UV I7: The Vioxx controversy

A File to Defend Merck

Facult de Pharmacie, Lille, 2005 Peinte A, Samier J, Serres A

Introduction

Who is Merck ?
Losartan COZAAR Alendronate FOSAMAX Rizatriptan MAXALT Montelukast SINGULAIR Timolol TIMOPTOL Cardiovascular Osteoporosis CNS Respiratory Ophtalmology

11 major research centers in US, Europe, Japan Manufacturers products in 32 facilities and sell in 150 countries

http://www.stelior.org/pdf/L'Hebdo_m%8Edicaments.pdf, 3 Fvrier 2005 Source http://bourse.lesechos.fr 17 Juin 2005

Introduction
On September 30, 2004, Merck withdrew volontarily Vioxx (Rofecoxib) from the market, a COX-2 inhibitor, non-steroidal anti-inflammatory drug (NSAID) that was approved by FDA in May 1999 for pain and inflammatory diseases. This withdrawal has been the subject of intense public interest and a real popular controversy. Merck is accused to have hidden informations about potentially cardiovascular risks following the using of Vioxx. Merck has acted with responsability about Vioxx: In response to a real need from the patients In carrying out rational medicinal chemistry In analysing of safety data
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Rheumatoid Arthritis and Osteoarthritis The problem of treatments

Osteoarthritis
Slow destruction of the cartilage: bones are in direct contact Inflammation, Pain, Rigidity 0.8% of the US population Lead to premature death if the disease is unchecked

Osteoarthritis_an untreatable disease; Nature april 2005

Rheumatoid arthritis
The immun system attacks the tissue. The synovial membrane become a synovial pannus. Inflammation leads to a cartilage destruction. The articulation loss her form and function and become very painfull. One of the most common forms of musculo-skeletal disease in all countries of the globe

Therapeutic strategies for rheumatoid arthritis, nejm, june 2004

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RA and Osteoarthritis: medicines

Opioid analgesics
respiratory distress) adverse events (drowsiness, constipation,

Glucosamine Chondroitin Efficacy remains controversial Hyaluronic acid Acetaminophen Less effective than NSAIDs and COX-2 inhibitors Corticosterodes NSAIDs
Osteoarthritis_an untreatable disease; Nature april 2005 Therapeutic strategies for rheumatoid arthritis, nejm, june 2004
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Corticosterodes
Dose dependant side effects Thinning of the skin Cataracts Osteoporosis Hypertension and Hyperlipidemia

Topical drug aplication: delivery of a hight local drug

concentration with a reduced risk of systemic side effects Steroids they might speed up the progression of OA

Therapeutic strategies for rheumatoid arthritis, nejm, june 2004

NSAIDs
One of the most widely used classes of drugs more than 70 million prescriptions more than 30 billion over-the-counter tablets sold annually (United States) NSAIDs are used regularly by at least 13 million people with various arthritides.

The painful reality Sin Renfrey, Christian Downton & James Featherstone www.nature.com/reviews/drugdisc 10

Epidemiology of GI complications
Within a six month period of treatment: 10 to 20 % of patients: dyspepsia 5 to 15 % of patients: discontinue NSAIDs. Annual number of hospitalisations in the US for serious GI complications is estimated to be at least 103,000. Mortality rate attributed to NSAID-related GI toxic effects is: 4.21 as compared with the risk for persons not using NSAIDs.

Gastro intestinal toxicity of non steroidal anti-inflammatory drugs NEJM, June 17, 1999
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Epidemiology of gastrointestinal complications

Gastro intestinal toxicity of non steroidal anti-inflammatory drugs NEJM, June 17, 1999
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 Gastro intestinal toxicity of non steroidal anti-inflammatory drugs NEJM, June 17, 1999
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The role of prostaglandins

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Clinical spectrum of injury

Peptic ulcers may lead to gastroduodenal hemorrhage perforation death After ingestion of an NSAID: within minutes: damage to the gastric surface epithelium within several hours: endoscopically detectable hemorrhages and erosions in the gastroduodenal epithelium

Patients really need new treatments in RA and osteoarthritis

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The COX 2-inhibitors An enthousiastic innovation

