Sanofi-Aventis' Ray Jupp, next to a mixture derived from botanical ingredients

What if a new drug could be trademarked instead of patented, keeping generics companies at bay for the life of the trademark, i.e., forever?

That was one of the ideas floated to reporters yesterday by Sanofi-Aventis’ Ray Jupp, VP of the fibrosis and wound repair therapeutic strategic unit, an early-stage research division created as part of Chris Viehbacher’s R&D restructuring in February 2010. Jupp said botanicals are typically patented by process, meaning it’s not the active ingredient or constituent that is proprietary, but the way those chemical constituents are extracted from the plant, and processed.

Since it’s nearly impossible to “back-engineer” a copycat from a finished botanical drug without understanding the extraction and processing methodology, Jupp wondered if there was a way to trademark a plant-derived drug “without giving everything away” during FDA’s drug approval process, which requires public disclosures detailing manufacturing processes. If so, a brand could conceivably retain its trademark forever, and shrug off patent expiry anxiety.

Ann Lamport Hammitte, an attorney focusing on intellectual property law at law firm Lando & Anastasi, said a trademark would protect what a product is called, but it doesn’t protect “what the product is underneath.” In the case of Sanofi, if the process methodology is the trade secret, that wouldn’t need to be disclosed to receive a trademark, but it would have to be disclosed for a patent, said Hammitte.

Jupp said botanical drug research in the past has focused on isolating single chemical constituents, but in many cases, efficacy is lost when plant extracts are fractionated out. In fact, plants themselves “can synthesize molecules in ways scientists can’t,” he said. Using different solvents to make extractions yields different groups of chemical constituents; those combinations mean that botanicals have the potential to impact multiple pathways, according to Ashfaq Parkar, director, transformational sciences, at Sanofi. The company is currently studying 12 unnamed botanicals, at 50 extracts each.

If it’s hard to know exactly what chemicals are at work in a botanical drug combination, wouldn’t that be problematic with respect to approval and commercialization? Well, not according to FDA’s guidance on botanical drugs, from 2004:

In many cases, the active constituent in a botanical drug is not identified, nor is its biological activity well characterized. Therefore, the [Chemistry, Manufacturing and Controls] documentation that should be provided for botanical drugs will often be different from that for synthetic or highly purified drugs, whose active constituents can be more readily chemically identified and quantified. For example, FDA would expect an NDA for a synthetic or highly purified drug to identify the active ingredient. However, it would not be essential for the sponsor of a botanical drug to identify the active constituents (although FDA recommends that this be done if feasible).

Currently, one in four drugs on the market comes from a plant, including Sanofi’s Taxotere injection (from taxus brevifolia, or the Pacific yew tree), said Jupp, adding that new applications for botanical-based drugs require new delivery solutions, since orally formulated products place inherent restrictions on chemists. Fibrosis (which is excessive scarring) and wound repair are therapeutic areas sorely lacking in treatments, said Jupp, using as an example diabetic ulcers; 12% of diabetics get ulcers, which can be debilitating, he said.

In a search through the trademark listings, no large pharmaceutical companies had products listed, though the Italian company Indena S.p.A. had nearly two dozen trademarks for botanicals trademarked for use in the preparation of pharmaceuticals products. Spectrum Pharmaceuticals licensed Indena’s ortataxel in 2007, a third generation taxane for solid tumors, but the drug hasn’t completed phase 2 trials, according to Spectrum’s website.

If Sanofi does end up developing a plant-based treatment for fibrosis, and they do try out the trademark route (and forgo a patent), they most likely won’t be letting reporters back into their research lab to observe the extraction process.

Sanofi has agreed to pay $74 a share for Genzyme — totalling a $20.1 billion upfront payment. But the CVR could boost the payments to Genzyme’s stockholders by up to $14 a share, dependent, largely, on Lemtrada becoming an MS blockbuster. Sanofi is backing this outcome — it says the drug has the potential to achieve annual sales of up to $3.5 billion — but the CVR, said CEO Chris Viehbacher in a press conference call announcing the deal, “was an extremely important tool to bridge differences in value.”

