DOTW: Early Stage Investing Pays Off

Preclinical protein platform play Envoy Therapeutics got taken out by Takeda this week for up to $140 million. That magical “up to” typically hides a multitude of sins, but here that may not be the case.

The milestones are all preclinical and achievable within a year and a half, Envoy investor John Diekman of 5AM Ventures tells In Vivo Blog. VCs invested a mere $8 million in Envoy, which was founded in 2009. That puts an exit at 17.5x, if all the milestones are hit. That means 5AM's investment of about $4 million could be parlayed into around $70 million.

Although that’s an amazing multiple, with such a small investment it doesn’t quite provide the home run that VCs often rely on to create venture returns. It will return almost half of the $150 million fund the firm raised in 2006. 5AM subsequently raised a $200 million fund in 2009.

Diekman said the board originally bargained hard to get paid entirely upfront but, once they realized Takeda had solely preclinical milestones in mind, they were happy to relent. Comps for the deal are hard to find; there haven’t been any disclosed acquisitions of preclinical companies this year that paid cash and had the potential to be worth over $100 million, according to our deals database.

He noted 5AM Ventures planned to put $20 million total into Envoy and said, “If there’s anything we don’t like, it’s that we didn’t get enough money into the company."

But Diekman said the next inflection point likely would have been Phase II data, when the company could again be a promising acquisition candidate. So when the investors started evaluating options, they took into account the amount of money and the time that would be necessary to take the company to that next stage.

Envoy has bacTRAP technology, which combines genetic engineering with molecular biology techniques to label and extract protein-making components of specific types of cells. “This is one of the nicest platform companies I’ve seen in my life. They have the ability to bind new targets in such as way that you can start screening them in CNS and other areas,” said Diekman.

The central nervous system application is the attraction for Takeda, which has moved aggressively into the field in recent years. 

Takeda and Envoy have history. Takeda Ventures participated in the 2009 Series A round for Envoy, so it already held 12.5% of shares ahead of the acquisition. Another strategic investor, Roche Venture Fund, also participated in that financing. In 2010, Takeda and Envoy did a deal to discover schizophrenia drugs that offer greater efficacy and safety than approved treatments. Envoy received $3 million upfront and an additional $2.25 million per year for three years. 

“Takeda was an investor from the beginning and saw the technology. They did a deal with us, discovering a number of compounds. They watched the technology and saw how good it was and where it was going. And they wanted more,” said Diekman.

While Envoy secured a Takeda partnership and then an acquisition, this week a couple other biotechs went in the opposite direction and lost partners. We’ll give you all the details in this week’s edition of. . .

Sun Pharmaceutical/Dusa Pharmaceuticals: India’s largest drug maker by market cap, Sun Pharmaceutical, acquired U.S.-based specialty dermatology company Dusa Pharmaceuticals, a step it said will help build a global specialty dermatology business. The deal valued Dusa at $230 million, which translates to about 4x sales and 36x annualized after-tax profits based on 1H12 figures. Sun marked the deal as a departure from the company’s usual strategy, which is to acquire distressed assets. Also, Sun struck a conservative agreement that gives it market depth compared to a jump in its top-line. In an earlier interview, Sun Pharma Managing Director Dilip Shanghvi tempered expectations of any large deals. Dusa drew most of its $45 million revenues last year from Levulan, a single drug-device combination therapy for treatment of non-hyperkeratotic actinic keratosis, or AKs, of the face or scalp. Actinic keratosis is a common precancerous skin condition caused by excessive exposure to ultraviolet light and made up of rough, dry, tan- or pink-colored blemishes that often appear on facial skin or other skin exposed to sunlight. Founded in 1991, Dusa had a long gestation and only turned profitable in 2010. In addition to Levulan, it sells Blu-U, a blue light device used to treat moderate inflammatory acne vulgaris and general dermatological conditions. With the acquisition, Sun said it expects to provide about five million treatments per year in the U.S. Shanghvi pegged the market at well over $1 billion, adding that the cost of treatment is a factor for the number of treatments received.-- Vikas Dandekar

Merck/ Regenstrief Institute: Merck & Co. signed a five-year agreement with The Regenstrief Institute to collaborate on a range of projects that will use clinical data “to inform personalized delivery of health care,” Merck said in a statement. Regenstrief, a non-profit medical research organization affiliated with the Indiana University School of Medicine, has access to a large data repository that includes de-identified clinical data on over 13 million individuals, according to Sanchin Jain, Merck’s chief medical information and innovation officer.  The foundation for the database is the Indiana Network For Patient Care, a healthcare information exchange that goes back to 1994 and captures a range of clinical and claims data from providers and payers across the state. The companies will use the data to explore novel methods for studying diseases and treatments for chronic conditions. The collaboration began in April, but Merck announced it on Nov. 8, so scientists from both organizations are in the midst of completing nine projects in 2012 and plan another 10 for 2013, focusing in total on osteoporosis, diabetes, hypertension, hyperlipidemia and insomnia. Financial details were not disclosed, but the collaboration aims to advance the science of bioinformatics and to “have a practical effect on Merck’s approach to bringing new products to patients,” Jain said. Study results could provide insights into medication adherence and patient outcomes, as well as improved methodologies for conducting observational research, he added. Results of collaboration studies will be published in peer-reviewed journals. Jain said that Merck selected Regenstrief, which is more than 40 years old, because of its expertise in biomedical informatics, health services research, and its world-class health information system. For Regenstrief, an alliance with Merck offers an opportunity to globalize some of its ongoing research and work with a leading pharmaceutical company.-- Wendy Diller