Discovery of the COX

1971, Sir John Vane Aspirine is an inhibitor of an enzyme on which depends the synthesis of prostaglandines. It explains the anti-inflammatory effect of the aspirine. 1991: Discovery of two isoforms of the COX 1993, scientific meeting in Keystone, Colorado COX-1 was present normally in the gastrointestinal tract (constitutive) COX-2 was induced in inflammatory cells at sites of inflammation. (inductible) Structures were sufficiently different to enable the discovery of selective inhibitors.
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Acide arachidonique

Cyclo-oxygnase PGG2 Proxydase

PG = prostaglandines TXA2 = thromboxane A2

PGH2

PGD2

PGF2

PGE2

PGI2

TXA2

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Inflammatory role of the COX-2

Stimulus

Douleur
Inflammation
Nocicepteur

COX-2 PGE2

PG
COX-2

Moelle

COX-1

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Gastric effect of the COX-1

COX-1 Inhibition Prostaglandine I2 Ulcerogen effect

Decrease of the H+ secretion Production of mucus Mucosis regeneration COX-1 inhibition has nocive effects: Being COX-2 selective could be very interesting !
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The VIOXX discovery

Within 18 months, Merck had COX-2 selective inhibitors candidates. Range finding: 12,5mg or 25mg in osteoathritis (chronic use) 50mg in acute pain 1999: Merck registers the Rofecoxib (Vioxx) in USA. Acute pain: Dysmenorrhae, osteoarthritis Enhanced safety for the gastro-intestinal tract 2000: Rheumatoid arthritis 2002: Discovery of a third isoform (COX-3) which is inhibited by the acetaminophen but physiological activity remains unknown.
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The high COX-2 selectivity of VIOXX

DFP:Toxic organophosphoric L 745,337: in development

Phramacology_Proc.Natl.Acad.Sci.U SA vol 96 pp7563-7568, june 1999

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Cyclooxygenases Structure
Oxydation Base of the chanel

Tyr 385

Affinity

Homodimeric structure with one heme on every subunit Arachidonic acid access to the catalytic site by a wide hydrophobic chanel

Lateral pocket

Selectivity

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Structural Activity Relation

R= lipophilic group

SO2CH3 ou SO2NH2
Sulfonamide Methyl sulfone

N
Heterocycle

Activity Selectivity

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Type Sulfonamide:

(Celebrex) Pfizer

(Bextra) Pfizer

(Dynastat) Pfizer

Type Methyl sulfone:

(Vioxx) Merck

(Arcoxia) Merck

(Prexige) Novartis 26

Medicinal chemistry
The sulfonamide group poses several problems. -Leads to inhibitor of the anhydrase carbonique (diuretic).

Acetazolamide (DIAMOX) The aim of Merck was to develop an anti-inflammatory drug with no diuretic effect.
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Sulfonamide use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis
NEJM, Dec. 14, 1995 p1600 Toxic epidermal necrolysis may kill or severely disable previously healthy people. very extensive skin detachment poor prognosis: death rates of 30 to 40 % On 7th April 2005, withdrawal of the Bextra because the FDA estimate that the benefit-risk ratio was unfavorable. Merck behaved responsibly when developing a methylsulfone rather than a sulfonamide.
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Toxic epidermal necrolysis

A fine metabolic profile

Feature
Effect of co-administration with Cyt P-450 inhibitors Influence of hepatic insufficiency

Celecoxib
Yes

Rofecoxib
None

AUC 40%180% higher

AUC 30%-70% higher

Pharmacology_Proc.Natl.Acad.Sci.U SA vol 96 pp7563-7568, june 1999

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Cyclooxygenase inhibitors and the antiplatelet effect of aspirin NEJM , dec 2001

The administration of ibuprofen antagonizes the irreversible platelet inhibition induced by aspirin. Rofecoxib has not this adverse effect.
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COX inhibitors and the antiplatelet effect of aspirin

Patients with arthritis and vascular disease may receive both low-dose aspirin and other NSAIDs. Rank order of interaction with the aspirin: Ibuprofen>Celecoxib>Valdecoxib>Rofecoxib

A high level of cyclooxygenase-2 inhibitor selectivity is associated with a reduced interference of platelet cyclooxygenase-1 inactivation by aspirin
PNAS july 2001
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Conclusion
Merck put a lot of effort into developing COX-2 inhibitors. The Rofecoxib posed fewer problems than others COX-2 inhibitors (interaction, hypersensibility, renal impact) and has to be taken once daily !