Sanofi will pay $1 per CVR if Lemtrada wins US approval, which the company expects will happen in the second half of 2012; increasing amounts of dollars-per-CVR depend on it passing various sales milestones. Lemtrada is currently in Phase III in the US. A Phase II trial of 334 people with early stage, active relapsing remitting MS, conducted over a three-year period in Cambridge, UK, reported in 2008 that the drug led to a 71% reduction in disability progression in participants (compared with those taking beta-interferon) and a 74% reduction in the relapse rate per year. On average, participants also experienced an improvement in disability at six months that was sustained for the three years.

But Lemtrada’s path to ‘blockbusterdom’ is far from certain. The side effects reported in the Cambridge study included a high rate of (mainly respiratory or urinary tract) infections (affecting 66% of participants). Around 30% suffered from thyroid disorders and there were six cases of immune thrombocytopenic purpura (ITP). Speaking to Bloomberg, Howard Weiner, of the Brigham & Women’s Hospital in Boston, said Lemtrada “is a theoretical cure, but to know that you need to follow people for 10 years. It’s a very strong drug and has potential side effects.” Phil Nadeau, an analyst with Cowen & Co.  (New York) added: “We think the side-effect profile is going to relegate [it] to later lines of therapy,” predicting “relatively modest peak sales estimates,” of $500 million to $1 billion.

Although the number of new MS therapies on way is showing that the basic science of innovation is working, the unknown side effect profiles potential in all these drugs show that the transition from bench to actual bedside is harder than ever.

The Multiple Sclerosis Activism Foundation has also expressed concerns about Lemtrada’s role in the Sanofi-Genzyme deal and what it might mean for subsequent pricing, saying that “for it to be used as a possible treatment for MS, and for Genzyme to be using this as leverage for a higher asking price, is… in our opinion, shameful considering the price of Campath, aka Lemtrada.” Campath, MS Activism goes on, “now sells for $30,000 for leukaemia treatment. But MS patients need only a fraction of the dose used in cancer patients. At the current price, MS patients could get Campath for $7,000 or so. That’s far less than other MS treatments.” But what would stop doctors from using the cancer-priced vials rather than the far more expensive MS priced vials, the group asks — could this have anything to do with rebranding Lemtrada “to make us think it isn’t a cheaper drug?”

The CVR aspect of the Sanofi-Genzyme deal, of course, reflects some of these uncertainties, despite Sanofi’s optimistic pronouncements of Lemtrada’s sales potential. But with both companies putting most of their eggs into the Lemtrada basket, there is a danger some of it could end up on their faces.

Reinvigorating the productive capacity of in-house R&D is the most prominent strategic challenge confronting big Pharma.  There are many options but few guarantees beyond the cold fact that the costs of remaining an innovative player in this industry continue to rise.  In its latest report on R&D trends for 2011, the Tufts Center for the Study of Drug Development estimates the average price tag for moving a compound from discovery and proof of concept to commercialization at $1.3 billion, after opportunity cost.  

Pharma has limited options in guaranteeing that any new investment will deliver a market-friendly innovation. One that comes to mind: restoring mastery over its own house. As a result, new models to more efficiently allocate the hefty internal stake in R&D are proliferating.

Sanofi-Aventis is the most prominent recent example of a company that has built a new organization precisely to manage its exposure to risk through a better orientation toward the needs of the patient – the ultimate consumer of health care. New management is also part of that mix, with the appointment last month of former National Institutes of Health Director Elias Zerhouni as global head of R&D.  Zerhouni initiated work on the redesign in his previous role as scientific adviser to CEO Chris Viebacher, so his appointment to the top job represents a vote of confidence in the approach.

New Focus on the “Big Five”
Simply put, the revamp follows previous changes in the structure of the company’s business units, dividing R&D resources and capabilities into five Therapeutic Strategy Units. [TSU].  Three of these cover major pathophysiology areas where there is significant unmet medical need: (1) immuno-inflammatory disorders, (2) infectious disease; and (3) fibrosis and wound repair.  The remaining two incorporate work in a challenging area of public health [the physiology of aging] and a high-potential geographic segment [Asia Pacific region].