Pfizer/Alliance For Lupus Research: Pfizer’s Centers for Therapeutic Innovation (CTI) announced a partnership on November 7^th with the Alliance for Lupus Research (ALR) to co-fund the translation of promising lupus treatments into Phase I trials. In a reminder of how the R&D ecosystem is rapidly evolving away from the only-within-our-walls mindset, the collaboration is the first in which a Big Pharma joins with academic investigators and a non-profit research foundation to accelerate emerging science. Tony Coyle, VP and CSO of Pfizer’s CTI, says the program’s presence in each of the major U.S. life science hubs enables it to assemble highly customized teams with specific perspectives and skillsets. Pfizer and ALR will split the funding of academic investigators in Pfizer’s CTI network during the three-year collaboration. The partners have agreed to start off with four projects, but Coyle expects that, driven by success, the collaboration may run additional ones. He envisions funding in the $1 million-$2 million range depending on the particular needs of the project and how rapidly it can progress from bench to clinic. Coyle believes the team model – pharma, disease research foundation, and academia – can be replicated to other diseases and locales. Lupus, which is poorly served by drug therapy, is a natural test case since it’s a multi-organ disease that has recently seen dramatic advances in the understanding of its underlying mechanisms. It’s also genetically heterogeneous, and will require multiple drugs to treat all symptoms and subtypes. Pfizer, with two early-stage lupus candidates in its clinical pipeline, already has a head start.-- Michael Goodman

Arena/Ildong Pharmaceutical: San Diego biotech Arena Pharmaceuticals secured a second marketing partner for obesity drug Belviq (lorcaserin), as Ildong agreed to market the compound in South Korea. In a deal announced Nov. 6, Arena receives an upfront of $5 million and an additional payment of $3 million upon the drug’s approval by the Korea Food and Drug Administration (KFDA). Arena will manufacture Belviq and sell it to Ildong for 35% of annual net sales. That price will increase on a tiered basis up to 45%, not to exceed $15 million. Eisai has rights to Belviq in the U.S., Canada, Mexico and Brazil. That deal has a similar structure in which Eisai purchases Belviq from Arena in exchange for a percentage of annual net sales. In its Q3 earnings call on the same day as the Ildong announcement, Arena said Eisai would start to market Belviq in the U.S. in early 2013, subject to the U.S. Drug Enforcement Administration's final scheduling designation. Arena expects a decision by EMA on Belviq in 1H13. Investors don’t seem particularly convinced of the strength of a Belviq launch: shares are off almost 10% since approval on June 27. Still, competitor Vivus is off by much more – almost 60% since its Qsymia approval on July 18 – on a rejection by EMA for European brand name Qsiva (phentermine/topiramate) and a weak early Qsymia launch.-- S.L.

Chiromics/GlaxoSmithKline/Bristol-Myers Squibb: New Jersey-based Chiromics announced a pair of tie-ups on Nov. 9 under which Bristol and GSK will get non-exclusive licenses to the biotech’s chemical compound library. Bristol also will receive an exclusive license to a collection of proprietary chemical compounds discovered by Chiromics. Central to each deal is a screening collaboration to discover and optimize novel small-molecule candidates against multiple undisclosed therapeutic targets using Chiromics’ “cascade catalysis” technology. No financial terms were disclosed for either transaction. Based on technology discovered at Princeton University, this platform enables “accessible complexity,” the discovery of diverse molecules, including novel classes of drugs, that are differentiated from existing small-molecule therapeutics while offering drug-like properties, the ability to develop structure-activity relationships and ease of re-synthesis, Chiromics said. The biotech’s proprietary hit recognition algorithm, Chalis, also will be used in the discovery process with both pharmas.-- Joseph Haas

Pfizer/Auxilium Pharmaceuticals: The parties mutually agreed to end a 2009 partnership for the development, commercialization and supply of Auxilium's Xiapex (clostridial collagenase for injection) for Dupuytren's contracture and Peyronie's disease in the EU and 19 other European and Eurasian countries. The deal ends as of April 24, 2013. Xiapex (the EU trade name) is approved to treat Dupuytren's contracture in the U.S. and E.U. and an sBLA has been submitted for Peyronie's disease. Asahi Kasei has development and commercialization rights for Xiaflex in Japan, while Actelion has them in Canada, Australia and Mexico. The treatment is in Phase IIa testing for Frozen Shoulder syndrome (adhesive capsulitis) and in Phase Ib testing to treat cellulite. Auxilium recognized $15.7 million in Xiaflex/Xiapex revenues in Q3, including $13.2 million in U.S. revenues. As a result of the Pfizer deal ending, Auxilium will recognize $94 million of deferred revenue and $9 million of deferred costs in Q4. Auxilium president and CEO Adrian Adams said on the Nov. 7 Q3 earnings call that both parties were “disappointed” in the deal and that he’s in the midst of weighing options for these regions. -- Stacy Lawrence

