THE UPSURGE AND FAILURE OF BAYCOL

Presented by : Dr. Pratistha SinghClinical Research Fellow Student, AAPSToronto, Canada2015-2016

Clinical Research and Pharmacovigilance Program Director : Prof. Peivand Pirouzi

CONTENT Introduction and discovery of baycol Pre-clinical studies of baycol Clinical trial phase of baycol Submission review and market approval Post authorization phase Post withdrawal phase

INTRODUCTION AND DISCOVERY OF BAYCOL GENERIC NAME : Cerivastatin

OTHER BRAND NAME: Lipobay

The empirical formula of cerivastatin is C26H33FNO5Na and its molecular weight is 481.5.

MOA : It is a purely synthetic competitive inhibitor of HMG CoA reductase -> inhibit cholesterol synthesis ->Reduces cholesterol level in hepatic cells -> Up regulation of LDL receptors -> increase in Hepatic uptake of LDL cholesterol from circulation.

PHARMACOKINETICS

Absorption :- Administered orally with mean absolute bioavailability of 60%.Terminal elimination half life is 2 to 3 hrs.

Distribution :- More than 99% of the drug is bound to plasma proteins(mostly to Albumin) ; which is reversible and independent of drug concentration up to 100mg/l.

Metabolism :- It is broken down in the body into metabolites named M1, M23, M24. The main action of the drug is due to parent compound.

Excretion :- Cerivastatin is itself not found in urine and faeces but its metabolites are excreted.

SIDE EFFECTS OF BAYCOL Skeletal: Myopathy, muscle cramps, rhabdomyolysis

(Rhabdomyolysis refers to muscle ache or weakness (myopathy) combined with creatine kinase (CK) levels usually greater than ten times the upper limit of normal, with decreased renal function or acute renal failure. If untreated, rhabdomyolysis may be fatal), arthralgia, myalgia.

Neurological: Tremors, memory loss, vertigo, paresthesia, peripheral neuropathy, anxiety, insomnia, depression.

Hypersensitivity reactions

Gastro-intestinal: Pancreatitis, hepatitis, cirrhosis, anorexia, vomiting. Skin: Alopecia, pruritis Reproductive: Gynecomastia Eye: progression of cataract, ophthalmoplegia

DISCOVERY OF BAYCOL Need For Drug Discovery : Too much cholesterol; especially LDL

have been documented as the major risk factor for CV diseases. In early 1950s- Canadian pathologist Rudolf Altschul of USask found

that large doses of nicotinic acid decreased serum cholesterol level in rabbits.

In 1955- Nicotinic acid became the first agent employed to lower serum cholesterol level (MOA is through activation of lipoprotein lipase).

In 1958 – First fibrate(clofibrate) was marketed. In 1958-1959 – It was documented that reduction of HMG CoA(3-

Hydroxy -3-Methyl-Glutaryl Co-enzyme A) to Mevalonic Acid is the major rate limiting step in Cholesterol biosynthesis. Therefore, inhibition of HMG CoA reductase would be an ideal approach to stop cholesterol synthesis in liver.

In 1971 – Akira Endo et al of Sankyo Pharmaceuticals began to screen microbial agents for HMG CoA reductase inhibitor activity.

In August 1973- First statin named Mevastatin was isolated from fungus Penicillium citrium.

In 1978- Under the guidance of Roy Vagelos, Merck with Alfred embarked on efforts to find a compound with HMG CoA reductase inhibitor activity; which lead to the marketing of first statin named Lovastatin( derived from fungus Aspergillus terreusi) in the year 1987.

In 1979 – Sankyo embarked on a small clinical trial of Mevastatin but halted it.

In 1980s- Merck’s Alvin and Gerrald et al disclosed their synthetic HMG CoA reductase Inhibitor. So, in 1984 first synthetic statin Fluvastatin sodium(Lescol) was released in US market.

In 1997- Atorvastatin was released in market which became the best-selling statins ever.

In late 1980s- Cerivastatin (Baycol) was discovered by Bayer scientists led by medicinal chemist Rolf Angerbauer and biologist Hilmar Bischoff. It was marketed in the year 1997 but was withdrawn in 2001.

PRE-CLINICAL STUDIES OF BAYCOL

Muscle wasting was not seen in pre-clinical animal tests, including rats, mice, dogs, or monkeys; only at very high doses were indications of effects on muscle tissue seen.19 The authors concluded that cerivastatin was well tolerated in all species. Post-withdrawal tests using rat and human muscle cells in vitro revealed that rat cells are 200 times more resistant to the drug’s effects. Eventually more than 100 deaths were linked to cerivastatin.

CLINICAL TRIAL PHASE OF BAYCOL It was studied in controlled trials in North America,

Europe, Israel and South Africa and was shown to be effective in reducing total cholesterol and LDL cholesterol.

Over 2800 patients with IIa and IIb hypercholesterolemia were treated in trials of 4 to 104 weeks duration.