Each TSU has a staff of anywhere between 30 to 200 professionals with a clear remit to foster candidates that, at a minimum, can demonstrate “proof of concept” during phase II.  The TSU integrates a range of internal and external capabilities that are leveraged very explicitly behind a critical analysis to determine how quickly a compound is progressed beyond proof of concept – or shelved. Managing this stage of the development cycle well can deliver significant gains to the enterprise, by ensuring that only the most promising work will progress to the truly high cost zone of testing that lies beyond phase II (b).

In a recent interview with Pharm Exec, Senior Vice President and Chief Medical Officer Paul Chew emphasized that the novelty of the structure lies in the investigatory latitude given to each TSU. “The premise here is there is no ‘one size fits all’ approach to modern therapeutics.  The patient element is the basic driver of our plans, and we know that individual patient needs differ drastically. ”

It follows that the TSU can come up with many different paths to finding a treatment — in most cases it will be a pill in a bottle, but not necessarily.   Vaccines can figure in the mix, as well as diagnostics, a high-tech instrument or remote access tool, even a new practice guideline or service offering.  “It is the total health solutions approach we are offering.  Each TSU has the full confidence of management to stretch the boundaries of what is traditional in our value proposition to the patient.  We work around a totally transparent question: what does the patient need and how does he want it?” Chew said.   Some of these adjacent but complementary technologies can be developed and led by others — 45 per cent of TSU work is now conducted with external partners.

Although the new structure has been in place for less than a year, it has already secured one benefit. “We are a much better partner,” relays Chew, “because the new structure provides a single ‘go to point’ in getting things done. There is now a straight line from the bench to the bedside, and less bureaucracy in between.”

It is true such logistical gains represent an early harvest. What remains to be seen is whether a redesign linked to process improvement can by itself induce the laboratory to generate good new medicines. Sanofi-Aventis is the current progeny of a culture that since the 1990s has endured no less than four disruptive mergers, involving two national champion drug makers once intimately connected to the political fortunes of France and Germany.   So keeping the new R&D organization intact long enough to give Sanofi’s long suffering scientists a chance to focus on their own work is another big if – and a prospective acquisition of Genzyme,, with its own fiercely independent scientific culture, won’t necessarily help.

“Without exception, each member of the Genzyme board believes this is not the right time to sell the company, because your opportunistic takeover proposal does not begin to recognize the significant progress under way to rectify our manufacturing challenges or the potential for our new product pipeline,” Genzyme CEO Henri Termeer wrote.

The letter goes on to state that the company outlined a laundry list of improvements it plans to make in its manufacturing facilities—an area that Genzyme has been chastised for recently—as well as future earnings from its much lauded multiple sclerosis treatment alemtuzumab, currently in development.

The board feels that Sanofi is low-balling the company with its $69-per-share offer, and should be willing to boost the price since Sanofi has openly talked about how much they are willing to pay for mergers and acquisitions as recently as last year.

According to analysts interviewed by Bloomberg, Sanofi should expect to pay upwards of $77 per share for Genzyme, but might not bump up the offer until its had time to thoroughly examine Genzyme’s financials.

Sanofi CEO Chris Viehbacher originally offered the same price for Genzyme in early July when the genetic firm’s stock hovered around $50.

“Notwithstanding this information and assistance, you have not increased your price above $69 per share,” Termeer stated. “You and your advisors claim you are willing to pay more but that you are unwilling to ‘bid against yourself.’ The Genzyme board is not prepared to engage in merger negotiations with Sanofi based upon an opportunistic proposal with an unrealistic starting price that dramatically undervalues our company.”