GlaxoSmithKline/Xenoport: When is a parting of the ways not really a goodbye? In another “No Deal” this week, GSK and Xenoport ended a sales partnership, but the multinational pharma still agreed to buy an equity stake in the smaller firm at a premium price. GSK terminated a five-year marketing partnership for Xenoport’s Horizant (gabapentin), under which the it commercialized the restless leg syndrome drug worldwide except for six Asian countries, including Japan, for which Astellas held marketing rights. GSK said it is exiting the partnership due to an increased focus on core products. It paid $75 million upfront in 2007 for commercial rights to gabapentin, with up to $565 million in milestones potentially going to its California-based partner. To date, Xenoport has collected at least $130 million in milestone payments under the deal. While departing, GSK also is buying a 4.3% share in Xenoport, spending $20 million to buy 1.8 million shares at $10.86 per unit, a 30% premium over the stock’s 10-day average prior to the deal’s disclosure. Xenoport, which gets back all rights to gabapentin that were held by GSK, also is able under the deal terms to require the pharma to buy up to another $20 million in equity over the next six months.-- J.A.H.

Photo courtesy of flickr user 401(K) 2012 via Creative Commons license. 

Supremes' Prometheus Ruling Has Dire Consequences for Personalized Medicine

by Michael Boss

It is astonishing when nine very smart people get it so wrong. I refer to the US Supreme Court decision in Mayo v. Prometheus.

The court’s decision was that Prometheus’ patents are not valid since they are attempting to cover a law of nature. The analogy to E=mc2 is made. All of biology follows the laws of nature!

Prometheus developed an assay to help identify the correct dose of thiopurine drugs in the treatment of autoimmune disease. If the drug is metabolized too fast the level will be too low and so not effective. Too slow a metabolism and the drug can be toxic.

Potentially lost in the supreme circus around arguments addressing the constitutionality of the Affordable Care Act, the court is going to announce today whether it will grant or deny the ACLU’s cert petition asking it to review its suit against Myriad and determine if genes are patentable. Lawyers anticipate the court will grant the petition, vacate the Federal Circuit’s decision in favor of Myriad and remand the case back to the Federal Circuit for reconsideration in light of its ruling in Prometheus.

While the specific circumstances of the Prometheus case revolve around analyte measurements, by simple analogy it seems to me that the argument can be extended to genes and any gene products. So the identification of genetic variants that, say, cause disease or resistance to treatment by a drug or potential toxic response to a drug would all fall under this Supreme Court ruling.

This is a devastating ruling at the dawn of the personalized medicine era. The Court has wiped out any incentive to figure out why certain individuals might do better on drug A rather than drug B and how much of drug B should be given. And what about all the technologies under development to define the optimal treatment of cancer? Again by analogy, finding out which drug kills the tumor cells to select the correct drug for the patient would seem remarkably similar to the Prometheus situation.

The patent laws were developed to foster innovation and development of commercial enterprises. This decision has set back a key field by as long as it takes to get the ruling reversed.

image of Jacob Jordaen's painting, Prometheus having his liver eaten by an eagle (in our version the eagle is apparently the Supreme Court), via wikimedia commons.

Michael Boss, a biotech executive with companies including Antisoma, Xanthus, Elan and Athena, is currently an independent consultant. He is also an inventor on a seminal biotech patent.

Plavix Label Change: Good For Effient Now, Bad For Brands in the Long Run?

The Food & Drug Administration's public health alert on Plavix is, as we point out in "The Pink Sheet" DAILY, a nice boost for Eli Lilly and Daiichi Sankyo, who market the competing platelet agent Effient.

But the back story to this regulatory action merits closer attention by all pharmaceutical sponsors. This is no ordinary labeling change, and the implications of how the regulatory response came about only underscore how difficult it will be for all sponsors who hope to sustain (or revive?) the blockbuster model in the years to come.

This labeling change suggests a model for application of pharmacogenomic research that biopharma companies will find very threatening: it sure looks like sponsors hoping to build blockbuster franchises are at a huge disadvantage against payors hoping to limit those opportunities.

And that's why this labeling change may end up being bad news for all brands in the long run--very much including Effient.

First, the news: FDA has revised Plavix labeling to emphasise that the Bristol-Myers Squibb/Sanofi Aventis blockbuster doesn't work too well in patients who are poor metabolizers of the drug. In particular, FDA is concerned about impairment of the CYP2C19 metabolic pathway, whether because of genetic variations or coadministration of other drugs, including the widely used proton pump inhibitor omeprazole (Prilosec).

Okay, none of that is actually news. FDA first issued the warning in January, and quietly modified Plavix labeling in May.

