Deals Of The Week: Novartis Places Bid To Dominate In Cancer

While the largest deal of the week, and certainly the one receiving the most attention, has been Actavis' expansion of its branded portfolio via its $25 billion purchase of Forest Laboratories, the deal that could have major implications for a hot target space in cancer is Novartis' pick-up of a small Massachusetts biotech.

Novartis nabbed young start-up CoStim Pharmaceuticals at the beginning of the week for an undisclosed amount – a move that could make it a major force in the red hot area of cancer immunotherapy.

The closely held biotech was founded in 2012 by MPM Capital and led by MPM managing directors Luke Evnin and Robert Millman. Atlas Ventures joined MPM in early 2013 to fund the company’s $10 million Series A round. While terms of the deal were not disclosed, Atlas partner Bruce Booth wrote in a recent blog post that “if the contingent milestones are paid, this deal will return a significant portion of the entire Life Science allocation in Atlas Fund VIII.”

The Swiss pharma knows a thing or two about oncology – it’s been marketing Gleevec (imatinib), one of the earliest targeted cancer treatments and a multi-billion dollar drug annually, since 2003. And it boasts one of the richest oncology pipelines in the industry, spanning numerous solid- and liquid-tumor indications and many of the hottest biological targets. Its latest R&D foray into chimeric antigen receptor technology (CART) – and the programs it’s acquired from CoStim – has enriched the pharma’s immunotherapy platform and upped its commitment to being a dominant player in oncology.

While Novartis has been cagey about revealing what CoStim actually has to offer, Bill Sellers, its global head of oncology, says the Cambridge biotech brings four to five late-stage programs to the table – programs the industry could start hearing about in early 2015.

“One of our strengths is attacking cancer from its genetic base,” said Sellers. “But we have not done a lot of work in immunotherapy until two years ago,” he admitted.

That’s when Novartis inked its deal with the University of Pennsylvania for its CART research. The deal is based on the work of Carl June, whose lab created T-cells that express the receptor CART 19, a synthetic fusion protein consisting of antibodies that attach to the CD-19 protein, commonly expressed in chronic lymphocytic (CLL) and other B-cell mediated leukemias. The genetically engineered T-cells are injected back into the patients, where they find their way to CD-19-expressing leukemia cells and kill them.

Since pairing up with Penn, Novartis has been “building expertise internally,” said Sellers, as well as opening a large-scale manufacturing facility in Morristown, NJ. “CART has shown dramatic efficacy, but it doesn’t work in everybody,” said Sellers. “So there is room to augment that.”

Sellers said Novartis has been looking for a way to get into checkpoint inhibitors and other immunotherapies for a couple of years, knowing it doesn’t have the expertise in-house. That’s where CoStim comes in – one of its late-stage assets targets the PD-1 pathway. The smokin’ hot PD-1 pathway – if you’ve paid any attention to, or even just glanced at, companies like Merck or Bristol-Myers Squibb in recent months, then you’ve heard about their anti-PD-1 drugs. Combination therapies with these checkpoint inhibitors are going to be huge - $35 billion huge, if some analysts are to be trusted.

Merck already is jumping on the combo bandwagon – it’s inked three deals with Pfizer, Incyte and Amgen just this month to combine its anti-PD-1 checkpoint inhibitor MK-3475 with assets in their respective pipelines.

Novartis is employing a different strategy – it’s hoping to move forward with a CART/PD-1 combo. “We are just starting to explore CART in solid tumors, which are thought to be more immunosuppressant,” said Sellers.

CART programs may be just as revolutionary as PD-1. On Feb. 19, Memorial Sloan-Kettering Cancer Center announced results from a trial of adult B cell acute lymphoblastic leukemia that showed 88% of patients achieved complete remission after receiving the modified T-cells. (The technology is the basis for the founding of high-profile start-up Juno Therapeutics, which currently is locked in a patent dispute over the CAR technology with Novartis.)

French biotech Servier also is getting in on the action, as you can read below in ...

