Pharma deals 2012

Last month Pharmaceutical Executive published a summary based on its annual panel of heavy hitters in business development on best practices in licensing and M&A for the year ahead. The discussion was built around the latest findings from Cambell Alliance's 2012 Survey of Dealmaker Intentions. The survey had many interesting conclusions, and I thought that I would summarize a few of their thoughts here - I recommend reading the full article.

Most attractive in-licensing therapy areas

In-licensors expects most deals to be made in oncology, cardiovascular, CNS, metabolic and respiratory drugs. Oncology has a unique characteristic in that interest is high at all levels of the development cycle, including early stages. In fact, the interest in doing deals in pre-clinical, Phase I and II was found to be higher than for those in Phase III. All other major therapeutic segments (except immunology) showed a preference for candidates in phase III. An interesting side note from David Thomas (BIO) was that oncology, CV and CNS have the lowest success rates (less than one in 10 compounds make it from phase I to commercialization). 

Trends within individualized treatments

FDA has approved 3 drugs in the last 12 months whose mechanisms are intended for a specialized target sub-population. Because the ability now exists (in some disease areas) to target and individualize therapies for patients, the per patient costs can be higher but it is also more likely the payers will support price premiums for some guarantee of better performance among a defined patient group. J&J did a deal with the UK NICE, to obtain payer buy in, in which it guaranteed that if Velcade did not work in a patient, it'd pay back the NHS. 

About asset valuation

A decade ago the approach in valuing a target incorporated a lot of material that frankly is irrelevant, such as the number of patents on file, the number of employed scientists, or the square footage of lab space. R&D is not a numbers game. Pfizer consistently spent the most money on R&D and employed the most scientists, yet the return from its effort was poor. Nowadays companies are valued more on the basis of their strong cash flow, and little credit is given for development stage assets. The early 1990s saw enormous valuations for "ideas" with early stage IPOs, but with investors unable to sort through the good from the bad and value assets appropriately. Many companies subsequently failed.

Deal-making with academia

Universities have been empowered and push very hard on the IP front, taking a major interest in leveraging intellectual capital to generate profit. The IP and know-how from academia is important in drug development but often represents a small piece of a very complicated value equation, currently there seems to be little understanding that their contribution may only be a small part of the very long and expensive process to bring products to commercialization. Data packages from academia are rarely done to industry standards. Negotiations have on the other hand started to change. For a long time, academic partners insisted on terms that were entirely one-sided: take all the patent rights, refuse exclusivity in partnering, and reimburse them for 75 percent of the overhead costs. Today, the approach is more similar to those made with small biotech partners: with upfront payments plus royalties linked to milestones. Many TTOs now hire people with background in venture, biotech or Big Pharma - this could be a sign of an improving relationship.

Tobias Thornblad

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Big Data development in Life Science

Big Data development in Life Science

Big Data is becoming an increasingly more popular concept and new companies are launched almost every week.  The first to go public - Splunk - was recently valued at $3 billion when it launched earlier this year on Nasdaq. Many players besides Splunk are approaching Big Data and some of these include Wavii, Metamarkets, Palantir and IBM. It seems like there is a race to collect, curate and analyze the vast amounts of unstructured data out there. On the non-profit side, it is reported in the latest issue of Fast Company that the Wikimedia Foundation will complete its first phase of development of Wikidata in August. Wikidata will extract data from Wikipedia to create a database focused on facts and figures with less subjectivity.

At the same time, more data is becoming available from various sources. When Facebook launched its $100-billion initial public offering, its userbase surpassed 980 million users worldwide. This means that nearly one in seven of the world’s population seems to be comfortable sharing personal data over the internet. What started out as a social network where we shared photos has transformed into a forum where we are comfortable in sharing geographical coordinates of our current locations and even position on whether we are organ donors or not. It is perhaps not far fetched to predict that we will be comfortable to share even more in the future. In spite of this trend, most of us still are more circumspect when it comes to sharing genetic, physiological and medical information online. An editorial in this month's issue of Nature Biotech brings up this issue and states that one key reason for poor uptake could be that there is still no simple and transparent way to track how personal data are being used, let alone a means to opt into, or out of, research using the data.

