Pharma faces major challenges after a year of failures and heated battles
（Nature Drug Discovery，作者：Simon Frantz）
http://www.nature.com/nrd/journal/v6/n1/full/nrd2230.html
Abstract
Trial disasters and patent issues look set to change the direction of the industry over the next few years.
2006 was always going to be a pivotal year for the pharmaceutical industry. Descriptions of an industry facing dwindling R&D pipelines while patents on lucrative blockbuster drugs are beginning to expire have been repeated almost to the point of becoming a cliché. But no-one can dispute the fact that the industry went through a tough patch in 2005, and 2006 began with all in the field hoping for some signs that the industry could be getting back on its feet. There were some notable successes in the field (Box 1) but the last thing that the industry needed was a brace of high-profile late-stage trial failures.
Box 1 | It wasn't all bad news
· Full box
The last thing that the industry needed was a brace of high-profile late-stage trial
failures.
The drugs don't work
Several companies received huge body blows from trials. Chief among them was AstraZeneca, which pulled the plug on two of its treatments for stroke. The anticoagulant treatment Exanta (ximelagatran) was withdrawn after a trial confirmed the initial concerns over liver toxicity in Phase III trials on the prevention of stroke and systemic embolic events in patients with atrial fibrillation. NXY-059 — a treatment developed with Renovis that traps free radicals that damage neurons after a stroke — had been successful in one Phase III trial, reducing disability in patients compared with a placebo. But the drug was withdrawn when it failed to show any clinical benefit in a second, larger trial.
Another drug class that had shown tremendous early promise, the dual peroxisome proliferator-activated receptor (PPAR) agonist in diabetes, also fell by the wayside in 2006. The FDA had granted conditional approval of Bristol–Myers Squibb's Pargluva (muraglitazar) in 2005 because of cardiovascular risks. At the time Merck halted its marketing deal for the drug, and BMS finally abandoned the drug in May last year, saying that it would not be worth spending the 5 years that it would take to carry out the trials to fulfil the regulatory requirements. AstraZeneca pulled Galida (tesaglitazar) after Phase III trials showed elevated levels of creatinine, indicating kidney damage.
No late-stage failure, though, came much bigger than the most recent one. Last month, Pfizer announced that it was immediately halting all trials on its most promising late-stage treatment torcetrapib for safety reasons (see page 14). Pfizer was hoping that this high-density lipoprotein (HDL)-cholesterol-raising drug would help to extend the lifetime of its top-seller Lipitor (atorvastatin), which goes off-patent in 2010, by combining the two treatments for cardiovascular disease. At an estimated clinical development cost of US$800 million for torcetrapib, and revenues of $12 billion a year for Lipitor now in danger of disappearing in 3 years' time, this failure couldn't be more expensive for Pfizer.
Cytokine storm in a teacup
As high profile as these large trials were, the trial that arguably grabbed the most headlines in 2006 was one carried out on only a handful of people. A Phase I trial in the UK on TeGenero's experimental antibody TGN1412 went disastrously wrong, leaving the six patients who received the treatment in intensive care. A single dose of the anti-CD28 antibody for leukaemia induced a 'cytokine storm' in the subjects, causing complications including lung injury, renal failure and coagulation in the vasculature within hours. The extreme reaction in humans highlights the uncomfortable truth that there is an awful lot about human immunology that we still don't understand. Tests on TGN1412 in monkeys had shown no major trouble, and the initial dose in humans was one-five-hundredth of the maximum safe dose used in animal studies. Doctors who treated the patients suggested that the reason for the disaster could be that affinity of TGN1412 might be different in humans than in preclinical models, or that laboratory models have more naive T cells than humans. Whatever the reason, the dose protocol was ill-advised. TGN1412 was given to all six patients at the same time, instead of staggering the dosing. The disaster left an indelible mark on the industry. TeGenero became bankrupt, and the UK regulators appointed an expert scientific panel, which concluded that more stringent safeguards are required for trials on new biological drugs like TGN1412 (see page 14 of this issue).
Risk assessment
With the number of high-profile failures last year it might have been easy to forget more longer-running drug safety issues. But the Vioxx (rofecoxib) situation still rumbles on. Merck was forced to retract the lynchpin of its legal strategy; that studies showed that the cardiovascular risk only emerges after patients have taken the drug for 18 months. The New England Journal of Medicine, which published the trial that led to Vioxx's withdrawal, removed the 18-month statement in a published correction. Post hoc analyses of the incidence curves used for the treatment and placebo groups are misleading and should not have been used, according to the journal, and a hypothetical analysis of cumulative incidence curves shows no support for the 18-month risk statement. The retraction could undermine confidence in Merck's handling of the data, but so far this doesn't seem to have upset Merck's strategy of trying each of the thousands of lawsuits on their own. Of the eleven cases so far, Merck has won six. The company has lost one out of four federal cases, three in state district courts, and a judge has called for a retrial of a case that was originally in Merck's favour.
The long-awaited Institute of Medicine's report, commissioned by the FDA to assess the US post-approval drug safety system in light of Vioxx's withdrawal, concluded that the system is outdated, inefficient and under-resourced. Twenty-five recommendations are listed in the report, among them for Congress to give the FDA more staff, funding and powers (such as being able to mandate post-approval studies); registration of clinical trial results to provide better access to drug safety information; and a fixed 6-year term for the FDA Commissioner, so that he or she will not be affected by changes in the political climate.