Actavis/Forest – Actavis is nearly unrecognizable from the little Icelandic company it was just three years ago. The company has merged with both Warner Chilcott PLC and Watson Pharmaceuticals during that time to become a generics behemoth with multinational presence. Now, it is continuing down the road of transformation with its $25 billion acquisition of Forest Laboratories. The stock-and-cash deal will turn Actavis into a developer of specialty brand name drugs, boosting specialty products to represent about 50% of combined company revenue. North American specialty pharmaceuticals currently comprise about 30% of Actavis’ standalone revenue. Forest shareholders will get $26.04 in cash and a portion of an Actavis share for each Forest share. The total, per-share price of $89.48 represents a premium of about 25% over Forest's closing price on Feb. 14, the last trading day before the deal was announced, of $71.39. For Forest this is an ideal exit for its shareholders; activist investor Carl Icahn has said in news reports that this acquisition is a good example of when activist measures work. Forest CEO Brent Saunders has been touted as having the magic touch – he flipped Forest in less than six months after taking over and was the architect behind the sale of Bausch + Lomb to Valeant Pharmaceuticals for $8.7 billion before that. - Lisa LaMotta

Servier/Cellectis – Servier wants a piece of the CART action; the French biotech inked a collaboration with cell therapy company Cellectis on Feb. 17 for $10 million upfront and $840 million in potential milestones tied to the development, regulatory and commercial success of six potential products. The deal includes the development of UCART19, Cellectis’ lead product, a CD19-targeting compound that is in early stages, but could be a potential rival to Novartis’ lead CART program – which also targets the CD19 T-cells. “These original cell-based therapies will well complement Servier's innovative clinical oncology pipeline, which currently includes immunotherapeutic monoclonal antibodies, an HDAC inhibitor, kinase inhibitors, antiangiogenic and proapoptotic small molecules,” said Jean Pierre Abastado, head of oncology at Servier. The deal initially will focus on leukemias and lymphomas, with Servier having the option to license the products and take over development after Phase I has been completed. - L.L.

Gilead/CURx - Gilead Sciences has had its hands full, what with plotting the domination of the market for all-oral HCV treatment. So busy, in fact, that the biotech has signed only one R&D deal in almost the last two years – a preclinical partnership with antibody company MacroGenics last January, according to the Strategic Transactions database. On Feb. 19, Gilead announced its latest R&D deal, but this time it has flipped the usual script and out-licensed a late-stage candidate for development. It’s calling upon CURx Pharmaceuticals develop non-core asset inhaled fosfomycin/tobramycin to treat Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients. The candidate met the primary endpoint in a Phase II trial in 2010 in this indication, but Gilead subsequently discontinued development. There already are two treatments for this indication approved in the U.S.: Gilead’s own Cayston (inhaled aztreonam) and Novartis' Tobi (inhaled tobramycin). In preclinical studies, inhaled fosfomycin/tobramycin has shown activity against several other pathogenic bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). About half of all CF patients become infected with Pseudomonas aeruginosa and about a quarter are infected with MRSA, according to CURx. The financial details of the transaction were not disclosed. - Stacy Lawrence

Pfizer/ MIT’s Synthetic Biology Center - Pfizer and the Massachusetts Institute of Technology are collaborating on the use of novel synthetic biology tools to enhance drug discovery and development. The three-year deal, announced on Feb. 20, covers multiple therapeutic areas at Pfizer and involves several core investigators at MIT’s Synthetic Biology Center, according to the MIT press release. Scientists have different definitions for synthetic biology, but, essentially, it involves integrating current and new biotech tools, systems biology and bioinformatics to enable engineering of new biological parts, in short, making new genetic codes from scratch. The ultimate goal of using such techniques is to make design and construction of novel biological systems into a professional engineering discipline. Synthetic biology as an area of scientific focus has taken off in the past decade, with support from the National Science Foundation, which funded creation of the first synthetic biotech research center, Synberc, in 2006. Participants in Synberc were the University of California at Berkeley and University of California, San Francisco, Stanford University and MIT. Since then, NSF has awarded millions of dollars more to other academic organizations to set up centers of synthetic biology research, including the J. Craig Ventor Institute and New York University. Start-up activity also is climbing, with one of the most visible practitioners, Intrexon, netting $171 million in an initial public offering last year. The ability to use synthetic biology parts as “programmable entities” presents the opportunity to create new biological processes. The partners plan to use cellular genome engineering to support development of next-generation protein expression systems. Pfizer didn’t provide more details, except for comments by Jose Carlos Gutierrez-Ramos, the company’s group  senior VP and head of Biotherapeutics R&D. He noted in a press release that “We are reaching a key inflection point where advances in synthetic biology have the potential to rapidly accelerate and improve biotherapeutic drug discovery and development, from early-stage candidate discovery through product supply.” - Wendy Diller