Portable legal consent (PLC)

To tackle this problem a new type of consent process - Portable Legal Consent (PLC) - has been launched. The PLC aims to simplify informed consent and allow feedback of results to any participants. This will put donors in greater control of their own data, which will hopefully lead to more data being shared. The feedback mechanism is thought to provide an incentive for individuals to donate data since the patients in the 'traditional model' usually learn nothing of the research outcomes from their specimens or data, which is particularly true if the results are never published. This, however, demands that informed consent is overhauled.

NBT writes that in the United States: informed consent is based on a uniform 20-year-old, almost pre-internet set of regulations, colloquially known as the ‘Common Rule’. Under the Common Rule, the patient’s signature on the consent form following an ‘informing’ conversation creates a legal agreement that allows research (or medical procedures) to go ahead. The scope of research depends on the consent form; in some cases, biological specimens and associated data can be used only in the research described in the original consent. Alternatively, consent can be broader, extending to future research, within or without some limits. Most donations of tissue and data can be used only once, in the original research project. Any subsequent analysis, reanalysis or pooling with other data is breaking the law.

The PLC (http://weconsent.us) provides a solution by permitting research participants to contribute their data to a common consented environment enabling broad and multiple research uses. Importantly, patients can withdraw their data from the database at any time. The withdrawal does not operate retrospectively, so derivatives of the data, or even copies of it held on computer drives, are likely to remain available. Publications based on their data would also be unaffected by data withdrawal.

Creating the incentives to share personal data

A crucial element, besides trust, in building a successful platform where personal data is shared is of course to provide incentives to share. Google Health failed to attract users because of many reasons but one may have been that people saw no real benefit in uploading their data. One incentive for donating data or specimens to medical research could be learning about how the data has been useful for the research community. Another may be to get access to a network of patients with the same condition (PatientsLikeMe) or learning about their genetic profile (23andMe). With the latest trends in the Quantified Self movement there will likely be multiple other incentives to share data from consumer-diagnostic tests, biometric devices to measure glucose levels, heart rate and indications of stress. The latest issue of Entrepreneur writes that Quantified Self company FitBit  says that the average user takes 43% more steps per day when they use their device. The biggest incentive, however, likely is the fact that FitBit users can track their progress online through infographics, pie charts and stated goals. For some products it may even be enough to just compile data into Facebook statuses to show friends and family how healthy you are (e.g. RunKeeper, WOD of the day, etc).

The question is not if we will share, it is when we will share our clinical data and where.

Tobias Thornblad

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IP activity in the pharma & biotech space during 2012

Much of the Life Science blogosphere has focused on the Supreme Court’s decision in Mayo v. Prometheus lately. The decision has jolted the biotech industry through a unanimous ruling that threw out two medical-testing patents and has questioned the very concept of what a law of nature is when it comes to medical testing. The case involved a group of drugs used to treat diseases such as Crohn's and ulcerative colitis. For patients taking thiopurine drugs for such immune system diseases, physicians must adjust the dose to make sure the drug works while side effects are avoided. The Prometheus patent described connecting the level of certain chemicals in the blood to the thiopurine dosage to balance between too high or too low dosage. This led justice Breyer to conclude that the Prometheus patents recited laws of nature, which has sparked a big discussion. Personalized medicine and companion diagnostics are examples of areas that are heavily affected by this and given the fact that thousands of patents for diagnostic tests have been issued in the past two decades - the court ruling could have dramatic effects on the biotech industry. One of the most cited examples is of course Myriad Genetics’ test for breast-cancer risk using information about the BRCA1 and BRCA2 genes. To follow the debate I recommend visiting Patent Baristas, Patently BIOtech or Holman’s Biotech IP Blog.

On the pharma/biotech side of the industry there is also activity in the IP-realm. Due to the commotion around Prometheus, IP analysis around pharma/bio seems to have been in the background lately. Therefore, this month, Intangitopia is providing you with an overview of IP lawsuits, settlements and infringements in the pharma/biotech space covering Jan-June 2012: 

As can be seen in the diagram above, most of the activity has been in the disease groups: 1) nervous system diseases, 2) nutritional and metabolic diseases, and 3) respiratory tract diseases. Below are summaries of the top IP news in media within these disease groups.

