Gastrointestinal Pipeline Drugs

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The American Journal of Pharmacy Benefits, October 2010, Volume 2, Issue 5

The continuing education article reviews emerging therapies for the treatment of gastrointestinal disorders.

Introduction

This continuing education article will review several drugs that have recently undergone, or are currently undergoing, late-phase investigation for the treatment of specific gastrointestinal (GI) disorders. Most of these drugs coming down the pipeline are for the treatment of inflammatory bowel disease (IBD) and diarrhea.

IBD encompasses 2 major categories of disease, ulcerative colitis (UC) and Crohn’s disease. While they share many characteristics, they have distinct pathologies.1 Crohn’s disease alone is estimated to affect more than 1 million people in North America.2 Standard therapies for both disorders include immunomodulators, corticosteroids, antibiotics, and 5-aminosalicylates; however, each treatment has limitations, including inconsistent mucosal healing.2 Recent focus has turned to the development of agents that target the infl ammatory cascade.

Clinical research on diarrhea has focused on 2 distinct problems, Clostridium difficile (C difficile) infection (CDI) and traveler’s diarrhea. CDIs are a major health concern, difficult to treat, and are often induced by antibiotics used to treat other infections.3 While metronidazole and vancomycin successfully treat these infections, new virulent strains have emerged, resulting in treatment failures and an increased need for new agents.3 Traveler’s diarrhea is the most common illness affecting travelers. It is estimated to occur in up to 55% of those visiting developing nations.4 Traveler’s diarrhea is not a major health concern because it generally resolves on its own, but it can result in dehydration and further complications.4

Clinical trials are also evaluating agents for the treatment of irritable bowel syndrome (IBS) and short bowel syndrome (SBS), and for the prevention of postoperative nausea and vomiting (PONV).

Inflammatory Bowel Disease

Adalimumab

Adalimumab is a recombinant monoclonal antibody that blocks the activity of tumor necrosis factor (TNF). Clinical trials have demonstrated its effectiveness in treating patients with Crohn’s disease who are nonresponders or intolerant to infl iximab. As such, the US Food and Drug Administration (FDA) approved its use in patients with moderately to severely active Crohn’s disease who have not had an adequate response to conventional therapy, or those who donot respond to or are intolerant to infliximab.5 Clinical trials are under way to determine the effectiveness of adalimumab in the treatment of patients with UC who previously failed therapy with infliximab. Results from a study of 10 patients with UC (who previously responded to infliximab and then lost response or became intolerant to treatment) did not support the use of adalimumab in UC. Although 40% of patients responded to treatment, 60% had no response. It is important to keep in mind, however, that the sample size was very small and there was no placebo group.6 In a 24- week uncontrolled trial with 20 patients, 50% had a clinical response. Although these results were more encouraging, the study was uncontrolled and had a small sample size.7 Phase 3, multicenter, randomized, double-blind, placebocontrolled trials designed to evaluate the efficacy and safety of adalimumab in UC have been completed; however, the results have yet to be published.8

Alicaforsen

Alicaforsen is a first-generation phosphorothioate-modified antisense oligodeoxynucleotide.9 Alicaforsen exerts its pharmacologic action by inhibiting intercellular adhesion molecule-1 (ICAM-1) protein expression. ICAM-1 has several functions in inflammatory processes, including leukocyte recruitment and activation, which plays an important role in UC and pouchitis.9 Alicaforsen was formulated as a retention enema to minimize systemic bioavailability and for the purpose of applying the drug directly to the colon.9 A phase2, dose-ranging study demonstrated that alicaforsen was effective and well tolerated in patients with left-sided UC, and suggested that alicaforsen may exhibit disease-modifying effects.10 Because oral mesalazine (5-aminosalicyclic acid) and other traditional therapies, such as steroids, have higher systemic absorption, alicaforsen may be advantageous. Although a mesalazine enema is available, and it is the current mainstay of treatment, a study comparing alicaforsen and mesalazine enemas demonstrated similar efficacy. The duration of response, however, was much longer with alicaforsen (128-146 days) than mesalazine (54 days).9 This supports preferential use of alicaforsen over current diseasemodifying therapies.9

