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As the standard first-line treatment for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and general pain reduction, naproxen and other NSAIDs are effective, but can induce ulceration and bleeding of the digestive tract, with much higher incidence in patients with comorbidities and in the elderly. In these patients, COX-2 selective NSAIDs (e.g., celecoxib) offer only a modest improvement in terms of gastrointestinal (GI) safety, but their use is associated with significant cardiovascular toxicity. For example, when COX-2 selective NSAIDs are co-administered with aspirin—a common practice in older patients, where both osteoarthritis and heart disease are more prevalent—GI protection is foregone.
The drug remained GI-safe when given to animals with compromised mucosal defense or pre-existing ulcers—situations in which selective COX-2 inhibitors cause ulcers and bleeding in humans. It also remained safe when co-administered with aspirin. In addition, otenaproxesul did not elevate blood pressure when administered to hypertensive rats, in contrast to a significant hypertensive effect with naproxen.
In 2018, Antibe completed a Phase IIB gastrointestinal safety trial of otenaproxesul in 244 healthy volunteers. The study was designed to demonstrate the superiority of otenaproxesul compared to naproxen, one of the most prescribed NSAIDs in the US. One group was treated for fourteen days with otenaproxesul (250 mg once daily), while the other group was treated for the same period with the standard prescription dose of naproxen (500 mg twice daily, totaling 1,000 mg per day). The primary endpoint for the study was the incidence of gastric or duodenal ulcers of at least 3 mm diameter with unequivocal depth, considered the ‘gold standard’ in assessing the gastrointestinal safety of NSAIDs. Otenaproxesul successfully met the primary endpoint in the study.
Subjects on otenaproxesul exhibited an ulceration rate of 2.5% (3/118) versus an ulceration rate of 42.1% (53/126) for subjects on naproxen at the end of the treatment period, with a very high degree of statistical significance (p<0.0001). The drug was also well tolerated.
In June 2020, Antibe reported positive top-line results from its Phase IIB dose ranging, efficacy study designed to validate the efficacy of otenaproxesul in reducing pain. This was a large study, involving 39 sites and 381 participants with osteoarthritis of the knee.
Subjects were randomized to placebo or one of three doses of otenaproxesul administered once daily: 150 mg, 200 mg or 250 mg. The primary endpoint was the change in the WOMAC pain subscale scores (the ‘gold standard’ in clinical pain assessment) over a fourteen-day treatment period. The results showed a high degree of statistical significance for the 200 mg and 250 mg doses, thereby demonstrating substantial efficacy in pain reduction. The lowest dose, although not powered for statistical significance, showed a distinct trend toward efficacy.
Further validating the WOMAC pain measures, otenaproxesul delivered profound COX inhibition, exceeding 90% for all doses, at very high degrees of statistical significance (p < 0.0002).
The chart above depicts the robust pain efficacy of otenaproxesul: The vertical bars depict the improvement in WOMAC pain subscale score delivered by each of three doses after two weeks of administration. (Further information about these WOMAC scores is available in our Corporate Presentation.) The horizontal dotted-line indicates the average efficacy of NSAIDs after twelve (or more) weeks, as set out in Comparative Pain Reduction of Oral Non-steroidal Anti-inflammatory Drugs and Opioids for Knee Osteoarthritis: Systematic Analytic Review; Osteoarthritis and Cartilage, S.R. Smith et al., 2016.
Complementing the drug’s pain efficacy, WOMAC results for the ‘real world’ therapeutic benefits of stiffness and difficulty in performing daily activities (DPDA) demonstrated efficacy at a very high degree of statistical significance compared to placebo. Patients also showed no change in blood pressure during the trial, in line with previous clinical and preclinical studies.
This Phase IIB efficacy study replicates the success of an earlier Phase IIA open label, efficacy study that concluded in August 2016. The primary endpoint of that study was the clinical assessment of pain over the ten-day course of treatment at 250 mg once-daily (n = 12), delivering a significant WOMAC pain score reduction on day 10, at a very high level of statistical significance in comparison to baseline pain (p<0.001).
1. Post hoc analysis. Results do not necessarily predict future efficacy results.
2. WOMAC pain subscale scores based on 500-point Likert scale; figures normalized to 100mm scale; shown with 95% confidence interval.
3. NSAID study data drawn from Comparative Pain Reduction of Oral Non-steroidal Anti-inflammatory Drugs and Opioids for Knee Osteoarthritis: Systematic Analytic Review; Smith; S.R., Deshpande, B.R., Collins, J.E., Katz, J.N., Losina, E.; Osteoarthritis and Cartilage; 24: 962-972, 2016.
4. Adjusted mean change from baseline computed with assumption that subjects who withdrew early due to insufficient efficacy had zero (0) change from baseline WOMAC pain subscale score.