What about the GI safety ?

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 Comparison of upper gastrointestinal toxicity of Rofecoxib

The VIGOR trial NEJM; November 23, 2000

Population prospective, randomized, double-blind in more than 8000 patients with rheumatoid arthritis. at least 50 years old Treatment Rofecoxib: twice the maximal dose recommanded for long-term use (decision imposed by FDA) Naproxen: standard dose (1000 mg per day)

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Characteristics of the Patients

8076 patients: 4047 rofecoxib vs 4029 naproxen The median followup: 9 months in both treatment groups Rates of discontinuation were similar in the two groups: 29.3 % in rofecoxib 28.5 % in naproxen

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Adverse gastro intestinal events

Fewer GI adverse events are observed with the VIOXX

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Rofecoxib and naproxen had a similar effect in the reduction of the activity disease score.

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2001

From 1999 to 2001, COX-2 inhibitors are widely used and their innovative characteristics are recognised.
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Cardiovascular events The professionalism of Merck

Before the NDA

Indication Acute pain Acute pain Osteoarthritis Treatment Vioxx vs Ibuprofen vs Placebo Vioxx vs Ibuprofen vs Placebo Vioxx vs Ibuprofen Duration 6 weeks 3 months 6 months

All study duration < or about 12 months Conformity to ICH E1 (chronic, non-life-threatening disease) Approval in 1999 Indication: Acute pain (Dysmenorrhae, Acute osteoarthritis) No cardiovascular impact suspected / observed
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ADR frequency Patients

1 in 100 1 in 500 300 1 500

1 in 1000 3000

1 in 10 000 30 000

1 in 50 000 150 000

Background incidence 1 in 1000

Patients to detect an adverse event (95 IC) 1 in 100 500 1 in 1000 16 000 1 in 10 000 1 100 000

J.A.Lewis Post marketing surveillance: How many patients? Trends in pharmacological sciences 2, 93 (1981)

Many people must be exposed to a recently-introduced drug in order to define risk levels too low to be detected in pre-market testing, but high enough to create controversy.
Some key points emerging from the COX-2 controversy Pharmacoepidemiology and drug safety 2005; 14:145-147 41

The VIGOR study

Comparison of upper gastrointestinal toxicity of Rofecoxib and Naproxen in patients with rheumatoid arthritis NEJM, November 23, 2000 Primary end point: gastro-intestinal effect Randomisation: 4047 Vioxx (50mg) vs 4029 Naproxen (2400mg) Vioxx 50 mg but the highest approved dose in chronic is 25 mg. Naproxen 1000 mg is the highest approved dose in chronic. Aspirin low-dose not allowed
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VIGOR: Safety data

Rofecoxib Mortality rate 0,5% CV deaths 0,2% Ischemic CVA 0,2% MI 0,4%*
* Significative difference

Naproxen 0,4% 0,2% 0,2% 0,1%

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The VIGOR study

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The VIGOR study

Cardiovascular events were not the primary end point: - Tobacco status ? - Independent committee to classify the events. - No control on the concomitant treatment (anti-HTA). - Lack of placebo group. Our results are consistent with the theory that Naproxen has a coronary protective effects and highlight the fact that rofecoxib does not provide this type of protection owing its selective inhibition of cyclooxygenase-2.

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Reactions after the VIGOR study

June 2000 Merck advices an association of low-dose aspirin with the Vioxx when required (even in the clinical trials). April 2002 This recommandation is officialised by the FDA. Vioxx Timeline, Cardiovascular safety data http://merck.com

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A compromising mail ?
March 9, 2000: An internal e-mail by Merck research chief, Edward Scolnick, referred to the potential safety risks of Vioxx. (Wall Street Journal,11/15) Some journalist considers this mail as an evidence that Merck has hidden cardiovascular data. In fact, this mail was Mr. Scolnicks reaction about the preliminary results from the Vigor study.

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The VALOR project

Why this cardiovascular study has never been launched ?