Golimumab

Golimumab is a recombinant human monoclonal antibody that targets TNF and neutralizes it.11 TNF is a pro-inflammatory cytokine in the normal inflammatory process. In chronic autoimmune conditions, such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and UC, TNF expression is upregulated, leading to tissue destruction and disease progression. Golimumab is already approved by the FDA for the treatment of moderate to severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis.5 Subcutaneous and intravenous formulations of golimumab are currently being evaluated in phase 3 clinical trials to determine their safety and efficacy in UC. Golimumab is considered to be a “next generation” antibody because it is a fully human antibody and it lacks the need for in vitro modification during production. It was believed that golimumab would invoke less of an immune response than infliximab. However, preliminary data from studies show that combination therapy with methotrexate is superior to monotherapy, suggesting that there is an unexpected immune response that will require further investigation. Beneficial treatment effects have been observed in patients who received previous anti-TNF therapy. Additionally, golimumab may offer a more convenient dosing schedule than infliximab because it has a longer half-life, allowing for treatment once every 4 weeks instead of every 2 weeks.12

Vedolizumab

Vedolizumab is a novel monoclonal antibody that acts as an alpha4 beta7 integrin antagonist in the gut endothelium.13 In a small clinical trial, patients with UC given vedolizumab had a higher rate of remission than those given placebo. A follow-up trial in patients with Crohn’s disease failed to meet the defined primary end point, but the higher of the 2 dose groups was significantly better than placebo. Based on pharmacodynamic data, the authors suggested that a higher dose may be necessary because there was inadequate saturation of alpha4 beta7 integrin.14

Mesalamine Rectal High Concentration

Although a wide range of mesalamine formulations are available for the treatment of UC, compliance is still a problem. A once-daily mesalamine suppository (administered in the evening) is being studied in clinical trials for the treatment of proctitis. In previous studies, a dose of 1 gram was found to be as effective as the standard regimen of 0.5 gram 3 times daily. Reduction in the dosing frequency has been shown to increase patient adherence with treatment regimens. Although the study did not specifically address patient compliance, it clearly demonstrated that patients preferred the once-daily regimen over administration 3 times daily. Also, in cases where the disease is limited to distal UC, rectal therapy is considered a first-line strategy according to several guidelines due to its effectiveness and favorable safety profile compared with oral mesalamine.15

Irritable Bowel Syndrome

Asimadoline

Asimadoline is a kappa-opioid receptor agonist with a diaryl acetamide structure that is being investigated for the treatment of acute pain in patients with IBS.16,17 Kappa-, mu-, and delta-opioid receptors, located in the peripheral and central nervous systems, modulate visceral perception of pain. Currently available opioid agonists exert their action by binding to μ receptors. Although these agents are effective in reducing pain, they are associated with constipation and dependence, which prevents their use in IBS. Kappa-opioid receptors play a role in the inhibition of the perception of noxious stimuli from the GI tract and they appear to be free of the aforementioned adverse effects seen with m-opioid receptor agonists.16 Asimadoline reduces visceral nociceptive reflux behavior associated with colorectal distention. In animal models, it has been shown to decrease the area under the pressure-pain curve versus placebo.17 One phase 2 study in female patients with IBS that evaluated on-demand dosing with asimadoline did not demonstrate efficacy in reducing IBS-related abdominal pain.18 A 12-week phase 2 study did not demonstrate significant treatment effects in the overall IBS population; however, improvement was observed in patients with diarrhea-predominant IBS (D-IBS).17 A 12-week phase 3 study investigating the effects of asimadoline on abdominal pain and bowel movements in patients with D-IBS is currently under way.19

Linaclotide

Linaclotide is a novel drug being investigated for the treatment of IBS and constipation. Linaclotide stimulates intestinal fluid secretion and transit through agonism of the guanylate cyclase C receptor. In a study evaluating the efficacy of linaclotide (75—600 micrograms) in patients with chronic constipation (n = 310), those given linaclotide demonstrated an increase in the weekly rate of spontaneous bowel movements compared with placebo.20

Diarrhea

Crofelemer

Crofelemer, a naturally occurring compound isolated from the plant Croton lechleri, is a proanthrocyanidin oligomer that has been used by native South Americans for the treatment of secretory diarrhea.21 The exact mechanism of action of crofelemer has yet to be identified; however, it is believed to inhibit apical membrane cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channels of epithelial cells lining the intestine, or to block CFTR channels directly.21 Inhibition of CFTR channels may decrease stool weight and frequency due to decreased chloride ion secretion in GI fluid tract cells, thereby providing symptomatic relief of diarrhea.21

The bacterial endotoxins Vibrio cholerae and Escherichia coli activate CFTR channels and increase chloride and fluid secretion. Therefore, crofelemer may be effective for the treatment of secretory diarrhea caused by these endotoxins.21 Current antidiarrheal medications inhibit peristalsis and can worsen endotoxin effects by inhibiting gastric motility. Crofelemer is unique in that it does interfere with GI transit time.21 Crofelemer has been studied in the treatment of AIDS-associated diarrhea, traveler’s diarrhea, D-IBS, and infectious diarrhea.21 Favorable results were observed in phase 2 clinical trials evaluating its safety and efficacy. Ongoing phase 3 studies will determine the clinical efficacy of crofelemer and its long-term safety. 21 Large, head-to-head studies comparing crofelemer with standard medications used to treat secretory diarrhea are also needed.