Photo credit: Wikimedia Commons

Deals of the Week: Is Botox On The Block?

Allergan Inc., the maker of blockbuster Botox (onabotulinimtoxinA), might be the next megadeal candidate for Big Pharma buyers. The specialty pharma and medical device maker’s market cap has taken a couple of big hits in 2013, dipping nearly 30% between mid-April and late June. That’s led to speculation, including a recent Bloomberg report, suggesting that interested buyers might want to move quickly while its stock price is depressed.

Neither of Allergan’s two primary setbacks was related to its Botox franchise, which brought in revenues of $1.8 billion in 2012 for both its cosmetic and non-cosmetic indications. The drug is known best for its wrinkle-remedying properties, but 52% of Botox sales last year were for other indications, including migraine prevention, overactive bladder, spasticity and underarm sweating. Botox accounted for roughly 30% of Allergan’s $5.7 billion in sales overall, and about 36% of its pharma revenue. (About a sixth of Allergan sales come from the device side, which includes cosmetic implants and obesity treatments such as Lap-Band.)

Rather, Allergan’s stock price has dipped for reasons related to a separate migraine drug and an eye-care product. In April, its inhalable Levadex (dihydroergotamine) for migraine received a second dreaded “Complete Response” letter from FDA, further delaying Allergan’s attempt to grab a larger share of the non-triptan migraine drug market with a convenient formulation. (Allergan recently bought out MAP Pharmaceuticals Inc., the manufacturer of Levadex and its dose-metering canister, for $884 million.) And last month, FDA said it wouldn’t require human clinical trials on generic competitors to dry-eye medication Restasis (cyclosporine), an $800 million drug facing patent expiration in  2014. That could lead to lost sales much sooner than previously expected.

While the setbacks raised some analysts’ doubts about Allergan’s long-term growth, the company still has a lot going for it. “Allergan could represent an attractive opportunity – a good, but recently diminished pipeline, a growing emerging markets strategy, a better cash-pay mix in the U.S. than traditional pharma, and some very durable franchises, such as Botox,” wrote BMO Capital Markets’ David  Maris in a June 25 note.

Allergan’s largest business segment is eye care, which generated $2.7 billion in revenue last year largely on the strength of dry eye remedies and glaucoma treatments. Given the recent pharma interest in ophthalmology, particularly around such areas as age-related macular degeneration and diabetic macular edema, its eye care specialty could prove appealing.

Many companies are sitting on large piles of cash, but few could match Allergan’s current market capitalization of about $26.5 billion, let alone the premium they’d owe to buy it outright. Past megabuyouts have included both stock and cash components. Pfizer Inc. paid $44 billion in cash for Wyeth, representing about two-thirds of the deal’s total value, while other mega-mergers have been weighted in favor of stock components. Merck & Co. Inc.’s $42 billion acquisition of Schering-Plough Corp. featured roughly 56% in equity, while Johnson & Johnson’s $21.7 billion deal for Synthes Inc. was tilted about 65%/35% in favor of stock.

At a price sure to exceed $30 billion, who might be interested? GlaxoSmithKline PLC already sells Botox in China and Japan, and could strike; it was rumored to be interested in buying out Allergan four years ago as well. And Merck was said to be in the running for Bausch & Lomb Inc. before Valeant Pharmaceuticals International Inc. swooped it up for $8.7 billion in May. Merck shares Allergan’s interests in ophthalmology, allergy medicines, and migraine as well as other areas of neurology.

