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COX-2 withdrawal - Therapeutic, R&D and pharmaceutical impact
Lead Discovery, Oct 2004, Pages: 59
At the beginning of October, 2004 Merck withdrew the blockbuster Vioxx (Rofecoxib) from the market. This move was in response to new, three-year data from a prospective, randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on Vioxx) trial. The trial, which has been stopped, was designed to evaluate the efficacy of Vioxx in preventing recurrence of colorectal polyps in patients with a history of colorectal adenomas. In this study, there was an increased relative risk for confirmed cardiovascular events, beginning after 18 months of treatment in the patients taking Vioxx compared to those taking placebo. In the wake of Merck’s announcement Pfizer affirmed the safety of their COX-2 inhibitor Celebrex; the FDA and European regulators stated that they will now be looking at other COX-2 inhibitors more carefully, impacting on newer agents such as Merck's Arcoxia, and Novartis' Prexige; and others are suggesting that now is the time to push forward other therapeutic classes that can reduce the pain of osteoarthritis such as the NO-NSAIDs and LOX/COX inhibitors as well as osteoarthritis and rheumatoid disease modifying agents. Accompanying these changes will be a realignment of the COX-2 inhibitor market.
The report was written to help all involved in drug development sector to:
-Fully understand the original rational behind the development of COX-2 inhibitors
-Evaluate pharmacological and clinical data surrounding Vioxx, remaining COX-2 inhibitors on the market, and drugs in development
-Understand the exact nature of the cardiovascular risk of the COX-2 inhibitors
-Differentiate between the efficacy, gastrointestinal safety and cardiovascular risk of the COX-2 inhibitors
-Predict the future sales of COX-2 inhibitors
-Introduce alternatives for COX-2 inhibitor indications.
The report opens with a detailed discussion of the eicosanoid pathway and the (patho)physiological role of the various products of the cyclooxygenase pathway. The report continues with an account of the discovery that aspirin acts through the inhibition of COX and the rational development of improved non-selective COX inhibitors.
During the 1970’s it became apparent that multiple COX isoenzymes may exist and this led to the eventual cloning of COX-1 and COX-2 in the 1990’s. This report pays especial attention to the COX-1 and COX-2 isoenzymes. In addition the recently identified COX-3 is introduced as a novel target for analgesics. Although Vioxx and Celebrex were the first specific COX-2 inhibitors to enter the market Nimesulide, Etodolac and Meloxicam were available much earlier and these agents were all found to be COX-2 selective. This report describes the therapeutic activity of these agents and then continues with a thorough evaluation of all approved COX-2 inhibitors and those in late stages of development.
The first two COX-2 inhibitors to be approved, Vioxx and Celebrex, are as effective as non-selective NSAIDs in reducing stiffness associated with osteoarthritis as well as pain in a wide range of conditions. Observations that the incidence of ulcer complications is reduced compared to other NSAIDs are consistent however the pivotal safety trial VIGOR and CLASS have revealed apparent differences between the two drugs.
VIGOR demonstrated a clear reduction in gastrointestinal adverse events but an increased incidence of non-fatal myocardial infarction in Vioxx treated individuals compared to those receiving naproxen. CLASS on the other hand failed to show a difference in cardiovascular risk with Celebrex compared to patients receiving either diclofen or ibuprofen, however the primary end point of ulcer indications was not altered either.
Critics claim that VIGOR demonstrated the cardiovascular risk of Vioxx, a view supported by an increase in blood pressure in patients with controlled hypertension; increased risk in the elderly and retrospective analysis of medical records. Supporters counter the claim citing the safety record of Vioxx in placebo controlled studies and in studies comparing Vioxx to other NSAIDs, and explain the VIGOR data as an “artifact” of the cardioprotective effect of naproxen.
Further analysis of CLASS suggests that the lack of improved gastrointestinal safety was because patients were allowed to take aspirin. When only patients not taking aspirin were investigated or when the combined incidence of ulcer complications and symptomatic ulceration was taken as an end point Celebrex demonstrated improved gastrointestinal safety.
