Development of a Long-Acting Lidocaine Formulation for the Treatment of Interstitial Cystitis/Bladder Pain Syndrome

Principal Investigator: ZUGATES, GREGORY
Institution Receiving Award: ALIVIO THERAPEUTICS INC.
Program: PRMRP
Proposal Number: PR170876
Award Number: W81XWH-18-1-0566
Funding Mechanism: Technology/Therapeutic Development Award
Partnering Awards:
Award Amount: $3,290,346.00


Interstitial cystitis (IC), or bladder pain syndrome (BPS), is a chronic disease that is characterized by the main symptoms of bladder pain and increased urinary frequency. It is a widespread condition that is estimated to afflict almost 8 million women across the United States. Although the cause of IC/BPS is unknown, the symptoms for many patients can be attributed to inflamed sores on their bladder wall. Irritation of these sores occurs as the bladder fills with urine, which causes patients to urinate more often to relieve the pain. As a result, patients typically urinate every hour or so, which can be extremely debilitating and significantly reduce their quality-of-life. As in the civilian community, IC/BPS is a common gynecological issue that requires treatment in the Armed Forces. Patients with advanced disease not only face the physical and psychological complications that come with pain and urgency, but also may be unable to deploy for combat or even perform active duties in non-combat situations. There are dozens of off-label therapies used to treat IC/BPS patients, but none are effective in consistently alleviating the pain and healing the inflamed sores that cause the symptoms. One particularly effective therapy is lidocaine, which can be administered through a catheter and provide short-term pain relief that lasts several hours, just as it does for dental procedures. It also has many recently discovered anti-inflammatory effects that could be leveraged to treat bladder lesions.

The primary objective of our program is to develop a long-acting lidocaine therapy that can relieve IC/BPS pain and treat the inflamed bladder sores. This goal can be accomplished using the Alivio hydrogel technology, which can deliver an array of drugs to inflamed tissues. Our technology works by combining the drug with a hydrogel coating that preferentially sticks to inflamed tissues. The drug is subsequently released by the patient’s own enzymes within the diseased tissue. In this way, the disease guides and controls drug treatment at the site of inflammation, with minimal impact on the surrounding healthy tissue. Importantly, the material used to deliver the drug is a food preservative that is considered "generally-regarded-as-safe," or GRAS, by the U.S. Food and Drug Administration. Our proposed product concept consists of a water-based formulation that contains lidocaine encapsulated in this GRAS material. The formulation can be administered to the inflamed bladder using standard supplies that every urologist is familiar with, such as syringes and catheters. In our preliminary work, our lead formulation was tested in a rat model of IC/PBS, which resulted in full pain relief for the entire study duration. In contrast, the free lidocaine comparator only provided two hours of pain-relief, which is consistent with lidocaine’s known short duration of effect.

The main objective of our proposed project is to build on our proof-of-concept work by optimizing and advancing a lidocaine-loaded formulation through preclinical efficacy, safety, and manufacturing to enable clinical evaluation. We have identified four specific aims to support this objective:

Aim 1: Optimize lidocaine-loaded formulations for duration of analgesia in two rat IC/BPS models. We propose to balance the drug-loading characteristics of the formulation to achieve both short- and long-term analgesia while concurrently studying the anti-inflammatory effects and pharmacokinetic properties.

Aim 2: Determine the safe formulation dosing range in healthy beagle dogs. Two studies are proposed to establish the intravesical procedure and determine the maximum tolerated dose (MTD), both of which will enable broader preclinical safety studies.

Aim 3: Demonstrate hydrogel safety in dose-ranging finding (DRF) and GLP toxicology studies. The optimized formulation will be advanced into DRF and definitive GLP studies that replicate the intended clinical use and provide a comprehensive safety analysis to support an IND submission.

Aim 4: Complete transfer and process scale-up at a contract manufacturing organization (CMO) to enable clinical batch production. Production capabilities will be developed at a CMO with good manufacturing practices to generate clinical-grade material for human trials.

At the completion of this project, we will have a clinically ready therapy for IC/BPS with demonstrated safety and efficacy that has multiple benefits for the military and civilian communities. For patients, it can provide immediate pain-relieving effects that enable a fast return to active duty while treating the underlying inflammation that is the hallmark of chronic cystitis. By using standard medical supplies and a fast out-patient procedure, the product can be leveraged even at far forward medical facilities. And in the long-term, we envision healthcare cost savings with an effective therapy that can improve the physical and mental quality of life for our military members suffering from IC/BPS.