Because of the relatively small size and restrictive inclusion criteria for subjects, pre-approval clinical trials for the drug were, however, unable to detect rare, serious adverse events. Cases of severe statin-associated rhabdomyolysis, therefore, had only emerged post-marketing as statins began to be used by a growing and diverse patient population.

In 1991, during internal discussions about the clinical development plan for the IND (Investigational New Drug Application) submission to the FDA, Bayer ‘s toxicologists stipulated that ‘”The highest daily dose which can be used in their clinical development program was 0.4 mg “. They emphasised that they felt very strongly not to allow a step up to higher daily doses because the slope of the dose response curve (of Baycol) is much steeper.

In a 24 week randomized, double-blind, placebo controlled US based trial in 934 patients with primary hypercholesterolemia, .05 to .3 mg dose once daily showed dose related decrease in cholesterol level. Significant reduction was seen in one week with peak effect in four weeks. This effect was maintained for remaining duration of the trial.

In a separate dose – scheduling trial, baycol was administered as 0.2 mg dose once daily and 0.1 mg dose twice daily. 4% more reduction in LDL-C was noticed with the dose administered once.

  Clinical Trial Adverse reactions : In the US placebo

based trial, discontinuation due to adverse events occurred in 3% of subjects on Cerivastatin and 3% of subjects on placebo. Cerivastatin was evaluated for adverse events in about 3000 patients and was reported to be well tolerated with mild and transient adverse events. 

STUDY ON SPECIAL POPULATIONS

Geriatric : Plasma concentration of cerivastatin was found same in healthy elderly and young males.

Gender : plasma conc is slightly higher in female subjects.

Pediatric : Not studied in pediatric patients.

Race : was studied in Japanese, Caucasian and Black subjects and no significant differences were reported.

Hepatic Disorders : It was not studied on subjects with active liver disorders.

SUBMISSION REVIEW AND MARKET APPROVAL OF BAYCOL Dosage and Administration :- Patient should be placed on

cholesterol lowering diet before cerivastatin administration and this diet should be continued with the treatment. The recommended dose was 0.3 mg once daily orally in the evening. This dosage was reduced to 0.2mg initially in patients with moderate or severe renal impairment.

Over dosage :- No specific recommendations about over dosage was made. But if encountered, it should be treated symptomatically.

Supply :- Supplied in bottles of 100 units of either 0.2 mg or 0.3 mg tablets. They should be kept in tight containers protected from moisture and temperature above 25oC.

MARKET APPROVAL OF BAYCOL

Bayer engaged in co-promotion and marketing partnerships in many markets, notably the US, France, Italy, UK, Spain and Japan. The UK was the first launch country in April 1997. In the US market, which accounted for over 60 per cent of worldwide statin sales, Baycol was launched in February 1998. The initial approved maximum dosage worldwide was </= 0.3 mg.

As the post-marketing reports of the other statins had identified rhabdomyolysis cases for both monotherapy and co-medication, Baycol ’s initial US labeling included a warning that rhabdomyolysis had been reported with statins, and that the combined use of statins and fibrates should be avoided. Baycol ’s EU labeling included similar warnings.

POST – AUTHORIZATION PHASE OF BAYCOL

Post-market spontaneous reports rapidly showed that Baycol, like the other statins, was associated with rhabdomyolysis. In the majority of cases, patients were taking Baycol and gemfibrozil at the same time. As a result, on 12th May, 1999 Bayer filed for a change in Baycol ’s US labeling to include a contraindication for concurrent Baycol and gemfibrozil treatment; which was finally approved in December 1999.

Peer pressure from atorvastatin led Bayer to undergo clinical trials for increased dosages. On 24th May, 1999, Bayer obtained FDA approval for a 0.4 mg dosage strength, which became the new starting dose. The 0.4 mg dosage allowed Baycol to compete in the biggest LDL-C efficacy segment of the US market, accounting for about 50 per cent of statin prescriptions.

In June 2000, a group of Bayer executives discussed issues arising from the spontaneous reports of rhabdomyolysis associated with Baycol in the US because of the high proportion of confirmed cases of rhabdomyolysis with Baycol concomitant medication (70 per cent during September 1999 – February 2000; 62 per cent during March – July 2000) concluded that the emphasis should be on making sure that everyone understands the nature of the contraindication of Baycol with gemfibrozil. One means to achieve this would be a patient package insert.

Keeping in account of the Bayer’s meeting with FDA on July 12, 2000 for the approval of 0.8 mg dose, Baycol, Consultant( who was FDA official earlier) to Bayer suggested not to disclose the label changes before the approval meeting as a fear of delay in approval. Consequently, 0.8 mg dosage of Baycol was approved by FDA in July 2000 in spite of the fact that 0.8 mg dose caused higher increase in CK than lower doses. Bayer sold 0.8 mg at a comparatively low price to gain hold of the market.

Though, inadvertently reporting of rhabdomyolysis due to Baycol monotherapy was ten times higher than other statins, then too Bayer did not considered it significant.