Nervous System Diseases

Indication	Companies	Products	Top news description
Pain	Merck & Co Inc	Vioxx	Merck Resolves Vioxx Litigation in Canada
Opioid Abuse/Pain	BioDelivery Sciences International (BDSI), Endo Pharmaceuticals	BEMA Buprenorphine	BioDelivery Sciences Receives Patent Allowance Triggering $15 Million Milestone Payment from Endo Pharmaceuticals
Pain	Zalicus Inc.	Hydromorphone hydrochloride	Settlement confirmed in litigation between Zalicus and Mallinckrodt and Watson Laboratories Inc
Parkinson's Disease	Orion Corporation	Stalevo	Orion sues Mylan to enforce its U.S. patents covering the proprietary drug Stalevo
Post-Herpetic Neuralgia	Watson Pharmaceuticals Inc, Endo Health Solutions Inc, Impax Laboratories, Inc.	Lidocaine, Lidoderm	Watson Announces Lidoderm Patent Challenge Settlement
Relapsing Remitting Multiple Sclerosis	Genmab A/S	--	Genmab Announces Patent Settlement Agreement for Ofatumumab
Sleep Disorders	Mylan Inc, Teva Pharmaceutical Industries Ltd	Modafinil, Nuvigil	Mylan Settles Provigil Litigation With Teva

Nutritional and metabolic diseases

Indication	Companies	Products	Top news description
Diabetes Mellitus	Lupin Pharmaceuticals Inc	Metformin hydrochloride	Lupin announces settlement with Santarus and Depomed for Glumetza Patent Litigation
Hypertriglyceridemia	Pronova BioPharma ASA, GlaxoSmithKline plc	Omacor	US District Court Rules in Pronova BioPharma's Favour on Lovaza Patents
Non-Insulin-Dependent Diabetes Mellitus	Novo Nordisk Inc, Sun Pharmaceutical Industries Ltd., Depomed Inc, Santarus Inc, Mylan Inc	Victoza, Glumetza, Pioglitazone hydrochloride, Metformin hydrochloride	Depomed files patent infringement lawsuit against Watson

Respiratory tract diseases

Indication	Companies	Products	Top news description
Allergic Rhinitis	Merck & Co Inc	Nasonex	U.S. District Court Rules Against Merck in Nasonex Patent Lawsuit
Asthma	Mylan Inc	Levalbuterol hydrochloride	Mylan Announces Settlement Agreement in Litigation Relating to its Generic Xopenex
Chronic Obstructive Pulmonary Disease	Mylan Inc	--	Mylan Announces Settlement Agreement in Patent Infringement Litigation Relating to Sunovion's Brovana Product
Infant Respiratory Distress Syndrome	Cornerstone Therapeutics Inc	Curosurf	Court Orders Dismissal of Curosurf Case

Tobias ThornbladTwitter

Crowdsourcing as IP-strategy

Crowdsourcing is a concept that is used ever more often when knowledge intensive industries are discussed. Arturas Vedrickas today briefly describes a location based social network known as Foursquare on the CIP FORUM blog that is planning to harness its large base of users. There are currently many interesting examples of crowdsourcing initiatives in the IT-industry where of course Wikipedia is one of my personal favorites. However, this concept is certainly spreading into other knowledge intensive industries such as the biomedical society. This is perhaps not surprising, given that the biotech revolution has transformed the whole pharma industry into a data driven reality where knowledge is key.

Crowdsourcing

Crowdsourcing refers to outsourcing tasks that would usually be performed by people within a company or institution to an outside 'crowd' of people, outside the organization. This way of harnessing the power of the many differs from other types of open innovation in that members of the crowd nowadays has grown accustomed to generally expect some kind of incentive or reward. This has been a rather quick transition given that the term 'crowdsourcing' itself was coined less than 5 years ago, by Jeff Howe writing for Wired magazine.

Harnessing the Global Brain in Life Science

Early efforts in the biomedical field to use this innovation strategy was - not surprisingly - implemented in the fields most closely similar to the IT-industry. Namely bioinformatics. Some of these efforts included BioJava, BioPerl, BioPython, Bio-SPICE and BioRuby. Two early initiatives, in 2000, without the word "bio" in their names were Screensaver Lifesaver and Folding@Home. Both of these harnessed the power of volunteers. Foldin@Home models the thermodynamics of protein folding, while the Screensaver Livesaver used 3 500 000+ volunteers to run molecular modeling simulations, docking potential ligands into the binding sites of known drug targets for various diseases.