Vioxx vs placebo in CV pathology was a non ethic study design. The APPROVe study was already launched. 3 years of follow-up, more than 2500 patients and low-dose aspirin stratification

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Time-line of the controversy

APPROVe enrollment completed

Mail from Scolnick VIGOR Feb. 2000 March June 2000 2000 Oct. 2001 Nov. 2001 VALOR project Jan. 2002 March 2002 Sept. 2004
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Cardiovascular Thrombotic Events in Controlled Clinical Trials of Rofecoxib

Published in october 2001, American Heart Association
http://www.circulationaha.org Circulation. 2001;104:2280-2288

Meta-analysis: 23 trials: Vioxx vs placebo or Naproxen or other NSAID 28 000 patients (>14 000 patient/year) Primary end point = Anti-platelet trialists collaboration (APTC) end point CV, haemorragic and unknown death + non fatal MI and non fatal stroke

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Chart1

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()

()

()

()

()

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Meta-analysis

No evidence for an excess of CV events for Vioxx relative to either placebo or non naproxen NSAIDs. Differences observed between Vioxx and naproxen are likely the result of the antiplatelet effects of the latter agent.
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Memo to file on CV data in Alzheimers studies

Food and Drug Admnistration, December 3, 2002

3 studies (prevention of Alzheimers disease) / nearly 3000 patients Median exposure: 14 months Elderly population (mean age 75 years) Not designed to evaluate cardiovascular outcomes Low dose aspirin for 6% of patients in each treatment arm

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APTC event KM estimates (95% CI) Vioxx in Alzheimers disease prevention

FDA, Center for drug evaluation and research, Updated March 2004 http://www.fda.gov/ohrms/dockets/ac/05/slides/
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Conclusion of the FDA

No excess for all cardiovascular thrombotic events in the rofecoxib 25 mg vs placebo Hypothesis: the excess of MI in the rofecoxib 50 mg in the VIGOR study would due to: the lack of an anti-platelet effect of rofecoxib relative to naproxen the biologically plausible pro-thrombotic effect and the effects on hypertension and fluid retention

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COX-2 inhibition and renal physiology

2001: COX-2 is constitutive of the kidney Physiological regulation of COX-2 in the kidney Harris RC Breyer MD.

Am J. Physiol Renal Physiol 2001; 281:F1-F11

2002: Renal effects of specific COX-2 inhibitors seem to be similar to those seen with traditional NSAIDs Celecoxib, Rofecoxib vs Naproxen COX-2 inhibition and renal physiology Raymond C.Harris, MD.

American Journal of Cardiology 2002;89(suppl):10D-17D

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Be strong and resolute: continue to use COX-2 selective inhibitors at recommanded dosage and in appropriate patients
Marc C Hochberg; Division of rheumatology and clinical immunology University of Maryland School of Medicine, Baltimore, USA

Published on December 11, 2002 in Arthritis Research and Therapy

Mr. Hochberg is a consultant for Merck Conclusion Coxib are recommended for patients with arthropathies. Dosages must be respected (Vioxx 12,5 or 25 mg in arthritis). Patients with CV risk: Coxib + low-dose aspirin Patients with high GI complications risk: Coxib+IPP
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UK yellow card scheme

N of prescriptions Year 1999 2000 2001 2002 2003 2004 Rofecoxib 162 600 784 500 1 269 800 1 780 000 2 128 600 / Celecoxib 109 500 109 500 1 374 200 1 957 800 / Valdecoxib 26 500 / Etoricoxib 86 700 396 100 / Vioxx yellow-card ADR reports MI 6 9 7 5 7 16* Fatal MI 1 4 1 0 0 2

*12 of these reports were received following the Vioxx withdrawal

T&F Informa UK Ltd; March 2nd, 2005

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UK yellow card
Ms Wintertons warning: Under-reporting: spontaneous reporting A yellow card report do not necessarily mean that the drug caused the adverse reaction
T&F Informa UK Ltd; March 2nd, 2005
One of the best spontaneous reporting schemes for adverse drug reactions in the world. Medicines and Healthcare products Regulatory Agency Chairman Sir Alasdair Breckenridge

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Time-line of the controversy