What is news is that FDA has decided that information is now a formal warning, rather than a milder precaution--and, more importantly, the agency chose to amplify that warning (especially regarding PPI use) via a media conference call.

It is easy to see why Lilly and Daiichi would be pleased: anything that complicates the decision to prescribe Plavix will help them make the case that doctors should prescribe Effient (and, as we've already pointed out, they need all the help they can get).

Okay, so this sounds almost reassuringly like a classic story of head-to-head competition in a blockbuster class, and how the regulatory process can play to one side's advantage. Plavix is dinged, Effient benefits.

But this is nowhere near that simple.

Because there are third parties involved: payors and pharmacy benefit managers. The interaction between PPIs and Plavix was first publicized by Aetna and by Medco, both of whom used claims data to suggest an association between PPI use and diminished outcomes for patients treated with Plavix.

Its not just that payors capitalized on a safety issue: they really drove the regulatory response and the application of a newly discovered pharmacogenomic marker. In Medco's case at least, Chief Medical Officer Robert Epstein told us, the whole idea was to find a way to test the emerging theory that CYP2C19 genotyping may predict Plavix response. Since Medco didn't have genotyping data on patients in its database, it looked at concomitant use of omeprazole instead, since the PPI is a known inhibitor of the 2C19 pathway.

FDA's first public health alert followed the Aetna and Medco claims studies; the latest one came after Bristol and Sanofi conducted a drug interaction study confirming the observational results. That's certainly not a regulatory model sponsors are eager to consider--especially since we would be willing to bet that the observational research that triggered the warning cost Medco much less than the clinical trial the sponsors were forced to conduct to confirm it.

Medco, at least, isn't done. As we reported here, the company is now taking the next step, conducting a large scale observational study to test the hypothesis that the superior efficacy demonstrated by Lilly in its head-to-head study of Effient vs. Plavix can be explained by the inclusion of poor metabolizers of Plavix in the comparator group.

And Medco's interest most definitely is NOT in helping either brand in this class.

Medco's interests include advancing the company's positioning as a leader in therapy management, particular as it comes to applying pharmacogenetic knowledge. And Medco certainly wants to work with its payor clients to make sure insured members receive the best possible care.

But what Medco wants above all is to carve out a long term market for generic clopidogrel--and in effect limit Effient's share (as well as the share of all future brands in the class)--to whatever slice can't be held for the generic.

The study design, as Epstein explained to us, is simple: Medco will (at its own cost) run a genetic screen on patients prescribed Plavix to identify those who properly metabolize the drugs. It will then compare 14,000 of those patients to 14,000 Medco members who receive Effient, and see if there is a difference in cardiovascular outcomes.

Medco clearly expects to demonstrate that there is no meaningful difference between the two.

Now this whole thing could backfire on Medco. Its data could end up suggesting superior outcomes even when the comparison arm is enriched for Plavix response. (And Medco has registered the trial on ClinicalTrials.gov, so while we doubt they would trumpet that result, they can't just bury it either.)

And the study could by itself end up promoting the launch of Effient. Certainly, Lilly and Daiichi are only too happy to have Medco's support in spreading the message that their drug is active regardless of that specific genomic marker.

Indeed, as part of the screening effort, Medco is likely to drive some conversions from Plavix to Effient: patients who are genotyped as poor metabolizers will be informed of that status (as will their physician). Medco will not make any recommendations, but it is safe to bet that many identified as poor responders to Plavix will switch therapies. Given that 30% or so of the population has the genotype in question, Medco is likely to notify about 6,000 people that they may not be getting the full benefit of their antiplatelet therapy with Plavix.

But that only underscores the bigger point. Medco is willing to make a relatively big investment--and even to help grow a potential blockbuster franchise in the short term--in order to help limit the size of that market in the long run.

And it will cost Medco far less to do that than it costs for sponsors to bring potential blockbusters to the market in the first place.

Now, Epstein wasn't willing to disclose how much this undertaking will cost, but he did suggest it isn't terribly expensive. Medco collects the outcomes data already, so the only cost will be running the genotyping program. Medco will be doing the tests in house, via its own CLIA-certified lab test, so that expense will be kept as low as possible.

All in all, that is not a trivial expense for a pharmacy benefit management company to take on spec, but we're willing to bet it is less than 1% what it cost for Lilly to "prove" the superiority of Effient in a head to head trial.

Which is why, when it comes to trying to establish blockbusters in an era of high payor influence and ever advancing knowledge of the heterogeneity of drug response, it seems like the odds are stacked in favor of those who want to keep market sizes small.

Look for much more on this topic in an upcoming issue of The RPM Report.

image from flickr user mafleen used under creative commons.

Notes from BIO: Merck's Take on Biomarker-Based Drug Development

Merck sees itself as a leader in biomarker-based drug development. "We are toward the extreme end" of peer companies in the field, Executive Director of Licensing & External Research Reid Leonard said during a BIO breakout session May 19.

"We actually have very aggressive internal goals for the requirements for a biomarker strategy that is coincidentally built up with the drug discovery strategy for any new target."