Allergan was even sold once before, way back in 1980, when Deals of the Week was but a mimeographed note delivered via carrier pigeon. According to a Los Angeles Times story from back in the day, SmithKline Corp. acquired it for the princely sum of $259 million, built its revenues all the way up to $80 million in 1988, then spun it out in the summer of 1989. Those were the days. - Paul Bonanos

We hope you spend the weekend reminiscing about your salad days too, but before you step out into the summer afternoon, take a look back at...

Amgen/Servier: A complex partnership between Amgen Inc. and Servier SA, with rights to compounds going in both directions, likely will provide the California  biotech with a quick entry into the cardiovascular therapy market. The move comes several years before Amgen hopes to launch AMG 145, a Phase III monoclonal antibody in development for hyperlipidemia. In the collaboration, announced July 9, Amgen obtains U.S. commercial rights to  the French company’s Procoralan (ivabradine), a novel, oral drug with utility in stable angina and chronic heart failure. Procoralan was approved in Europe in 2005 and now is marketed in more than 100 countries, but the privately-held Servier  never filed for its U.S. approval. The drug’s sales rose healthily after Servier garnered a second indication last year in chronic heart failure, tallying about $280 million in net sales in 2012, roughly a 30% increase over 2011 totals. Amgen soon plans to file an NDA for ivabradine, relying strongly on the filings Servier compiled for the EU registration. The biotech will pay a $50 million upfront for the U.S. rights to the drug, and Servier also could earn undisclosed milestones and royalties related to ivabradine. The U.S. firm also gets an option to develop and commercialize a second heart failure compound, S38844, in the U.S. Little is known about the Phase II candidate, with Amgen volunteering only that it shares a “similar” mechanism of action to ivabradine with potential for once-daily dosing. Meanwhile, Servier obtains European commercialization rights to Amgen’s Phase II heart failure compound omecamtiv mecarbil. No terms around S38844 or omecamtiv were disclosed. - Joseph Haas

Forma/Cancer Research Technology: Forma Therapeutics Holdings announced also on July 9 a collaboration with Cancer Research Technology Ltd., the for-profit arm of Cancer Research UK, to discover drugs that target a large protein family with implications in the broad and emerging field of protein homeostasis. As Forma and CRT advance compounds that target deubiquitinating enzymes, they will create separate corporate entities to house the drug candidates and their intellectual property. No financial details were released, but the new partners said that the separate entities, which Forma has dubbed Asset Discovery and Development Companies, or ADDCos, would be wholly owned subsidiaries of Forma. CRT would take no equity stake, but it is eligible for performance milestones and a share of revenue as the compounds progress. Forma will pay research costs. CRT has named five principal investigators to shepherd the collaboration from among its network of researchers, all of whom are at least partially funded by the private charity Cancer Research UK. The ADDCo structure is a twist on the asset-financing model gaining popularity in biotech, as investors look to place bets on specific products without having to support research infrastructure. Forma says it would like to sign up other academic groups for similar arrangements. - Alex Lash

Immunocore/GlaxoSmithKline: Immunocore has scored a second high-profile partner in as many weeks through a deal inked with GlaxoSmithKline. The UK-based biotech will receive £142 million ($210.7 million) in preclinical milestones across several targets as well as £200 million ($296.7 million) in development and commercial milestone payments for each target that reaches the market, plus double-digit royalties on sales. Immunocore develops ImmTACs, a new class of bispecific therapeutic proteins that consist of high-affinity T-cell receptors linked to an antibody fragment, anti-CD3, which activates the immune system. T-cell receptors recognize intracellular changes that occur, and Immunocore’s ImmTACs are designed to target and destroy cancer cells without affecting healthy cells. Cancer immunotherapy has become a hot space of late with several Big Phramas putting a lot time and money behind programs in this space. Two weeks prior to the GSK tie-up, Immunocore signed its first significant partner in Roche’s Genentech. In that arrangement, Immunocore will receive an upfront payment of $10 million to $20 million for each program, as well as $300 million in development and commercial milestones related to each target and tiered royalties. - Lisa LaMotta

