Withdrawn painkiller returns aiming to fight opioid crisis

Before Merck voluntarily withdrew Vioxx from the market in 2004 it was one of the world’s best-selling painkillers.

Earlier in 2022, BriOri BioTech was granted a US patent for the topical formulation of Vioxx, which has the generic name rofecoxib. At a time when opioid misuse is high in the US, the patent is significant as rofecoxib is a non-opioid option for pain relief. Bruce Register, PhD, the founder and CEO of BriOri BioTech, shares more about this drug and its potential for patients.

Pharma IQ: Can you describe the history of Vioxx and why it was discontinued?

Bruce Register: Before 1999 all Non-Steroidal Anti-inflammatory Drugs (NSAIDs) inhibited two genes called Cyclooxygenase Type 1 (COX-1) and Cyclooxygenase Type 2 (COX-2).

COX-1 regulates mucus production in the gastro-intestinal tract and when it is inhibited, mucus production is reduced, resulting in perforations, ulcers, and bleeds which cause over 16,000 deaths a year.

Prior to 1999 the COX-2 gene was thought to only be involved in inflammation and the resulting pain. It was reasoned that creating COX-2 specific inhibitors, such as Vioxx, would spare the gastro-intestinal tract and still reduce inflammation and pain. This thesis was proved to be correct in long term clinical trials of Vioxx.

Unexpectedly, in these year-long trials it was observed that there was an increase in cardiovascular (CV) events. Merck was asked by the US Food and Drug Administration (FDA) to do placebo-controlled trials to determine if this CV risk was real in trials longer than one year. After 18 months of a daily dose of 25mg a day of Vioxx, a statistically significant increase in CV events was found. We now know that there is dose-dependent risk of CV events with all NSAIDs.

Pharma IQ: What did Merck and other companies do as a result of the increase in CV events?

BR: Merck took Vioxx off the market voluntarily in September 2004. The following spring the FDA had an advisory board meeting to review all the data and it turned out that Vioxx was no better or worse than other NSAIDs. We now know that the greater the inhibition of COX-2 systemically the greater the risk of CV events.

Companies started to look for ways to reduce systemic exposure to COX-2 inhibition while targeting the point of pain. This resulted in the development of topicals such as Voltaren Gel and Pennsaid. These were a good first step in the evolution of pain medications but are only marginally effective, because the active ingredient in both is diclofenac.

The half-life of this drug is only 1.5 hours and it must be applied four times a day. In addition, diffusion through the skin is 6-8 percent of the applied product. As a result, only 30 percent of patients report efficacy with these topicals.

Pharma IQ: What makes BriOri BioTech’s formula for rofecoxib different?

BR: Our solution is to develop a longer lasting topical with better efficacy. Rofecoxib meets these goals – it is the strongest, longest lasting COX-2 inhibitor ever approved by the FDA. The half-life of rofecoxib is 17 hours which means it can be dosed once a day. In addition, our patented formulation, RelŸva, delivers more rofecoxib through the skin than Voltaren and PENNSAID with low systemic exposure.

Pharma IQ: What advantages does it have over opioid medications?

BR: After the withdrawal of Vioxx from the market and the media coverage of it, physicians increased prescriptions for oxycodone by 30 percent for patients with osteoarthritis, which after 3-5 days of use is addictive.

However, oxycodone is not as effective as NSAIDs and COX-2 specific inhibitors to treat pain, according to the National Safety Council. This is contrary to what most people believe about oxycodone, the most widely prescribed opioid. 

Pharma IQ: Do you think RelŸva has the potential to tackle the opioid epidemic?

BR: I do believe this will help to fight the opioid epidemic. Doctors are looking for safe effective solutions for pain relief. The first line of treatment recommended by both the American College of Rheumatology (ACR) and for osteoarthritic pain of the knee is topical NSAIDs.

Forty three percent of people with osteoarthritis are 65 or older and 88 percent are 45 or older. Annual incidence of knee osteoarthritis is highest between 55 and 64 years old and more than half of individuals with symptomatic knee osteoarthritis are younger than 65.

For this population oral NSAIDs must be used sparingly or not at all as the incidence of gastro-intestinal and CV events increases with age. In fact, in nursing homes if the topical NSAID fails the only alternative is an opioid. Having RelŸva, a topical version of rofecoxib, which is a longer lasting, very strong NSAID, will reduce the conversion of patients to opioids.

Pharma IQ: What typically happens with discontinued medications?  Is there value in reformulating and reviving these, and how often does this happen?

BR: Reformulation of drugs is a common practice in the pharmaceutical industry. The FDA approved 68 reformulations of drugs in 2020 with a cost of US$3-$50 m dollars per drug approval. In contrast, 53 new drugs were approved by the FDA in 2020 at and projected cost of over $2.5 bn dollars per drug.

Economically it makes sense to reformulate drugs into new products. Doing so reduces the cost to the consumer.

Quick links: 

• The benefits of drug reformulation
• Why R&D must digitalize and become data-centric
• Keeping tabs on pharma: Investors call for better vaccine access, Purdue mediation

Get exclusive access to member-only articles, reports, videos, interviews, webinars and other premium content from industry experts and thought leaders by signing up to Pharma IQ here.