But before you put Merck down as an advocate of personalized medicine, listen to how he described the company's approach:

"Ultimately our goal, despite the overall objective of being able to stratify patients where its appropriate and necessary, given the choice, if we are going to find a therapy that will treat a disease that many people will have, our preference is to find a way of doing that that in fact doesn't require stratification, that in fact picks a target that is intrinsically less sensitive to genetic variation than another target. So its using all the same data to try to essentially come up with a drug that in fact the physician can have some confidence will work in 80% of the people."

It's not that Merck will ignore stratification if it appears appropriate in clinical trials. That's just not the goal.

Notes From BIO: The Pathology of Personalized Medicine

Translating the vision of personalized medicine into reality is no simple matter, but here's an obstacle we hadn't considered before: the need to update the 19th century science of tumor pathology to address 21st century demands for biomarkers.

Pathologists rely on microscopic analysis of formalin-fixed, paraffin-embedded dead tumor cells--an analytical process that is logistically complicated and involves destroying most of the biological information contained in living tumor cells. For biopharma companies hoping to develop more targeted cancery therapy, there has to be a better way.

That, in a nutshell, is the business plan for Baltimore-based Biomarker Strategies, a 2007 start-up formed by Johns Hopkins professor of pathology and oncology Douglas Clark. Clark described the problem--and his company's proposed solution--during a panel discussion this morning on Integrating Genetic Markers in Drug Development.

Biomarker Strategies is developing an ex-vivo life tumor cell biomarker identification device--called SnapPath--which, Clark says, can help identify appropriate biomarkers and guide treatment choices, essentially at the patient's bedside.

We have no idea if SnapPath is a viable solution, but we appreciate the case study in the complexity involved in making targeted medicine a commercial reality. The science is revolutionary, but it will work only if there are also revolutionary changes in the practice of medicine to enable their use in the real world.

New Business Models for Personalized Medicine: Look to the Stars?

Rare diseases have often been the starting point for breakthroughs in medicine and biology: Oliver Sachs, for one, has made a career out of writing about rare neurological conditions as a window to a deeper understanding of how the human brain works.

Can business models built around rare diseases similarly serve as a starting point for a breakthrough in understanding or even reinventing the biopharmaceutical industry business model?

If a thought provoking forum hosted by the Institute of Medicine June 23 is any indication, the answer may be yes.

Entitled "Breakthrough Business Models: Drug Development for Rare and Neglected Diseases and Individualized Therapies," the workshop took an in-depth look at creative approaches to drug development. We were fascinated by approaches like the sustainable non-profit vision of the Institute for OneWorld Health, the patient advocate-driven research agenda crafted by the Cystic Fibrosis Foundation, Peter Corr's new venture with Celtic Therapeutics, and the orphan-drug as blockbuster model created and maybe perfected by Genzyme. And that was just the first panel!

Rare and neglected diseases may not sound like a promising opening for pharma execs struggling to make up for looming losses of blockbuster brands. But a little perspective is useful. Most in industry would agree that the future will bring many more specialty products focusing on relatively smaller patient populations, for a whole host of reasons--scientific advances in understanding the basis of disease, regulatory concerns about safety, payor insistence of value versus standard therapy, etc. etc.

In other words, the question may not be whether Big Pharma needs to focus more on rare diseases, but rather how Big Pharma can best prepare for a world in which, in effect, every disease is rare.

That, at least, is the argument that Tim Cote, head of the Food & Drug Administration's Office of Orphan Products Development, is making. He made it in person during the Pharmaceutical Research & Manufacturers of America trade meeting earlier this year, and repeated some of the points during the IoM forum. Cote wants Big Pharma to take more interest in the orphan drug program, since, as he points out, it has been largely the province of biotech companies.

Cote also highlighted some earlier work by IoM in the area that may now be a must-read for everyone in drug development: a 2001 report on "Small Clinical Trials."

Talk about a problem most Big Pharma R&D heads haven't had to think about! In an era where the central question has been how to keep the cost of Phase III trials below the billion dollar mark, most executives probably haven't spent a lot of time wrestling with the challenges of generating a robust data package from a study involving dozens--or even fewer--patients.

But that just might be the central regulatory challenge for the personalized medicine era.

It may feel like we've gone to another world here, but that is only appropriate. As Cote pointed out, the 2001 IoM report was commissioned by the National Air & Space Administration, which wanted to understand as much as possible about the effects of zero gravity on human health. NASA, as Cote points out, has "a lot of data, but very few astronauts."

One small step....

Personalized Medicine vs. Comparative Effectiveness Mailbag

Better late than never. Readers of IN VIVO Blog responded to a previous post on whether proponents of personalized medicine can also be supporters of comparative effectiveness research. We asked readers to weigh in on that question. Their emails initiated a lively discussion on the future of healthcare so we’ve picked excerpts from the most noteworthy responses to share. Here they are:

“Here’s an example to answer your query: Drug A is generic, Drug B is not. Compare their effectiveness and B works “better” so we all pay more for the newer drug. However, Biomarker Q indicates that some people do not respond to A at all. Remove those people from the analysis and now A&B work the same except for in the people with Biomarker Q, who have to get Drug B, although most would benefit from the less expensive drug A.” -Amy Miller, PhD, public policy director, Personalized Medicine Coalition

“Sure they go together. Right now, we characterize the groups in whom we compare therapies for ‘effectiveness’ based on their clinical diagnosis. For example, in cancer research we might compare a new treatment with an older one in ‘breast cancer’ as diagnosed by a pathologist reading a biopsy slide of a breast mass.

