Late last month, Johnson and Johnson (J&J) announced the results of Phase III clinical trials comparing tapentadol extended release compared to oxycodone controlled release and placebo. In this study, J&J reported that tapentadol ER was superior to placebo on multiple measures, including a significantly higher percentage of patients achieving at least a 50% improvement in pain intensity versus placebo.
The study also included oxycodone controlled release as an active comparator. They found oxycodone to be superior to placebo in terms of average pain intensity at Week 12. However, the data showed that oxycodone CR did not differ from placebo in patients with at least 30% and at least 50% improvement in average pain intensity.
This result provides an excellent example of why clinical development can be so difficult in Pain, especially the market for chronic pain drugs. A few points:
Three-arm Studies – Few therapeutic areas essentially require three arm studies, where the arms are the drug under study, placebo, and an active comparator. The active comparator data would enable the innovator to suggest equal or superior efficacy and safety to a marketed product. Yet the release does not directly compare tapentadol and oxycodone.
Which Endpoint? – What is the most relevant endpoint, or basket of endpoints? Is it 30% improvement in pain intensity after Week 12? 50%? Why Week 12? Careful readers will note that the placebo effect in these trials is also strong, a common occurrence in chronic pain studies.
Dosing – Subjects in both the tapentadol and oxycodone groups were allowed to take various doses of the drug during the study. For example, tapentadol subjects consumed doses between 100 mg and 250 mg twice a day. Similarly, oxycodone subjects were dosed at a range between 20 mg and 50 mg twice a day. What if more tapentadol subjects took higher doses of their drug, while oxycodone subjects took lower doses? Would this bias the results towards tapentadol? Is the reverse true?
These points suggest that developing new drugs in chronic pain is incredibly challenging, not only for the pharmaceutical companies, but also for the physicians who must review these data and make an informed decision.
Yet the need for safer, let alone more effective, chronic pain medications has never been more needed. As the COX-II inhibitors have effectively disappeared from the market (especially in the US), a gap exists between medications for mild-moderate pain (i.e., ibuprofen, acetaminophen with codeine) and more severe pain (i.e., opioids).
Tapentadol is an exciting new product for the treatment of moderate to severe acute pain (Nucynta®), It was approved by the US FDA in November, and the extended release version is being developed for chronic use.
Unfortunately, many companies have avoided the chronic pain market because of a relative lack of innovative new molecules and mechanisms of action. While novel formulations of older drugs may provide incremental value, they rarely receive the pricing and reimbursement to make the development investment worthwhile for pharmaceutical companies. Further, as demonstrated above, the clinical development program is not trivial. Multi-arm studies are increasingly necessary both for US and European regulatory bodies.
All of these factors makes the out-licensing of pain products a tremendous challenge for innovators. But all is not lost. Compounds which are safe alternatives to the COX II inhibitors may attract substantial attention from the licensing community.