Array/Loxo: Array BioPharma has added to its laundry list of partners for its oncology platform, with the addition of Loxo Oncology, a venture-backed start-up that is centering its resources around an Array asset. According to the companies, Array will handle preclinical development of an undisclosed oncology target in exchange for an equity stake in Loxo, as well as the potential for $434 million in milestone payments and eventual royalties on any products that result. Loxo was founded in May 2013 by Josh Bilenker, a partner in Aisling Capital, a life science venture firm headquartered in New York. Aisling currently is investing out of its $650 million third fund. Array has done a number of deals around its platform resulting in more than 11 clinical candidates, eight of which are in Phase II/III. The company uses the funds garnered through upfront payments and milestones to fund the development of its two wholly owned programs: ARRY-520 for multiple myeloma and ARRY-614 for myelodysplastic syndrome. ARRY-520 is in Phase II and Array intends to announce its plans for pursuing approval before the end of the year. The company also is finishing up Phase I trials of ARRY-614 and intends to make a decision regarding proof-of-concept trials by the end of 2013. - L.L.

Chiesi/uniQure: Chiesi Farmaceutici and uniQure BV announced on July 9th a co-development and commercial deal in which Chiesi will sell Europe’s first approved gene therapy, Glybera (alipogen tiparvonvec) for the ultra-orphan monogenic disease lipoprotein lipase deficiency and another uniQure gene therapy, now in Phase I/II for hemophilia B, in Europe and selected emerging markets. UniQure retains commercial rights on both products in the U.S., Japan, parts of Latin America and Asia, and Australasia. The deal paves the way for an emerging field that has been long in the making and is only now beginning to deliver on its early promise. Chiesi will pay uniQure €17 million ($21.8 million) in upfront cash and will make an equity investment of $18 million. It will also pay royalties ranging from 20%-30% over time on both products. In addition, Chiesi will fund and collaborate on the remaining clinical program for the hemophilia B product. Chiesi’s investment triggered the conversion into new uniQure shares of $18.1 million in outstanding convertible debt that uniQure raised last May from Coller Capital and other investors. Chiesi, an acquisitive and innovative midsize Italian pharma, has recently increased its focus on rare diseases in addition to its respiratory and hospital products franchises. Armed with a fresh infusion of $58 million in total equity and collaborative funding, uniQure’s immediate task, according to CEO Jörn Aldag, is twofold: develop its substantial pipeline of gene therapy programs and build out commercial infrastructure especially in North America in preparation for FDA approval of Glybera. Longer range, the company must pioneer the pricing for an unprecedented therapeutic modality so that it can build a sustainable company and reward its investors. - Michael Goodman

Vivus/Menarini: While it waits for results from a contentious proxy contest, Vivus Inc. is still striking deals. The company is still fending off a challenge centering on its marketing plan for weight-loss drug Qsymia (phentermine and topiramate), but it’s found a partner for erectile dysfunction treatment Stendra (avanafil). Italy’s Menarini Group agreed July 9 to pay €16 million ($21 million) to obtain Stendra’s rights in Europe, Australia and New Zealand, although Vivus says it expects another €23 million during the first year of the deal. Milestone payments could add €79 million to the deal, which also includes a provision under which Menarini will pay Vivus’ obligations to Mitsubishi Tanabe Pharma Corp. and a ten-year supply agreement. Menarini already markets premature ejaculation drug Priligy (dapoxetine) in Europe, and says it will field a sales team of 1,350 representatives for Stendra. The Italian company plans to conduct a commercial launch in early 2014. Stendra is a phosphodiesterase-5 inhibitor in the same class as Viagra (sildenafil citrate). Top Vivus shareholder First Manhattan Co. is challenging company leadership, which elected not to choose a marketing partner as it launched Qsymia, a slow seller in danger of being eclipsed by Eisai Co. Ltd. and Arena Pharmaceuticals Inc.’s rival drug Belviq (lorcaserin) despite a first-to-market advantage. - P.B.