Show Notes:
This week we discuss:

• Pfizer’s medical education relationship with the Canadian Medical Association
• Journalists take FDA to task for not being transparent enough
• Layoffs and job cuts at Sanofi-Aventis
• New report shows that DTC receives more funding than sales calls in certain drug categories
• CEO compensation bump in life science

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According to the report, The Eastern European Pharmaceutical Market Outlook to 2014, the main player in the region is Novartis, which led the market with $1. 5 billion in sales in 2007 thanks to the marketing of both generic and branded pharma products. However, the leading treatment in 2007 was Sanofi-Aventis’ Lovenox (enoxaparin) with sales of $152 million.

Traditionally, pharma companies have been quite successful in Eastern European countries; however, healthcare systems have become increasingly complex during the past few years. As a solution, governments have been attempting to reduce costs by launching healthcare reforms. Many countries have now introduced regulated health insurance systems to replace state-controlled healthcare, and the Czech Republic and Slovenia have also opened up health insurance markets to competition from private insurers. This move to curb pharmaceutical expenditure could lead to new opportunities for pharma companies involved in the manufacture of generics.

Due to pharma’s voluntary moratorium on doling out totefuls of freebies and all the lattes you can swallow, thousands of docs, researchers, and reporters had only their sleep-deprived selves to carry from data dump to data dump at this week’s American Society of Clinical Oncology (ASCO) annual confab in Orlando, Florida.

Some 4,000 studies were reported. We humbly submit a few of the highlights.

But first a note of warning: “Success” is currently defined, for treatments of advanced or aggressive cancer, in very modest terms: by weeks, perhaps months, of survival, or survival free of disease progression, whether measured by the occurrence of symptoms or by the growth of tumors. Expectations, compared to some other clinical areas, are low.

WINNERS’ CIRCLE

PARP inhibitors

Two Phase IIs of an experimental class of drugs called PARP inhibitors reported modestly positive data for triple-negative breast cancer, raising hopes a bit for the 15 percent of breast cancer patients who are hit with this fast-growing cancer that none of the standard receptor-targeted treatments can touch.

The plainly named compounds block the PARP protein, which is used by damaged cells to repair DNA and continue growing; when a PARP inhibitor is added to chemotherapy and/or radiation, it can prevent cancer cells from regrouping.

The first study, testing PARP inhibitor BSI-201 in 116 women with triple-negative cancer that had spread to other parts of the body, reported that women who got chemo plus BSI-201 lived for an average of 9.2 months, compared to the chemo-only crowd’s 5.2 months; adding the anti-PARP drug shrunk 48 percent of the tumors, compared to chemo-only’s 11 percent.

This Phase II success is a score for Chris Veihbacher, whose aggressively acquisitive streak since taking over the top spot at struggling Sanofi-Aventis included Cali biotech BiPar, a pioneer in PARP inhibitors, including BSi-201. SA paid $500 million.

The second Phase II study tested AstraZeneca’s PARP inhibitor, olaparib, in 54 women with treatment-resistant breast cancer that is deficient in tumor-suppressing BRCA1 and 2 genes. Of those who got the higher dose of olaparib, 40 percent had tumor shrinkage.

Merck and Abbott are also grooming compounds in the PARP-inhibitor race.

Therapeutic Vaccines

BioVest International’s patient-specific vax—it contains antigen primed from your own cancer cells—prevents the relapse of follicular lymphoma by 14 months. And not a moment too soon, since Biovest filed for bankruptcy last fall.

Similarly, a gp100-marker vaccine made by the National Cancer Institute doubles response rates to standard treatment for metastatic melanoma and increased survival from 2.9 to 17.6 months.

PLACE

Herceptin (ho, hum)

Roche’s breast-cancer blockbuster won its first new use—in a subtype of stomach cancers that overexpress the her-2 protein (about 22 percent). In a 3,807-person Phase III study, the 594 patients with advanced her-2 stomach cancer lived almost for an average of 13.8 months after receiving chemo plus Herceptin, compared to the 11.1 months clocked by those in similar straits who took chemo alone. That’s 25 percent longer, as Roche will no doubt be keen to advertise—and even keener to add an extra billion or to the $4.74 billion in global sales the biologic earned last year.

Yet the drugmaker isn’t required to assess the quality of those 2.6 average extra months of life, so whether or not Herceptin, which would run you about $40,000 for 13.8 months of treatment, is truly cost-effective is anyone’s guess. (Fortunately, it’s a relatively rare disease, at least in the United States.)

