Hexokinase Inhibitors
Overview
In benign prostatic hyperplasia, hyperplasia of the prostate gland increases the number of smooth-muscle cells, and smooth-muscle tension causes bladder outlet obstruction leading to lower urinary tract symptoms . Drugs that reduce total prostate volume, either by slowing cell multiplication or inducing cell apoptosis, reduce symptoms of benign prostatic hyperplasia. Emerging therapies, such as hexokinase inhibitors, that can take advantage of this strategy offer a different approach to treatment than drugs that are currently available, and they may avoid associated side effects such as orthostatic hypotention, reverse ejaculation, decreased libido, and impotence.
Mechanism Of Action
Recent research has shown that hexokinase inhibitors have the ability to disrupt glycolysis. Because prostate cells depend more on glycolysis than the citric acid cycle for energy to maintain and regenerate tissue, hexokinase inhibitors can cause prostate cell death, which relieves bladder outlet obstruction. Reducing prostate size through metabolic targeting is a novel method of treating benign prostatic hyperplasia. So far, there is only one drug in this class in active development for benign prostatic hyperplasia, and it has shown promise.
Lonidamine
Lonidamine, also known as TH-070, originated from the company Angelini, which licensed development outside of Europe to Threshold Pharmaceuticals. Lonidamine is currently marketed by Pfizer in Italy under the brand name Doridamina for the treatment of various cancers. For benign prostatic hyperplasia, lonidamine has entered Phase III clinical trials in Europe and Phase II trials in the United States as part of a registrational program approved by the FDA. The Phase II and Phase III multicenter, double-blind, randomized trials will involve approximately 200 and 480 men and will last 4 weeks and 4.5 months, respectively. The goal of these trials is to investigate patients’ dose-response in terms of safety and efficiency.
Results from a Phase II clinical trial conducted in Italy were published in August 2005. Thirty benign prostatic hyperplasia patients were treated with 150mg of oral lonidamine for 28 days, and follow-up observation was continued for six months after the end of therapy. Researchers found that lonidamine is well tolerated and correlates with a significant decrease in prostate volume and International Prostate Symptom Scores. On day 28, the average decrease in prostate size was 11.2% (p < 0.001). Fifteen patients (50%) had a reduction of at least 10%. Interestingly, there was no significant change in the sizes of the transitional zone of the prostate. The average decrease in International Prostate Symptom Scores was 7.3 points (p < 0.001); 47% of patients had an improvement of more than 7 points. Patients with higher baseline International Prostate Symptom Scores were more likely to have greater improvements in symptom scores. By day 200 (the last day of follow-up), International Prostate Symptom Scores had decreased further to a change of almost — 10 points.
In addition to reductions in prostate size and symptom score, lonidamine treatment correlated with an improvement in measures of voiding symptoms, Qmax, and post-void residual volume. After 28 days of active treatment and 6 months without treatment, Qmax increased by 4.3 mL/s. Average residual volume reduced from 82 cc at baseline to 32 cc after 28 days of treatment. Lonidamine also decreased PSA levels by 17.8% at day 28 and by 14.8% at day 200.