In the future, the ‘groups’ will be characterized not by their tumor biopsy’s look under a microscope, but by the unique genes expressed by the tumor. It’s the grouping parameters that will change and that’s how personalized (or genomic) medicine assists comparative effectiveness research. Personalized medicine just means we have better tools.” -Leonard Zwelling, MD, University of Texas M. D. Anderson Cancer Center

“The end-goal of personalized medicine and pharmacogenomics (the right drug in the right dose for the right person at the right time – comprising multiple, different ‘right’ answers) is very, very different from so-called ‘evidence-based medicine’ or comparative effectiveness, which looks to find a single best answer across an entire population. And it’s surprising how often people mix up the concepts—after all, each is an approach to improving medical care, but the underlying unit of analysis (individual versus population) is completely different.” -Bryan Walser, CEO Perlegen Sciences Inc.

“I hardly see the two options as diametrically opposed. The key concern for any legislator is getting the most value for every healthcare dollar spent. Comparative effectiveness attempts to divine the best option among multiple treatment options. Personalized medicine does the same thing, albeit for a narrower subset of patients. If one concedes that personalized medicine will always focus on smaller and smaller subsets of patients, it is not hard to imagine that comparative effectiveness will always be one subset above.” -Howard Hechler, director of business development, XL TechGroup

“Consider that personalized medicine can never be unique for each individual patient. Rather, it will be various medicines aimed at specific subsets within a disease state. For instance, multiple genetic defects can be responsible for inhibiting the production of a specific vital protein. One drug can treat one specific defect, while another drug could be used when the defect is at another location within the same gene. We could end up with dozens of drugs to treat the same disease, yet each treats very different specific defects.” -Steve Evans

“Think of personalized medicine as The Promised Land. Even its biggest boosters concede that it’s some way out on the horizon. There’s still a lot of progress to be made on the biomedical, informatics, education and training, and economic fronts. So, while we’re still wandering around in the wilderness treating patients with one-size-fits-all drugs, comparative effectiveness trials seem like a good idea.” -Michael Goodman, VP research products, AVOS Life Sciences LLP

“Personalized medicine and comparative effectiveness may indeed be strange bedfellows as you say in your post. In some ways, though, I think they both represent the triumph of science over marketing, and that appeals to a certain segment of the health policy community. With both of those principles fully in place, drug firms couldn’t use promotional muscle to get scripts written; they’d have to use data. And while it’s true the generalizations of comparative effectiveness are the opposite of the specifics of personalized medicine, I don’t think CE advocates would really object to a step therapy formulary that would eventually bring patients to the treatment that’s best for them personally.” -Anonymous

“My understanding is that the concepts are consistent because both personalized medicine and comparative effectiveness are based on making the best use of available information. In some cases we have enough information to craft therapies to particular patient situations (e.g. we might know that someone with a certain gene will respond in a certain way). Whereas comparative effectiveness deals with those cases where we simply do not have enough specific information but we do have statistical averages suggesting what the best practice would be given no other information about the specific case. Sometimes that’s all the information we have.” -Jason Bradfield

“Perhaps the similarity is that both personalized medicine and comparative effectiveness medicine use comparative measures. The difference is that one is in an individual population, while one is in a “smeared” population. The lowest standard for the measure of the safety and effectiveness of personalized medicine is on a comparative scale to other therapies used within the broader population. A higher, and probably unachievable standard, is for personalized therapy to be measured on an absolute scale for safety and effectiveness within a single person. Because this former standard is the more achievable standard, the two proponents can align, at least for now.” -Anonymous

The Other FDA Drug Chief

The drug industry is breathing a sigh of relief now that Janet Woodcock has permanently assumed the role as head of FDA's drug center.

But let's say Woodcock had turned down returning to oversee the Center for Drug Evaluation and Research, who would have been Commissioner Andrew von Eschenbach's next choice? Well, you can take a look at my incredibly accurate odds-making piece I wrote a few months ago. There were a number of internal candidates who may have been the choice. To read it, click here.

However, if von Eschenbach had decided to look outside, there were a number of names being thrown around as candidates. Two that I've mentioned before are Cornell pharmacologist Marcus Reidenberg and former University of Utah cardiologist Jeffrey Anderson. You can read a little more about them in The RPM Report by clicking here (registration required for non-subscribers).

Recently, I learned that another outside candidate was being pushed heavily by former FDA officials: Indiana University pharmacologist David Flockhart.