Heated battles
2006 was notable for a number of high profile failures in late-stage trials.
Safety issues haven't been the only headache for bigger companies. The battle between brand and generic drug companies is becoming more fevered, reflecting just how much revenue is at stake.
The Canadian generics company Apotex started selling its version of Plavix in August after a deal to settle a patent dispute with Sanofi–Aventis and BMS fell apart. A deal was cut in March, in which Apotex agreed to wait until the patent on the branded drug expired in 2011. In return Apotex would get paid by Sanofi–Aventis and BMS and also received a guarantee that it would not be undercut. But when regulators delayed this settlement in August, Apotex stunned the market by launching its generic Plavix. Apotex executed a clause in its agreement that stated that if the deal did not go through, the generics company could start selling its generic version with 5 days' notice. Embarrassed by being outmanoeuvered by Apotex, BMS fired its Chief Executive Peter Dolan (Box 2). A preliminary injunction by a federal district court judge at the end of August blocked Apotex from selling generic versions of the anticoagulant, and a federal appeals court upheld the injunction last month. But the damage had already been done. The injunction did not require Apotex to recall any drug that it had already sold, and it is thought that Apotex shipped out around 6–8 months' supply of its generic treatment.
Box 2 | An annus horribilis
· Full box
Confronted by increasing pressure from generics companies, some big companies began to bite back. Desperate to counteract the revenue losses on big-selling drugs whose patents had expired last year, branded companies took the controversial step of licensing out their own drugs to a generic company during the period of market exclusivity, producing what are known as authorized generics. For instance, AstraZeneca signed a deal with Par Pharmaceuticals to sell a generic version of its third-best-selling treatment Toprol (metoprolol succinate), which will grab some revenue share from a rival generic version being produced by Eon Labs. Other companies are making their own generics; for instance, Pfizer reactivated its generic subsidiary Greenstone, and over the summer launched its own generic version of Zoloft (sertraline) for depression. With the patent expiring on its best-selling drug Zocor (simvastatin), Merck took even more aggressive action. Merck struck a deal with several US health insurance companies to place its brand version of Zocor in the cheapest tier of their three-tier list of drugs, but the generic version was placed in the most expensive tier.
Patently obvious?
It was also a year in which the very essence of what is patentable was called into question. Pharmaceutical companies looked on nervously as cases in the technology industry over so-called 'patent trolls' — companies that invest in patents with the sole purpose of seeking out and suing infringers — were being played out in court. At the same time, two drug companies began a landmark case over a patent that covers a biological pathway. Ariad had licensed a patent from Harvard, MIT and the Whitehead Institute that covers the use of NF-KB activity. Ariad then sued Lilly because two drugs — Xigris (activated protein C) and Evista (raloxifene) — modulate the NF-KB pathway, and therefore infringed the '516 patent. Critics were furious, saying that placing broad patents on pathways hinders innovation. A district court disagreed, and awarded the plaintiffs around US$65 million in back royalties and a 2.3% royalty on future US sales of Evista and Xigris until the patents' expiration in 2019. However, the US Patent and Trademark Office re-examined the patent and dismissed the majority of the claims, including those involved in the ruling against Lilly. The patent office said that the functional language used in many of the claims is overbroad, and many of the claims are anticipated by prior art, some from such wild and wonderful sources as the Bible and the studies of the benefits of red wine.
Growth pills
With companies facing pressure from all sides, it's no surprise that thoughts are once again turning to mergers and acquisitions as a way of filling pipeline gaps and trimming costs to preserve growth. The year started with a domestic battle in Germany between the industry's oldest companies. Merck KGaA made an unsolicited offer for Schering AG, but this was eventually trumped by a friendly takeover bid of $21.56 billion from Bayer. Merck KGaA responded by buying the Swiss biotech Serono for $13.3 billion.
Several companies made acquisitions worth over a billion dollars in 2006 (see online Box 1). Even biotechnology companies got involved. Genentech made its first acquisition in its 30-year history when it bought Tanox, and Genzyme made the rare move in the biotech world of making a hostile takeover of the Canadian company AnorMED. More deals for outright acquisitions were being made at higher prices than usual. For instance, Merck paid over a 100% premium to the pre-announcement share price for the RNA interference company Sirna.
The major question is whether this activity will spark off another round of mergers between the big companies (see Box 3). Rumours have been growing that BMS and AstraZeneca could both be the target of other large companies. Jean-Pierre Garnier, CEO of GlaxoSmithKline, added fuel to the flames when he said in an interview in Magasin Manager earlier this year that "[o]f the 15 pharma companies that have a significant role in the world, only a handful will remain." But many analysts do not believe that these mega-mergers have succeeded in their quest either to improve shareholder value or to produce economies of scale. Sales and marketing might be scalable, but a company stands or falls on its pipeline, and so far there is no evidence that R&D has benefited from the mega-mergers. In fact, many analysts say that much of the trouble that the industry finds itself in could be precisely because of the last mega-merger wave. If 2006 was a pivotal year in establishing and defining the problems that companies face over the coming years, what is clear is that 2007 could be the year that decides the future direction of the industry.
编辑：蓝色幻想