SHOW

Zactima

For this first-in-class compound that combines the best of both cancer-targeting worlds by inhibiting both the cell-growing EGFR receptor and the blood-vessel-growing VEGF receptor, no. 3 is the charm. Well, maybe.

Long in development by AstraZeneca, Zactima (vandetanib) failed two Phase III studies in non-small cell lung cancer last fall. In this one, of the 1,391 patients with the advanced, recurring cancer, those on Zactima plus chemo got an average of 17.3 weeks free of disease progression, compared to the chemo alone crowd’s 14 weeks. The improvement in overall survival, though, was not statistically significant: 10.6 months versus 10 months. Will an average of a whopping 3.3 weeks free of worsening symptoms satisfy the new regime at the FDA? Stay tuned…

Lung cancer maintenance therapy

The most common cause of cancer-related death in US men, the second-most common (after breast cancer) in US women. Most are diagnosed with advanced stage disease, and most with that diagnosis live less than a year.

Pretty grim.

So the concept of maintenance therapy has taken hold among doctors recently, in an attempt to keep people alive longer—maybe long enough for a second bout of chemo and/or radiation. This idea got a lift from two studies.

Eli Lilly’s Alimta (pemetrexed), given to patients with advanced non-small cell lung cancer by an average, produced survival of 13.4 months, compared to the 10.6 months of those who receiving only “supportive care.” (Alimta-takers with the nonsquamous type of the cancer were luckier—they averaged 15.5 months.)

OSI Pharmaceuticals and Roche can boast a modest success combining their comarketed Tarceva (erlotinib) with Avastin as a maintenance treatment following chemo for advanced non-small-cell lung cancer. Those on the combo in the 768-patient Phase III had an average of 4.8 months free of disease progression, compared to 3.7 months for those on only Avastin.

That’s less than a month.

But since these targeted therapies are generally not as hard on your system as the full-on poisoning (chemo) and/or burning (radiation) that precedes them, you generally feel “better.”

LOSERS

Dendreon

The Seattle biotech’s experimental immunotherapy for prostate cancer, Provenge, after years of high drama at FDA, may have just got the sand kicked in its face. OGX-011, the lead compound of OncoGenex, when given with chemo to men with prostate cancer was associated with survival of 23.87 months, compared to 16.9 months for those on chemo alone.

Analysts and researchers are combing over the data, with some reporting that when you get deep into it, OGX-011 may have the edge on Provenge. Releasing the data that fast means OncoGenex expects big pharma partners to line up, like, right now.

ALSO RANS

Ovarian cancer marker

Early treatment of recurring ovarian cancer based on the diagnosis of raised CA125 levels offers no survival advantage over delaying treatment until actual symptoms hit. Overall survival was identical for both groups—41 months—meaning that the women who waited won an average of five extra months free of treatment and its side effects.

This was only one of the hundreds of small “target” or “marker” studies released at ASCO that will help to turn personalized medicine from a model to a practice in the treatment of cancer. Some day.

Promotions and hires for September 26, 2008:

• Merck named Barry J. Goldstein, M.D., vice president of clinical development for diabetes and obesity

• Sanofi-Aventis announced that Chris Viehbacher will succeed current CEO Gerard Le Fur in December

• GlaxoSmithKline named Ellen Strahlman chief medical officer

• Questcor Pharmaceuticals appointed Gary Sawka CFO

• Encorium appointed David Ginsberg president and CEO

• Wyeth named Daniel J. McIntyre vice president, corporate communications

• Genesis Pharmaceuticals appointed John Yang Wang to its board of directors

• Zosano Pharma appointed Gail Schulze chair and CEO

• Lilly named John Lechleiter its board of directors chairman

• Merz Pharmaceuticals named Jack Britts president and CEO

• Ferring Pharmaceuticals appointed Paul Korner, M.D., vice president, medical affairs

• Zafgen appointed Thomas Hughes the company’s first CEO