Flockhart appears to be exactly the type of candidate the agency would have been looking for in an external contender. Flockhart, chief of the division of clinical pharmacology at Indiana, is a believer in the personalized medicine revolution and the basic tenets behind FDA's Critical Path Initiative. To read more about his points of view on medicine, science, genetic testing and drug safety, click here.

A former Georgetown University researcher, Flockhart is credited with establishing Indiana as a site for NIH/National Institute of General Medical Sciences’ Pharmacogenetics Research Network. He received his MD from the University of Miami School of Medicine and PhD from the Welsh National School of Medicine in Cardiff.

So why does this matter? Well, it's interesting, isn't it? But more importantly, these are the types of thought leaders to keep on your radar for later down the road in different administrations or as possible liaisons between FDA and the academic world for key FDA/NIH/CMS initiatives. That's why they matter.

I'll keep my ear to the ground for other candidates that were interviewed or championed for the CDER director position so we can start a whole web series on "People Who Weren't Named CDER Director."

Finally, tune in next week for my Personalized Medicine Mailbag blog post. I wanted to thank everyone for the overwhelming response to my personalized medicine post. Apparently, people care about this issue. It's not too late to email me with your take on the personalized medicine vs. cost effectiveness debate.

Personalized Medicine: Kennedy Weighs In

So now, even Ted Kennedy is talking about personalized medicine.

The Dean of the Senate stopped by a policy breakfast put together by The Hill newspaper and sponsored by AstraZeneca at Johnny’s Half Shell near Capitol Hill on April 8. He had some encouraging words for the personalized medicine enthusiasts out there.

“A new era of personalized medicine” is coming, Kennedy said at the breakfast. “And those are words we’re going to hear a great deal more about.”

He added: “The opportunity is unlimited.” AZ CEO David Brennan later echoed Kennedy, “the point Senator Kennedy made about personalized medicine is an important one.”

If the senior Senator from Massachusetts is aligned with the pharmaceutical industry on the future of medicine, ladies and gentlemen, break out your checkbooks, call your broker and start buying up biopharma concerns.

Kennedy’s comments were brief, so I don’t want to give the impression that his talk was a treatise on customized medicine. However, he made it a point to highlight the approach, along with prevention and disease management, as one road that should be well-traveled as the nation seeks solutions to the “health care crisis.”

Brennan related a story of meeting with the health minister of a foreign country and the minister said to him, “what we really need are the big breakthroughs.” Brennan shot back, “so do we.”

The AZ CEO continued: “Our experience with innovation is it’s incremental. We didn’t go from the Model T to the Mercedes 500 class in one step.... The bar for scientific innovation has been raised significantly.”

Personalized medicine—the right therapy for the right patient—is quickly emerging as one answer to various health challenges, including the innovation conundrum (incidentally, Brennan pointed to better science allowing companies to “kill products earlier” in the development cycle as a major reason for the low number of new molecular entity approvals over the last several years. Do with that what you want).

While there is still a lot of skeptical noise about turning a buzz word into real commercial success, it’s undeniable that the idea of customizeable therapy is gaining steam. HHS Secretary Michael Leavitt has made personalized medicine an agenda priority. Here is what he said during the Personalized Medicine Coalition’s annual meeting last March:

“It’s clear to me, and to many others in government and throughout the health care enterprise, that we’re on the threshold of a new era made possible by phenomenal leaps forward in two areas: first, new discoveries in bioscience, especially human genomics; and second, new tools in the computer age – meaning health information technology. These great leaps will enable us to give better care to all patients – by targeting the unique biology of every patient.”

HHS also issued a comprehensive report on the opportunities of personalized medicine last year to kick start the initiative. To read the full report, click here.

One thing I’ve found interesting is that a number of personalized medicine proponents are also comparative effectiveness proponents. Kind of odd since the two ideas are diametrically opposite each other. One looks at having the right medicine for the right patient while the other looks at comparing one therapy to another as they relate to a broad population and typically assigning a value to that comparison. Right? If you can better explain the relationship, click here to email me and I’ll blog about your response(s).

Kennedy mentioned comparative effectiveness as a tool in the health care debate but it was hardly a ringing endorsement. “If we’re going to have a debate about health care cost issues are going to be front and center,” but said “it’s not enough to analyze one treatment for another.” He discussed regional disparities in cost for care, something Congressional Budget Office director Peter Orzag often cites on his personal campaign for a comparative effectiveness infrastructure.

It’s a funny scene seeing Ted Kennedy, arguably the drug industry’s most vocal critic in Congress over the course of the last 30-some years, standing up in front of an AstraZeneca banner essentially saying ‘we’re here to solve America’s health problems together.’ And it’s not just paying lip service. Kennedy is putting words into action by providing a roadmap for the drug industry to get more of their drugs approved at FDA with provisions in the FDA Amendments Act, as well as serving as a driving force for a fair and balanced approach to follow-on biologics.

He's not done either: "I'm committed to enacting genuine health care reform in the coming year."

The Hope and Challenge of Personalized HealthCare

"Industry should take on the burden of showing the value of new technologies in terms of relative costs and benefits to the Federal government."