Mitsubishi/Medicago: Mitsubishi Tanabe has been a small stakeholder in Canadian vaccine developer Medicago Inc. for a couple of years, but the Japanese pharma now plans to acquire 60% of the company. In a deal announced July 12, Mitsubishi said it would pay C$1.16 per common share, a 22% premium to Medicago’s July 11 closing price, to obtain the majority stake. The deal has a maximum price of C$179 million ($172.6 million); Philip Morris International Inc. will retain the 40% of Medicago shares it currently owns. Mitsubishi Tanabe has held a 6% share in Medicago since 2011, and the companies signed a deal in March 2012 to collaborate on vaccines – including rotavirus – using Medicago’s virus-like particles. Medicago announced June 20 it successfully produced a rotavirus vaccine based on virus-like particles (VLP) that comprised all four rotavirus antigens and filed an international patent application for the product, claiming it was the first time for a rotavirus VLP to be produced in plants. Medicago’s lead compound is an H5N1 vaccine currently in Phase II development that uses plant technology instead of egg-based or cell production, followed by a quadrivalent seasonal influenza vaccine in Phase I. Medicago has a rabies vaccine in preclinical development as well as an undisclosed target in collaboration with a top 10 pharma, according to the company’s pipeline. - Dan Poppy

Thanks to Flickr user vancouverlaser for the Botox shot, reproduced under Creative Commons license.

Servier Chief Steps Down from G5 Presidency

Well, he couldn't exactly remain the figurehead at the top of France's cosy little posse of pharmaceutical firms, the G5, could he? Indeed, Jacques Servier, head of the family-owned firm that has been in the spotlight for months over its now-withdrawn diabetes drug Mediator, was among the founders of this nationalist group, which has colluded since 2004 to protect...er..promote the drug sector in France and ensure its competitiveness on the global stage.

Jacques Servier has resigned his position as G5 president, the group declared in a release today, "in order to devote his time to defending the interests of his firm during the current period" (rough translation). There's a bit to defend, certainly: Servier faces over 100 lawsuits from alleged victims of its tarnished drug (generic name: benfluorex), and the full wrath of the country's media, whose efforts have helped escalate the affair right up to the President de la Republique, Nicolas Sarkozy.

On Jan. 19, Servier was booted out of industry association LEEM, too; likewise so the agency can pursue 'serenely' its discussions with public bodies and to allow Servier to 'freely' organize its defense.

Of course, Servier's resignation as G5 president doesn't come close, in price-to-pay terms, to that of poor old Jean Marimbert, head of the country's regulator, AFSSAPS. He has become the most prominent (indeed, so far, the only) scapegoat in this somewhat sordid affair. Not the right scapegoat, either, say some.

But while Servier devotes his time to defending Servier (not an apology in earshot), the G5 -- of which Servier remains a member -- is staunchly supportive of the Mediator-triggered proposals (some emanating from Marimbert himself) for increased transparency within France's drug regulatory process. "In particular, we fully approve of the idea of publishing the list of links between experts and drug firms, as well as any payments made" between the two, says the statement.

The irony of this statement, not really diluted by the fact of Servier's resignation, becomes apparent when reading through French media reports of goings-on within the French firm, not least the accusation that it doctored some of the clinical assessments of Mediator's risk-profile. And accusations of all-too-cosy relationships between doctors, drug firms and politicians. Yup, you remember rightly, Sarkozy decorated Jacques Servier with the highly esteemed Legion d'Honneur in...2009, the same year Mediator was withdrawn.

Ok, so France isn't the only place where this seedy stuff happens. It's just that this 'French scandal', as the national media calls it, has drawn a big bright spotlight onto the country's back-room wranglings, regulators and pharmaco-vigilance processes.

The light may yet draw out some more suspicious goings-on from the shadows; equally (if not more important) will be the impact on the country's already tight pharmacovigilance processes.

Meanwhile, Ipsen's new CEO Marc de Garidel takes up the mantel of G5 presidency, with Pierre Fabre's Olivier Bohuon stepping in as spokesman. These appointments, the group declares, will allow the association to pursue its activities...including those focused on 'le rayonnement international de la France'. That's France's influence, prestige...literally, its radiance.

