel that is delivered to distal regions of the bowel by retention enema. The objective, in essence, is to deliver high concentrations of the active anti-inflammatory ingredient in a topical form directly onto the inflamed mucosa of the patient. AesRx is currently testing Aes-210 for the treatment of pouchitis in a double-blind, dose-escalating, placebo-controlled, cross-over Phase 2 clinical trial. The initial results of this trial have been very encouraging.
Activity
The exact mechanism by which CLT achieves its effects on inflammatory diseases of the lower bowel is not specifically known. However, AesRx hypothesizes that it acts by one or a combination of mechanisms potentially including inhibition of pro-inflammatory cytokines and/or indirectly inhibiting transmigration of polymorphonuclear neutrophils (PMNs) across the intestinal epithelial barrier into the lumen. Intestinal epithelial cells play an active role in the mediation of intestinal inflammation through the production and regulated secretion of pro-inflammatory cytokine IL-8. It has been demonstrated that CLT is able to inhibit the expression of IL-8. In addition, the transmigration of PMNs across the intestinal epithelial barrier and into the lumen represents a feature of acute and active chronic intestinal inflammation. The transmigration of PMNs often results in mucosal ulcerations or frank crypt abscesses and can occur in a broad spectrum of inflammatory conditions including ulcerative colitis and pouchitis. In patients with chronic inflammatory bowel disease, the degree of PMN transmigration has been clinically shown to correlate with the extent of disease, as defined by an increase in patients’ symptoms and by a loss of intestinal epithelial barrier function. CLT has been shown to block potassium and calcium channels that may play a role in PMN cellular volume regulation.
Delivery
In previous studies in which commercially available CLT was delivered as a troche/lozenge to oral mucosa, it displayed significant tissue binding and a slow release from oral mucosa (anti-mycotic salivary concentrations were measured at least three hours after dosing). Similarly, when delivered as a vaginal suppository, therapeutic concentrations were noted in vaginal secretions for up to 48 to 72 hours after tablet insertion. These data demonstrate that CLT displays high mucosal tissue binding. This muco-adhesive property should augment the anti-inflammatory actions of CLT when delivered as a rectal retention enema in patients with inflammatory diseases of the lower bowel. In addition, the high tissue binding should reduce the need for frequent enema administration, facilitate patient compliance, and result in improved clinical outcomes.
Initial Target Indication: Pouchitis
Although AesRx believes the largest market for Aes-210 is distal ulcerative colitis, the Company has chosen to target pouchitis as the first clinical indication. There are several reasons for this choice. Pouchitis is an orphan indication and Aes-210 has already been granted Orphan Drug status by the FDA. This confers a number of regulatory advantages in the development of the drug, including the potential for marketing approval based on more limited clinical trial data than would be required for other indications. Consequently, choosing pouchitis as the first clinical indication offers the possibility of achieving marketing approval faster and at a lower cost.
In addition to the regulatory advantages, there are also clinical reasons why pouchitis makes an attractive initial target indication for Aes-210. In general, individuals with pouchitis represent a much more homogeneous patient population than those of patients with alternative indications such as distal ulcerative colitis (DUC). This means the clinical “signal” for efficacy, if achieved, can potentially be obtained with a smaller sample size in a pouchitis trial than for alternative indications. Smaller requisite sample size means trial enrollment can potentially be achieved faster and the cost of the trial will lower for pouchitis than for alternative indications.
Assuming successful development of Aes-210 for pouchitis, AesRx plans thereafter to seek development of Aes-210 for other indications such as DUC and radiation proctitis.
Phase 2 Clinical Trial: CAPTURE Study
The Company is currently testing Aes-210 for the treatment of pouchitis in a double-blind, dose-escalating, placebo-controlled, cross-over Phase 2 clinical trial named the CAPTURE study (Clotrimazole Adult and Pediatric Therapy Utilizing Retention Enemas). The first part of this trial was funded under a grant from the FDA’s Orphan Drug products group. The CAPTURE study is expected to enroll a total of 34 patients with active pouchitis for whom currently available standard therapies have failed. The patients will be dosed at four dose levels: 2500mg, 4000mg, 6000mg and 7500mg each dose to be administered once daily. Each patient will receive the same dose for the entire time of his/her participation in the trial. The primary endpoint of this Phase 2 clinical trial is a reduction in the pouchitis disease activity index (PDAI), a composite index of clinical, gross, and histologic parameters that represents an established and previously validated continuous-scoring system for this indication.
The CAPTURE study has to date been conducted at Children’s Hospital Medical Center, a Harvard University-affiliated hospital. AesRx expects to open additional sites. The first dose cohort of the trial (2500mg and 4000mg), which was designated Cohort A, enrolled and treated a total of 11 patients. The results for Cohort A have been unblinded and an analysis was conducted by an independent data safety monitoring board (DSMB) convened to review the safety and early efficacy of the trial. The analysis indicated a dose-dependent decrease in the PDAI index score. Of the treated patents, 63 percent experienced a drop of 3 points or more in their PDAI score compared to 33 percent in the placebo group (average PDIA score at entry for all patients was 12 on a scale of 18). In addition to the primary endpoint of PDAI, a secondary endpoint —quality of life—was measured using a validated scoring system known as the Reference Form for Inflammatory Bowel Disease Patient Concerns (RFIPC). For the patients treated with Aes-210, a substantial increase in quality of life was noted (p<0.07) as measured by the RFIPC. There was also noted a dose-dependent decrease in fecal urgency and abdominal cramping as well as a decrease in stool frequency.
The results of Cohort A with regard to the trial’s primary endpoint are illustrated in the following graph:
Based on the DSMB’s findings, the DSMB allowed the study to continue to Cohort B, which will treat patients at two higher dose levels: 6000mg and 7500mg per day.
Upon successful completion of the CAPTURE study, AesRx plans to commence a pivotal Phase 3 study of Aes-210 for the treatment of pouchitis. Assuming a successful completion of the Phase 3 study, AesRx believes it will be in a position to file with the FDA for regulatory allowance to market Aes-210 for the treatment of pouchitis.