APPROVe enrollment completed

Mail from Scolnick VIGOR Feb. 2000 March June 2000 2000

Metaanalysis

Memo to file (FDA) VALOR project

Oct. 2001

Nov. 2001

Jan. 2002

March 2002

Sept. 2004
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The APPROVe study

The Adenomatous Polyp Prevention on Vioxx study 2586 patients with a history of colorectal adenomas 1287 Vioxx (25 mg) vs 1299 Placebo 3 years of follow-up Cardiovascular SAE were adjudicated in a blinded fashion by an external committee All safety data were monitored by an external safety committee
Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial NEJM February 15, 2005; 352:1092-102
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The APPROVe study

Inclusion >40 years old, confirmed large-bowel adenoma removed Exclusion Previous cardiovascular event Due to the Vigor study, low-dose aspirin is allowed when required Stratification according the clinical center and the use of low-dose aspirin
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Design of the study

Run-time period Compliance evaluation 6 weeks Placebo

Vioxx 3 years follow-up Placebo

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65

During the first 18 months, the events rates were similar in both groups. On Sept 30, 2004 the independant safety commitee decided to stop the APPROVe trial. Immediately, Merck announces the end of all clinical trials and the withdrawal of the Vioxx.
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A future for the Vioxx ?

One come-back drug example: LOTRONEX

There is limited precedent for a drug that has been withdrawn from the U.S. market for safety reasons to be returned to marketing A recent example: Lotronex
It is a selective antagonist of 5-HT3 receptor to treat only women with severe diarrhea-predominant in irritable bowel syndrome (IBS) because of serious complications

Glaxo-Smith-Kline withdrew voluntarily November 2000 returned to the market in June 2002 under restricted conditions of use that application was reviewed by an advisory committee before FDA reached a final decision on the sponsors request
http://www.fda.gov 68

FDAs view about a possible return of Vioxx

In a memorandum of April 2005, FDA declared that Vioxx case will be considered to envisage a possible return of Vioxx on the market BUT:

With revised labeling for safe and effective use of the drug In populations where the potential benefits would outweigh potential risks (juvenile arthritis, patients allergic to sulfonamide) After advices of an advisory committee meeting specifically devoted to the resumption of marketing of Vioxx before the FDA reaches a decision on final action

http://www.fda.gov/cder/drug/infopage/COX2/default.html http://www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.pdf 69

Risk-swapping
An extensive meta-analysis of known risk factors for coronary heart disease (The Lancet, Yusuf, September 2004,) shows
the cox-2 risks, as published in APPROVe study: risk linked with Vioxx use: 2.8 are within the same range of all the recognized life-style factors that can play on coronary risk (smoking, hypertension, obesity) (The
Lancet 2004; 364:2021-2029)

smoking hypertension diabetes Abdominal obesity High ApoB/ApoA1 ratio

3.33 2.24 2.96 1.79 4.35

Odds ratios for relative effect of risk factors Both sexes - Young

Pharmacoepidemiology and drug safety, january 2005; 14: 145-147

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Vioxx has promising potential using: Colorectal adenoma chemoprevention

COX-2 is expressed at sites of inflammation such as in neoplasms raising the possibility that COX-2 inhibition might also be useful in the treatment or prevention of various cancer Prevalence of Familial Adenomatous Polyposis (FAP) : 1 in 80 000 Characteristics: inherited disease hundreds of colorectal adenomas, eventually colorectal cancer Unless prophylactic colectomy, colon cancer risk: nearly 100% average age at the time of the diagnosis of cancer: 35 years

http:www.molecular-cancer.com/content/2/1/10

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In 1999: Indication of Celebrex in FAP1 Few drug are on the market with this indication
Sulindac: lower COX 2 selectiv no slow-down in the development of colorectal adenomatous polyps in subjects with FAP2

Feb 2000, APPROVe colorectal adenoma chemoprevention with Vioxx: higher COX 2 selectiv3 APPROVe stopped in September 2004
1Cardiovascular 2Primary

risks associated with celecoxib in a clinical trial for colorectal adenoma prevention, NEJM 342:1946-1952, June 29, 2000 chemoprevention of familial adenomatous polyposis with Sulindac NEJM 346:1054-1059, April 4, 2002 3Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial, NEJM 72 352:1092-1102, March 17, 2005

Conclusion