Afssaps Boots Marimbert, a Victim of His Own Success

Jean Marimbert’s resignation from his post as the Director General of the French medicines agency, Afssaps, carries the whiff of scapegoating and smacks of a blunt sense of irony. His departure, however, prompted by revelations concerning Servier’s diabetes drug, Mediator, which is rumored to have caused upwards of 2,000 deaths, may cause France’s regulatory establishment more problems than it might solve.

Marimbert wasn't a born regulator, but since being appointed as head of Afssaps for a three-year term in 2004, he has become known in European regulatory circles as a solid and determined leader. He was re-appointed in 2007 and once again in 2010. This alone is testament to his ability and the respect accorded him by the health ministry.

His tenure hasn't been without challenges. Since 2004 the number of marketing authorization applications seen by Afssaps has risen by over 30%. At the same time, the agency has had to contend with a plethora of new laws from Brussels, including the Orphan Drug, Paediatric Medicines and Advanced Therapy Medicinal Products Regulations. Over the same period, the number of staff at the agency has risen by barely 6%.

The Vioxx withdrawal prompted Marimbert to focus on specific measures to promote drug safety. Spurred on by politicians who claimed that Afssaps was not doing enough in this area, Marimbert had all of the minutes of the agency’s regular committee meetings published online, starting with those for pharmacovigilance. This was a first for Europe.

Moreover, he tightened the pharmacovigilance system itself, and placed more emphasis on risk management plans within this framework. The irony is that it is transparency and pharmacovigilance, linked with Mediator, that have prompted his downfall.

The Mediator scandal has grown in size since breaking last November, and links between Servier, government ministers and even President Sarkozy have been called into question. Health Minister Xavier Bertrand has in the first instance pointed the finger of blame at Servier, but he also referred to severe failures in the functioning of the regulatory system, a veiled reference to Afssaps and Marimbert. The government’s main aim, it would appear, is to put an end to the Mediator scandal well in advance of the presidential elections in 2012. Marimbert’s departure serves well to deflect attention.

Bertrand is now looking at whether pharmacovigilance should be carved out of the medicines agency and set up a separate entity to carry out this task. This is unequivocally the height of folly. What’s more, it comes at a time when European competent authorities have identified and begun to consolidate the link between risk-benefit assessment and the regular monitoring of marketed drugs.

For example, the Heads of Medicines Agencies, the network of the Heads of the EU National Competent Authorities says that an effective medicines regulatory system must be able to estimate the risk-benefit of medicines, communicate that information effectively and take regulatory action when necessary to protect health. All of this must be ongoing in unison during the life cycle of the product.

This approach benefits not only patients, but also manufacturers. Thus, if an adverse incident is flagged up through effective pharmacovigilance, instead of simply withdrawing the product, a re-assessment of the risk-benefit of the product in light of the new information can be made. Marimbert made this point clear in his resignation letter, published in the French daily Liberation, last week.

What direction he will take is as yet uncertain. However, there is a job going at the European Medicines Agency, following the departure of its Executive Director, Thomas Lönngren on Dec. 31, 2010. However, whilst Marimbert hovers in limbo, Lönngren has been snapped up by independent regulatory and market access consultancy NDA and has been asked to play a strategic advisory role.

The problem for Marimbert is that he may have to wait a while before the taint of scandal fades. On the other hand, he should be safe in the knowledge that the government owes him one. -- Faraz Kermani

Witty: EC Raids? Who Cares

You'd have thought that the recent European Commission raids on AstraZeneca and Nycomed, aimed at uncovering potential anti-competitive behavior, might have ...we won't say shocked, coz what's shocking these days... but at least jolted the industry. Raised an eyebrow or two. But this does not appear to be the case. GSK's CEO Andrew Witty on Friday Dec. 3 gave the impression of a man with either supreme confidence, or in extreme denial.

At a conference held in the grounds of the Belgian senate, Witty appeared to suggest that the Commission enquiry into the pharmaceutical sector, and originators' alleged intent to block or hinder generic market entry (block generics? Never!) was at best due process, and at worst a waste of time.

