An estimated 700 million people are adversely affected by irritable bowel syndrome (IBS), that is one out of every ten people in the world. While IBS is not a life-threatening disease, it has a significant impact on quality of life. Small Intestine Bacterial Overgrowth (SIBO) is implicated in majority of the cases of irritable bowel syndrome (1). Beyond digestive disorders, SIBO has also been shown to have a positive correlation with a wide spectrum of diseases including Alzheimer’s (2), Parkinsons (3), Multiple Sclerosis (4), Coronary Artery Disease (5), Psoriasis (6), and Cancer (7). The treatment of SIBO is multi-faceted, but a major aspect is addressing bacterial overgrowth via use of antibiotics.
The standard treatment of SIBO is a non-absorbable antibiotic – Rifaximin for patients with Diarrhea. Rifaximin is paired with another antibiotic – Neomycin for patients with Constipation. The treatment, if able to resolve SIBO as measured by a standardized breath test is shown to have significant improvements in IBS symptoms. The problem is that these antibiotics work only 35% of the time (8). To make matters worse, SIBO comes back 44% of the time with aggravated symptoms nine months after antibiotic therapy (9).
The microbes involved in pathogenesis of SIBO are primarily gram-negative bacteria including but not limited to E. Coli, Klebsiella Pneumoniae, Actinomycetes, and Citrobacter spp. (1). In addition, methanogenic archaea are implicated for SIBO associated with constipation. The current portfolio of antibiotics has a poor efficacy for eliminating these bacteria.
The current clinical pipeline for SIBO treatment is severely depleted due to lack of economic attractiveness, and inherent challenges in eliminating gram-negative pathogens. Therefore, a target product profile is proposed below to bring all the key stakeholders together and develop a new non-absorbable and non-systemic oral antibiotic for SIBO.
Target Product Profile
- Indication For Use: Treatment of small intestine bacterial overgrowth
- Target Population: Adolescents and adults
- Safety / Tolerability: Comparable to current therapies with rifaximin and neomycin, no toxicity signals in preclinical reproduction toxicity studies.
- In-vitro Activity: against gram negative pathogens including E. Coli, Klebsiella Pneumoniae, and Citrobacter spp.; low cross resistance to known antibiotic classes (new class/target/ mode of action); low propensity for mutational resistance development
- Clinical Efficacy: Non-inferior clinical activity to current therapies in small intestinal bacterial overgrowth: rifaximin and neomycin. Clinical trials should include elderly patients (> 65 years).
- Formulation: Tablets / Capsules
- Dose Regimen: 1–3x daily, treatment duration up to 14 days
- Route of Administration: Oral
- Product Stability and Storage: Heat stable, 3-year shelf life in hot tropic / humid climate (simulated with 30°C and 65% relative humidity)
- Pharmacokinetics: data available to support non-absorbable use in gastro-intestinal tract (> 80% concentrations and activity in feces)
- Drug Interactions: Comparable to current therapies, no drug-drug interactions (DDIs) with commonly prescribed drugs in the patient population
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8. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. The American Journal of Gastroenterology. 2003 Feb 1;98(2):412–9.
9. Lauritano EC, Gabrielli M, Scarpellini E, Lupascu A, Novi M, Sottili S, et al. Small intestinal bacterial overgrowth recurrence after antibiotic therapy. Am J Gastroenterol. 2008 Aug;103(8):2031–5.