Recent interim analysis of the APPROVe study designed to compare the chemoprotective effect of Vioxx to placebo demonstrated an increased incidence of myocardial infarction after 18 months treatment with Vioxx. The report provides an in depth argument on the safety of Vioxx in light of this trial discussing how convincing the arguments for and against a cardiovascular risk are, and if there is a risk, possible mechanisms. The effects of these three pivotal trials has however been that Vioxx was withdrawn by Merck in October 2004 while its main competitor, Celebrex has not been allowed by the FDA to claim improved gastrointestinal safety on its prescribing literature.
Given the issues surrounding the clinical data for Celebrex and Vioxx, the development of second generation COX-2 inhibitors takes on extra importance and the report fully evaluates Pfizer’s Bextra and Dynastat which have been launched in the US but not Europe and Merck’s Arcoxia which has been launched in Europe but not the US. The report also evaluates Novartis’ Prexige which is of particular interest since its structure is novel and also because it offers the greatest COX-2 selectivity of all COX-2 inhibitors that have entered advanced stages of development. Most importantly, in the pivotal TARGET trial, the incidence of ulcer complications was significantly reduced in patients taking Prexige compared to those receiving NSAID. TARGET also demonstrated that the risk of cardiovascular events did not differ between Prexige and the pooled NSAIDs data irrespective of aspirin use.
Having fully profiled current COX-2 inhibitors, the report continues with an in depth look at the market. It is estimated that over 80m people worldwide take prescribed NSAIDs daily. The US COX-2 inhibitor market has previously seen high double digit prescription growth but this has declined over the last few years following fears that COX-2 inhibitors may lead to increased risk of cardiovascular events even before the release of the APPROVe trial data. Consequently the proportion of COX-2 inhibitors prescribed has stabilized out at around 30% of the total NSAID market. As a result of Vioxx’s withdrawal the market will change still further. Within 24 hours of Merck's announcement approximately 2.4% of the 1.2 million Vioxx prescription holders in the US had received new prescriptions for alternative therapies. Of those active prescriptions, 58% had moved to other drugs within the COX-2 inhibitor therapeutic class, while 33% received a prescription for a NSAID such as naproxen. Among competitive COX-2 products, prescriptions for Pfizer's Celebrex and Bextra increased 78%, while prescription strength NSAID dispense rates increased 17% for the same three-day time period. Of current US Vioxx prescription holders 32% had taken the drug for more than 18 months, the timeframe in which Merck cited that individuals would be at risk for increased cardiovascular events.
From now on the FDA and European regulators will closely monitor other COX-2 inhibitors for similar side effects and the report concludes that this will delay the approval of Arcoxia and Prexige. In addition further cost-benefit analysis will be required to justify the use of COX-2 inhibitors over NSAIDS in chronic conditions. In order to prevent a further dampening down in the growth of the COX-2 market the report also concludes that it may be necessary for the existing COX-2 players to invest in educational and advertising campaigns to reassert the safety of COX-2 inhibitors in the chronic treatment of rheumatoid arthritis and osteoarthritis and allay patients and physicians safety fears.
The report provides a detailed scenario analysis forecasting major events over the next 6 years and predicts that following a transient increase in sales in 2004 due to prescription switching, the market will contract in 2005. By 2006 growth will begin to return as second generation products gain broader indications and Prexige becomes established in the European markets. The report forecasts sales of the major COX-2 inhibitors over the next 6 years globally, in the US and outside of the US.
Over the medium term companies will likely increase efforts placed on developing alternative approaches to regulating the cyclooxygenase pathway. One attractive approach discussed in this report is the development of nitro-NSAIDs which combine the advantages of traditional NSAIDs with the gastroprotective effects of nitric oxide donors. Over the longer term, disease modifying rheumatoid-or osteo- arthritis drugs will continue to receive interest.
In short this report describes in detail the past, present and future of COX-2 inhibitors and allows researchers, strategic planners, marketing personnel and investors alike to plan for the field of analgesia now that Vioxx is no longer available.
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