Witty’s main defence appears to be that all contentious patent issues will eventually be tested in the courts. “So if there is one thing that should reassure you, it is the number of patent cases that end up being litigated in European and US courts," he said. "That is what keeps the system healthy," he stressed, denying any suggestion of shadowy wrongdoing.

Fair enough (as concerns patent issues finding their way to court). But Witty also maintained that the Commission's comprehensive sector enquiry, which began in January 2008, had already been concluded. “I think the end-point of that enquiry was that there was no significance – there was no action, if you will, that came out of that enquiry,” Witty stated.

Coming in the same week that news emerged of raids on AZ and Nycomed, the timing of Witty's somewhat dismissive comments looks, well, interesting. Furthermore, in July this year, the Commission issued a Statement of Objection to Servier (a previous host to an EC raid, along with Teva, back in late-2008) indicating that the privately-owned French company was not co-operating in the investigation process. It added that if it eventually found that there was sufficient evidence that Servier, intentionally or negligently, provided misleading and incorrect information, it could impose a fine of up to 1% of the total turnover of the company in the preceding business year.

So the Commission doesn't, then, appear to share Witty's view that the initial enquiries are concluded. In fact, following the latest raids, the Commission stressed that there is no legal deadline to complete inquiries into anticompetitive conduct. “Their duration depends on a number of factors, including the complexity of each case, the extent to which the undertakings concerned co-operate with the Commission and the exercise of the rights of defence,” a Commission statement said.

But Witty's certainly right as regards the likelihood that the Commission uncovers anything from its latest round of raids. Servier has served as a warning to any company that has anything anti-competitive to hide. You can be sure that guilty parties have long since done their shredding.

--by Faraz Kermani

image by flikrer NickPiggott used under a creative commons license

Bleak Winter for Servier

Winter is coming early to Europe this year, particularly for one company situated in the suburbs of Paris. Servier faces its first court case, filed yesterday by two patients at Nanterre, France, in connection with its diabetes drug Mediator (benfluorex).

An investigation by the French medicines regulator (Afssaps) led to claims earlier this month that Mediator, and its generic equivalents – manufactured by Myland and Qalimed – may have caused 500 deaths since 1976.

Servier is being charged with “serious deception, based on the nature, substantial quality and composition of the product”, “placing the lives of others in danger”, “administration of a noxious substance” and “involuntary homicide”.

Harsh accusations, indeed (even by pharmaceutical industry standards). However, the actual number of deaths associated with Servier's drug is derived from two separate studies assessed by Afssaps and the association is, for the most part, hypothetical. At Afssaps' request, three expert epidemiologists examined the study results and suggested that on the basis that some 7 million people were exposed to the drug between 1979 and 2009, the number of deaths was likely to be in the region of 500.

Put in that context, 500 deaths doesn't sound too unusual. But use of benfluorex also significantly increased the risk of hospitalisation as a result of thickening of the heart valve (valvulopathies), according to the pharmacovigilance studies that Afssaps pulled together.

Faced with this first case, Servier has a number of factors running in its favor. Firstly, it voluntarily withdrew Mediator from the French market in November 2009, following several reports of cardiac valvulopathy and pulmonary arterial hypertension. The European Medicines Agency followed suit in December 2009.

Next, Servier may be deemed to have a point when it retorts that the “inflated” number of deaths was the result of an “extrapolation” and therefore did not represent actual Mediator-caused deaths. Moreover, the company revealed that, even if this morbidity were proven, it would only correspond to a risk of 0.005%.

The Nanterre court will have to examine the question as to whether this represents an acceptable level of risk. It certainly may do, particularly as regulators frequently stress to the public that “no drug is risk free”.

Still, Servier would do well to use this as a test case for what may yet be to come. Success for the appellants could spell trouble, not just for Servier but also, potentially, for Myland and Qalimed too.

If this first snowflake in Nanterre turns into a snowstorm, France could be prompted to re-examine the case for class actions – which the country hasn't, until now, allowed, and which health minister Xavier Bertrand is keen to avoid. That said, given the inordinate length of the legal process in France, Servier may do well to go into hibernation until winter is over.

--Faraz Kermani

image by flikrer taivasalla used under a creative commons license