Non-antibacterial preclinical candidates

In addition to Cempra's clinical stage antibacterial programs, non-antibacterial candidates have been identified with the potential to treat inflammatory, endocrine and gastric motility diseases.

Macrolides have a proven history of safety and oral bioavailability and have potential as therapeutic agents. In addition to their well known antibiotic activity, erythromycin and its analogs possess non-antibiotic activities that can be optimized to yield products for treating inflammatory diseases, such as chronic obstructive pulmonary disease and psoriasis, endocrine-related diseases, such as endometriosis, uterine fibroids, precocious puberty, prostate and breast cancer and intestinal motility in diseases such as diabetic gastroparesis.

Cempra has screened its library of more than 500 macrolides in functional assays for motilin receptor activity, anti-inflammatory activity and GnRH receptor antagonism. The screening was accomplished in partnership with international experts in each field.

Modification of the macrolide ring at the 5-position also allows Cempra to create non-antibiotic macrolides by eliminating bacterial ribosome binding activity. Several compounds have been identified through screening programs that could potentially address therapeutic needs in the areas of inflammation, diabetic gastroparesis and cancer.

Anti-inflammatory Lead Compounds

The discovery that erythromycin is a useful treatment for COPD and diffuse panbronchiolitis, potentially fatal disorders of the airways, has focused attention on the anti-inflammatory effects of macrolides. Clinical and experimental data indicate that macrolides have anti-inflammatory properties that function independently from their antibacterial effects. They are being used to decrease the steroid dose in chronic inflammatory diseases such as COPD and persistent asthma.

Erythromycin and its analogs have been shown to increase HDAC2 levels by activating the HDAC2 promoter, which has been shown to be down regulated in COPD and other chronic inflammatory diseases. Cempra has screened its library and found several potent candidate compounds that increase HDAC2 levels with little or no antibiotic activity. Elevating HDAC2 levels should re-sensitize lung tissue to corticosteroids and bolster their anti-inflammatory activity. These lead compounds have been shown to decrease cytokine expression and increase sensitivity to steroids in stimulated inflammatory cells. These compounds are in preclinical development.

Chronic Obstructive Pulmonary Disease (COPD)
COPD is caused by oxidative stress induced by tobacco smoke or other inhaled pollutants. Inhalation of these agents induces an inflammatory response in the small airways and alveoli that results in airway remodeling and increased resistance to airflow. Pharmaceuticals either treat the symptoms (bronchodilators) or reduce the underlying inflammation (corticosteroids). There is nothing available to alter the course of the disease.

Psoriasis is a chronic immune-mediated hyper-proliferative inflammatory skin disease in which a cytokine network concept is established. The disease presents as plaques that appear anywhere on the body. It can be disfiguring and diminishes a patient's quality of life. 

Available treatments include topical therapies, phototherapy, oral immune mediators such as methotrexate and cyclosporine, and injectable anti-TNF agents. All these therapies present tolerability and/or long-term safety issues and the anti-TNF agents are quite expensive.

Cempra has evidence that the HDAC2 up-regulation generated by macrolides may be an effective approach to treat chronic inflammation in diseases like COPD and psoriasis.

Motilin Receptor Activity

Motilin is a hormone released by enterochromaffin cells in the upper small intestine, which helps control the pattern of smooth muscle contractions in the upper gastrointestinal (GI) tract. It is secreted into the circulation at 100-minute intervals between meals to stimulate GI motility in a process known as a migrating motor complex (MMC). The MMC is a wave of activity that sweeps the stomach and small intestine of undigested material during the fasting state.

A disturbance in motilin function can result in motility disorders such as irritable bowel syndrome and diabetic gastroparesis or delayed gastric emptying. Erythromycin and related antibiotics are known to be motilin agonists.

Through its screening program, Cempra has identified macrolide candidates that contain motilin agonist activity (without antibacterial activity). Three leads have been selected that are active in the motilin receptor binding assay as well as in rabbit duodenal strip contraction assays. These compounds are in preclinical development.

Gonadotropin-releasing Hormone (GnRH) Receptor Antagonism

Gonadotropin-releasing hormone (GnRH), previously called luteinizing hormone-releasing hormone (LHRH), is secreted from the hypothalamus and binds to the GnRH receptor in the pituitary gland, stimulating the release of the gonadotropins, luteinizing hormone and follicle-stimulating hormone.

GnRH antagonists inhibit gonadal functions and are useful for treating endocrine-related conditions such as endometriosis, uterine fibroids and precocious puberty, as well as several steroid-dependent malignancies, including breast and prostate cancers. Most GnRH antagonists are synthetic peptides, thus their activity is short-lived, resulting in the need for daily injections or injections of one-to-three month depot formulations. An oral, safe GnRH antagonist for long-term use is needed to simplify treatment and optimize therapeutic flexibility.

Macrolide analogs have been identified with potent GnRH receptor antagonist activity. Cempra is screening its library for GnRH antagonists that have potent GnRH receptor antagonist activity but lacking antibacterial activity.