That was one of Hoffmann-La Roche Inc. CEO George Abercrombie’s key points in his address on Personalized Healthcare during Windhover's FDA/CMS Summit for Biopharmaceutical Executives December 6. (You can read more about the Summit's various talks elsewhere on the IN VIVO Blog--here, here, here, and here--and in the upcoming issue of The RPM Report.)

"It is our fault if we allow Federal programs and other insurers to view each advance in personalized healthcare as merely adding the costs of an additional test to their program without taking into account the health and economic benefits of prevention, safer health interventions and more effective health outcomes," Abercrombie said.

He offered an example from Roche's own experience, the commercial failure of AmpliChip, the first FDA approved micro-array. "Even though the FDA cleared it, many insurers declined to cover it because its utility was considered experimental, investigational, or unproven. Others declined to cover it because its clinical value has not been established."

If industry does its part, Abercrombie said, government needs to do its part too. "Even if the new therapy results in additional costs to the Federal government in the short term, the government should still provide premium reimbursement for these products if a case can be made for coverage based on the relative benefits to patients and the product saves the government money over the long term."

An example? How about Roche's once-monthly bisphosphonate ibandronate (Boniva), marketed to treat osteoporosis.

"Biochemical markers of bone turnover in patients with osteoporosis are reliable indicators of successful treatment as early as three months after start of bisphosphonate therapy," Abercrombie says. "Adoption of inexpensive testing, combined with pharma therapy should be embraced by the Government to control costs and improve individual patient outcomes."

Unfortunately, "payers have decided to cover bone mineral density screenings after one to two years of bisphosphonate therapy."

"We believe early feedback and positive reinforcement from biochemical markers of bone turnover in patients with osteoporosis could encourage responders to continue to take their medicine regularly. Likewise, if the bone turnover markers show that a patient is a non-responder; their physician should have that information available in deciding whether to change the patient’s bisphosphonate therapy or discontinue therapy, even if it hurts Roche’s market share."

All in all, sounds like a company willing to put its money where its mouth is.

If you missed Abercrombie's keynote address at the FDA/CMS Summit December 6, you can read it here.

While You Were Finally Watching Some Football

Autumn's here, and the NFL is back. IN VIVO Blog's contingent of Philadelphia Eagles fans is predictably feeling a little uneasy about the season ahead. Meanwhile, here are a few odds and ends from the weekend.

• More GSK hand-wringing in the UK papers, this time it's the Financial Times. (Hat Tip: Pharmagossip.)
  
• Hey look, free access to medical journals. (via the NYT)
• The SF Chronicle looks at personalized medicine, and how the FDA is encouraging drug developers to find genetic patterns in responses to treatment.

(Photo by Jonathan Daniel/Getty Images)

Science Matters: A small personalized medicine bailout for Cox-2s?

There was little attention paid to last week's paper suggesting that PPAR delta agonists might be used to prevent the cardiovascular side effects of Cox-2 inhibitors (coxibs) such as Vioxx and Celebrex.

The study in the Journal of Experimental Medicine (JEM) showed that Cox-2 suppresses the expression of tissue factor (TF) -- the primary activator of blood clotting and a proximal cause of coxibs' CV problems -- via the activation of PPAR delta.

Of course, there are no approved PPAR delta drugs, although pharmas including GSK have tried developing them to treat cardiovascular disease. (One news outlet suggested GSK's drug could be an "unlikely savior" for Vioxx, but that's a far stretch.) And no one would think to couple a PPAR delta with a coxib for use as a combination analgesic--the risk/benefit ratio of that presumably is way off.

But there's another, intriguing aspect to this research result.

The problem with Vioxx is that it is associated with cardiovascular complications in a small number of patients. "We should look at these patients in terms of their TF levels and other clotting parameters," suggests Timothy Hla of the University of Connecticut Health Center and a principal author of the JEM paper. "Is the TF gene in these people somehow different? Is it regulated differently? Are they more sensitive or more resistant to the effects of the PPAR delta they produce? Instead of looking at the selectivity of Cox-2, let's look at patients' sensitivity."

Hla has a longstanding interest in Cox-2's role in normal blood vessel physiology and angiogenesis: he cloned the gene from human vascular cells in and named it Cox-2 in 1992, while at the American Red Cross Research Institute.

A first step would be to measure TF levels, which can be easily collected from plasma, in patients taking Celebrex and correlate them with treatment results. It's all well and good to talk about testing PPAR delta agonists for their therapeutic effects regulating the TF gene. (The most advanced may be GSK's GW 501516, which the Hla group used in its experiments. GSK in-licensed the compound from Ligand Pharmaceuticals, but its development has lagged at Phase II. Ligand's most recent 1o-K says the drug's development is 'on hold' pending the review of preclinical studies, and there is no mention of it on GSK's own clinical trials web site or in any recent publicity [clintrials.gov lists a 'completed' Phase II study], so for all we know it has been terminated.)

So that's a long way off. Most of the focus on the mechanism of Cox-2 has centered on its effect on platelets. A simple blood test might go a long way towards refining that effort.