Pipeline match for possible Bristol-Myers Squibb and Sanofi-Aventis merger

Bristol-Myers Squibb and Sanofi-Aventis could join forces to become the world's largest pharmaceutical company, according to media reports this week.

The two pharma giants might even have signed a pre-merger agreement last week, according to a newsletter from French finance publication l'Expansion.

Les Echos, the UK-based Financial Times' French sister newspaper, disclosed unconfirmed reports that the two companies have agreed to jointly study whether a deal would be worthwhile.

The resultant company would be worth around $175bn (€135bn), making it similar in size to Pfizer, which is valued at $188bn and currently the world's largest pharmaceutical company.

However, in terms of sales, a BMS-Sanofi merger would outstrip Pfizer.

The new company would also be the world's largest spender on research and development, spending slightly more than Pfizer but more than double that of GlaxoSmithKline.

In an age when developing a single drug can cost $800m, the largest companies enjoy a distinct advantage.

However, most of the industry players see strategic acquisitions as the way forward, as opposed to giant mergers.

However, Sanofi and BMS already work closely together because they jointly market hypertension drug Avapro (irbesartan) and Plavix (clopidogrel), approved as an anti-coagulant since 1989.

Both companies currently deny the speculation.

Combined late-stage pipelines Sanofi have 17 compounds in late clinical development compared to BMS' six (see table).

Although any merger would inevitably attract the attention of competition regulators at the US Federal Trade Commission and the European Commission, a Drugresearcher.com analysis of their combined late stage pipeline reveals there is unlikely to be any divestment requirements.

Although both campanies are developing drugs for thrombosis and diabetes, it is their cancer programmes that reveal the most overlap.

Sanofi and BMS are both developing drugs that target the formation of microtubules - the network of proteins that contribute to cell structure.

For tumour cells to divide, the microtubule structure must be broken down and so drugs that stabilise microtubules can prevent a cancer tumour from growing.

Bristol-Myers Squibb has developed two drugs that stabilise the microtubule network.

Ixabepilone is a semi-synthetic analogue of epothilone B whereas Javlor (vinflunine) is a vinca alkaloid synthesised from vinorelbine.

Javlor works by disrupting tubulin assembley into microtubules.

Sanofi has also developed a drug to stabilise microtubules, the taxoid Xrp9881.

Industry insiders have pointed out that the only potential blockbuster in the Sanofi pipeline is Acomplia (rimonabant).

Already approved in Europe to treat obesity and associated risk factors, such as type II diabetes, the drug inhibits the cannabinoid type 1 (CB1) receptor to lower appetite.

Although BMS are developing saxagliptin, another drug aimed at type II diabetes, the mechanism is different.

It inhibits dipeptidyl peptidase-4 (DPP-4) to reduce glucagon - and therefore glucose - levels.

BMS and Sanofi are also developing a compound that could reduce potentially fatal blood clots but, again, the mechanisms of action vary.

Sanofi's idraparinux is a synthetic analogue of the functional part of heparin.

Since the 1980s, the company has also marketed the world's best selling low molecular weight heparin, Lovenox (enoxaparin).

Meanwhile, BMS is conducting Phase II/III trials of apixaban, a direct factor Xa inhibitor that could prevent blood clot formation.

If marketed, this drug could be in competition with Bayer's rivaroxaban, currently in Phase III trials.

Christopher Schott, a pharmaceuticals analyst at Banc of America Securities points out any overlap in pipeline compounds, coupled with that in released products could be used to save costs and increase competitiveness.

Schott is also concerned that Sanofi has "only recently completed digesting Aventis," after the $66bn acquisition in 2004.

He said: "Sanofi maintains a more levered balance sheet than its peer group with $7.4bn in debt at the end of third-quarter 2006."

However, he added that Sanofi has demonstrated its ability to manage debt, reducing it from a peak of $16bn after the Aventis acquisition.

Patent challenge a possible stumbling block Any possible merger would also be complicated by the fact that both companies are embroiled in a court case trying to defend patent protection of Plavix.

Despite Plavix being patented until 2012, Canadian pharma Apotex gained FDA approval for a generic version over a year ago.

A deal between BMS, Snaofi and Apotex that sought to delay the generic release until 2011 collapsed after an investigation by US lawmakers.

Apotex then flooded the market with its generic product for three weeks before further sales were stopped.

In that short time, Apotex managed to gain a majority market share, and remaining supplies are clearly still hurting Bristol-Myers Squibb sales.

Subsequently, the BMS chief executive lost his job and the company is yet to appoint a permanent successor - a detail that would make BMS Bristol-Myers Squibb a more attractive candidate for a takeover.

Although prescription demand for the fourth quarter of 2006 increased by 14 per cent, sales of Plavix halved to $500m in the same time.

BMS estimates the generic challenge has cost them up to $750m. Since sales of $6.5bn in 2005, Plavix has dropped from being the world's second best selling drug to fourth (according to figures from IMS Health as of October 2006).

In the fourth quarter of 2006, sales of Bristol-Myers Squibb's Pravachol (pravastatin), a cholesterol lowing drug, plummeted 75 per cent to $146m thanks to generic competition.

Table - an overview of the late stage (Phase III) pipeline of Sanofi-Aventis and Bristol-Myers Squibb.

Any potential overlap is highlighted in blue.

Company / Therapeutic Area Sanofi-Aventis Bristol-Myers Squibb No of Drugs Description No of Drugs Description Cardiovascular 1 dronedarone - Antiarrhythmic agent, atrial fibrillation Thrombosis 1 idraparinux - long-acting pentasaccharide, indirect Xa inhibitor.

Deep vein thrombosis / pulmonary embolism 1 apixaban - Direct Factor Xa-Inhibitor (Phase II/III)

Metabolic Disorders 1 Acomplia (rimonabant),CB1 antagonist, T2 diabetes 1 saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitor, T2 diabetes Internal Medicine 2 SR 121463 and ALVESCO (ciclesonide) Vaccines 2 prevention HIV infection and Pentacel Oncology 3 XRP9881,new taxoid, tubulin inhibitor, breast Cancer tirapazamine (SR 259075), activated by hypoxia to make cancer cells more sensitive to chemotherapy,Head and neck cancer.

xaliproden (SR 57746), neurotrophic, chemotherapy-induced neuropathies 3 ixabepilone, semi-synthetic analog of epothilone B, microtubule- stabilising agents to prevent cell division.

Javlor (vinflunine), Vinca alkaloid synthesised from vinorelbine, disrupts tubulin assembly into microtubules.

ipilimumab, antibody to inhibit CTLA-4, prevents suppression of immune response Central Nervous System 7 rimonabant**CB1 antag, T2 diabetes, dyslipidemia, atherosclerotic disease.

SR 58611, Beta3 agonist, Depression, anxiety.

SSR 591813, Nicotinic partial agonist, Smoking cessation.

xaliproden* (SR 57746), Neurotrophic, Alzheimer's.

teriflunomide (HMR1726), Immunomodulator, multiple sclerosis.

saredutant (SR 48968), NK2 inhibitor, Depression.

eplivanserin (SR 46349), 5-HT2A inhibitor, Insomnia Immunology 1 belatacept, immunosuppressant to prevent organ rejection after transplant (kidney)

* also in oncology ** also in metabolic disorders