In August 2000, after the FDA had approved the 0.8 mg dose, Bayer submitted an application for a patient package insert that would inform patients that they should not take Baycol if they were taking gemfibrozil, among other information. This change was not brought to the package inserts in other countries than US.

In December 2000, Bayer Drug Safety and Regulatory dept. proposed that the UK Medicines Control Agency (MCA) should be asked to strengthen the statements to the contraindication. But, Eric Pauwels, head of the Baycol Global Strategic Marketing Team, was not in favour of this move, finding the data unconvincing: “A total of 35 cases over the last 3.5 years; 10 cases per year”. Until now, the 0.8 mg had been approved only in the US, and Pauwels feared that the requested changes might delay the introduction of the 0.8 mg elsewhere.

In February 2001, following the assessment of the latest spontaneous reporting data and responding to a request by the UK MCA, Bayer asked that Baycol’s EU prescribing information be updated to include a contraindication with gemfibrozil.

Between September 2000 and February 2001, 18 cases of Baycol-associated fatal rhabdomyolysis were reported worldwide, compared to eight and two, respectively, for the preceding two six-month periods. During a teleconference on 26th March, 2001, Bayer Drug safety authorities reviewed the spontaneous reports of deaths in the US, which amounted to 12 since the beginning of 2001. It was noted that only one of the fatal cases involved concomitant use of gemfibrozil, the others being overwhelmingly associated with the use of the 0.8 mg dose. Bayer therefore requested a change in US prescribing information, and stopped shipping 0.8 mg samples to US physicians.

On 21st May 2001, the FDA updated Baycol’s prescribing information by emphasizing that the starting dose should be 0.4 mg. A “Dear Healthcare Professional” letter was prepared to inform healthcare professionals of these changes and remind them of the gemfibrozil contraindication. Bayer sales reps were told on 24th May to communicate the contents of the letter, which was sent out on 17th June 2001.

In the meantime, Baycol 0.8 mg had been launched in the UK in April 2001. During the same month, the Spanish authorities raised concerns about a number of reports in Spain of fatal cases of rhabdomyolysis associated with Baycol.

May 2001, the launch of Baycol 0.4 mg in France and Italy.

In June 2001, all the participating countries were sent Dear doctor letter for not using more than 0.4 mg dose of Baycol and not to use concomitantly with gemfibrozil. Bayer volunatrily suspended the marketing and distribution of 0.8mg dose in UK.

On 24th July 2001, during a meeting between the FDA and Bayer, the FDA presented an analysis of spontaneous reports showing that “The crude reporting rates for fatal rhabdomyolysis with Baycol 0.8 mg alone or in combination with gemfibrozil were in marked excess over reporting rates for this event in association with certain other marketed statins”. On 1st August, Bayer decided to suspend the marketing of Baycol 0.8 mg in the US and met again with the FDA to discuss additional risk-management plans and safety analyses for Baycol up to 0.4 mg.

Bayer proposed the following black box warning: “Concurrent treatment of Baycol with gemfibrozil is contraindicated due to a risk for rhabdomyolysis. The maximum total daily dose of Baycol must not exceed 0.4 mg due to a risk for rhabdomyolysis”. But the FDA requested a differently formulated black box warning on 3rd August where the warning should be given so as not to use dose beyond 0.4 mg.

On 7th August, 2001, Bayer took the decision to withdraw Baycol from all markets except Japan (In Japan, highest dose was 0.15 mg and gemfibrozil was not available in Japanese market).

On the same day, the FDA issued an “FDA Talk Paper” that informed the American public about the withdrawal. Except for the FDA, the other regulatory agencies and healthcare professionals were informed by Bayer in the days following the withdrawal. Completely taken by surprise, healthcare professionals and the European regulatory agencies were left scrambling to provide answers to questions raised by patients, the media and politicians. Bayer had never mentioned the idea of a complete withdrawal to the European agencies, nor did the data of which they were aware justify such a radical course of action. On 23rd August, Bayer announced Baycol’s withdrawal from the Japanese market. The decision was motivated by the forthcoming approval of gemfibrozil in Japan.

Bayer decided on the timing of the withdrawal based on stock market considerations, without providing prior information to the tens of thousands of physicians and pharmacists concerned.

POST WITHDRAWL PHASE OF BAYCOL

Faith in the healthcare system and the pharmaceutical industry was shaken.

Bayer’s share price dropped from S45 to S33 within a week of the withdrawal announcement due to direct loss because of baycol withdrawal and cost of litigation.

The total number of persons treated with Baycol worldwide was estimated at 6 million, including around 2 million in the US, 1 million in Japan, with the remainder mostly in Europe.

The Baycol withdrawal significantly changed the dynamics of the statin market by turning statin safety from a nonissue into a sensitive issue. The heightened concern with statin safety raised the entry barriers for AstraZeneca’s Crestor, slowing down its market entry and speed of market penetration, thus contributing to the continued sales growth of Pfizer ’s Lipitor.

REFERENCES Books.google.ca - Drug Discovery Accessdata.fda.gov Drugs.com Ncbi.nlm.nih.gov