Fidaxomicin

Fidaxomicin is a new macrocyclic antibiotic that is a member of the tiacumicin family. This narrow-spectrum antibiotic works by inhibiting bacterial protein synthesis through inhibition of transcription, relying upon the sigma subunit of RNA polymerase.3 Fidaxomicin is currently being investigated for use in mild to moderate infections caused by C difficile, an organism responsible for 15% to 25% of all antibiotic-associated diarrhea. Specific characteristics of fidaxomicin, including minimal systemic absorption, activity against gram-positive aerobes and anaerobes, and high fecal concentrations, make it an excellent candidate in the treatment of CDIs.3 Unpublished results from a phase 3 noninferiority study demonstrate that fidaxomicin is safe and effective for CDI compared with oral vancomycin. Another phase 3 study comparing fidaxomicin to oral vancomycin in CDI has been conducted; however, the results are not available.22 Further studies are needed to compare fidaxomicin and oral metronidazole, the current first-line therapy for CDI.3Prulifloxacin

Prulifloxacin is a new fluoroquinolone antibiotic with activity against gram-positive and gram-negative pathogens. Prulifloxacin is a prodrug that is converted to its active metabolite, ulifloxacin, following oral administration. A phase 3 clinical trial assessing the safety and efficacy of prulifloxacin in the treatment of infectious diarrhea,specifically traveler’s diarrhea, has been completed and another trial is ongoing. Evidence suggests that the active metabolite has broad-range activity against a global collection of gastroenteritis pathogens, with a susceptibility pattern similar to ciprofloxacin. However, ulifloxacin is 2 to 4 times more potent than ciprofloxacin. Compared with other fluoroquinolones, prulifloxacin levels remain high in the bowel because only 50% is absorbed—giving it a unique pharmacokinetic profile. Studies are evaluating a 3-day course of therapy with 600 mg once daily.23

Rifaximin

Rifaximin is a member of the rifamycin class of antimicrobials that exerts its bacteriocidal effect by inhibiting bacterial DNA-dependent RNA polymerase. Rifaximin is already approved by the FDA for the treatment of traveler’s diarrhea, but clinical trials are assessing its effectiveness in CDI.5 Structurally related to rifampin, the drug has been modified so that systemic absorption is minimal, yielding high concentrations in the GI tract. While studies have identified that spontaneous resistance develops rapidly with this drug, this may not be clinically significant, because high concentrations are achieved after oral administration.24,25

Other GI Disorders

Fosaprepitant

Oral aprepitant is the only FDA-approved neurokinin-1 receptor antagonist for the prevention of PONV.5 Fosaprepitant is an intravenous, water-soluble phosphoryl prodrug of aprepitant.5,26 Thirty minutes after intravenous administration, fosaprepitant is converted to aprepitant by phosphatase enzymes.26 No studies are currently evaluating fosaprepitant for the treatment of PONV. Considering the complications associated with PONV and the increased focus on patient satisfaction, fosaprepitant could be another option for practitioners, even though cost-effectiveness remains a concern.5

Teduglutide (ALX-0600)

Teduglutide is a recombinant human glucagon-like peptide-2 (GLP-2) analogue that is resistant to enzymatic degradation by dipeptidyl peptidase-4. It is currently being studied for the treatment of patients with SBS resulting from surgical resection secondary to conditions such as Crohn’s disease, mesenteric infarction, congenital anomalies, and multiple structures due to adhesions or radiation. GLP-2 is an endogenous meal-stimulated hormone that is secreted primarily from the terminal ileum and colon that acts to slow gastric emptying, reduce gastric secretions, increase intestinal blood flow, and stimulate growth of the small and large intestine. Absence or decrease of endogenous hormone secretion can lead to gastric hypersecretion and rapid intestinal transit time, causing patients to suffer from malnutrition, dehydration, and weight loss. Although some patients can maintain weight through hyperphagia, fluid and electrolyte balance remains difficult and generally requires supplemental fluid therapy. Parenteral nutrition is often required in these patients, but it is associated with serious complications such as catheter sepsis, venous occlusions, and liver failure. While clinical trials have included a small number of patients, significant results have been demonstrated; larger, randomized controlled studies are needed to confirm results.27