Indianapolis based pharma giant Eli Lilly was one of the first Life Science companies to implement this way of thinking. In fact, it is more accurate to say that Eli Lilly was part of creating and defining the field of openness within Life Science. At the same time as Folding@Home and SL were launched, Sidney Junell, then head of Lilly, organized a group of executives to explore new ways of working. Impressively, no fewer than three successful open innovation companies—InnoCentive, based in Waltham, Massachusetts, YourEncore, in Indianapolis and Cincinnati, and Collaborative Drug Discovery, based in Burlingame, California—sprang from these discussions. For the past decade, Eli Lilly has maintained a leading position in the Life Science field of internet-led open innovation.

Several interesting initiatives have sprung up over the last few years in this industry. Within genomics, 23andMe (a model I have written about here on Intangitopia in the past) is a company that accumulates data from its customers through crowdsourcing. Customers of the personal genomics startup who submit samples of their saliva for genotyping have the opportunity to take part in surveys, which, when combined with their genetic information, can provide useful information to the wider group about genetic linkage. This approach of course becomes even more powerful still when genetic data are combined with contributions from patients. For Parkinson's disease 23andMe tries to achieve this through to collecting genetic data from individuals in a partnership with PatientsLikeMe and the Michael J. Fox Foundation. Patients Like Me, in turn, is also a crowdsourcing site that allows its - by now 80 000 - members to share details of symptoms and treatments with each other, as well as with the research and medical communities. The reward in this case is to learn more about one's condition through the experience of others.

Business implications and using crowdsourcing as innovation strategy

Given the intellectual property difficulties that is generated by the volunteer computing models (Folding@Home and Screensaver Livesaver), these have largely been embraced by the academic and not-for-profit sectors. But what about the other models: are these also incompatible with IP? Of course not.

A recent example of an implemented corporate model for harnessing crowd-sourcing is that of Life Technologies (LT). The company announced in December a $7 million crowdsourcing initiative called the Life Grand Challenges Contest. Focus of the contest is on LT's new Personal Genome Machine acquired from Connecticut–based startup Ion Torrent. The sequencing technology costs $50,000 to buy and can sequence a sample at a cost of $500 in just two hours. But that is apparently not good enough for Jonathan Rothberg, founder and CEO of Ion Torrent. The first three $1-million challenges in the contest ask innovators to devise ways to make Ion Torrent's technology even faster, cheaper and more accurate.

Implementing crowdsourcing in your IP-strategy

A model that I have seen successfully implemented in the IP-strategy of a large biotech company actually used crowdsourcing. This particular company often used the Innocentive platform for this very purpose. Innocentive connects a community of solvers with seekers (companies that post technically challenging research or management problems). Any individual may register as a solver. Solvers pay no fees, but most formally register for a challenge before they receive the full, confidential outline of the project. While seekers pay to register on the site and again to register each challenge. If a problem is solved, pre-defined reward(s) is/are paid to one or more solvers out of the registration fee. Intellectual property is thus protected under secrecy agreements (formal registration for solvers) and transacted to the seeker as a reward is paid to a solver.

When the company had made a new discovery it posted the problem (not its solution/discovery) on Innocentive. This way, the company was typically able to "purchase" additional solutions to the same problem by paying out Innocentive rewards. An approach that was much cheaper than inventing these solutions in-house. Patent applications covering the various solutions would then be filed and consequently a much stronger position against invent-around risks resulted.

Alternative IP-strategies and IP-based business will be discussed during CIP FORUM in May.

(Btw, don't miss the early bird fee before the end of March)

Looking forward to see you there.

Tobias Thornblad

Personalized medicine - a growing market

In March, I wrote about how personalized medicine is becoming an increasingly important concept in the biotechonomy worldwide. This development is now becoming more apparent and actors seem to be moving in this direction. One of the driving actors pushing this development certainly is insurance companies. Against this background, it is interesting to reflect upon how the U.S. health reform that President Obama signed into law last month. This is certainly one of the most comprehensive legislations concerning healthcare provisions in U.S. history. Obviously the health reform will have a tremendous impact on innovation for its many stakeholders, although some may feel more that they will reap more benefits than others will.

Health reform impact on new biotech business

April's edition of Nature Biotech (Vol 28 No 4) reports that "In return for supporting the bill and stumping up $90 billion in fees and discounts on Medicaid and Medicare pricing, the drug industry receives tax breaks, a biosimilars pathway and a massively expanded drug market." A key question for the Biotechnology Industry Organization (BIO) has been the exclusivity term for biosimilars, which in the reform was left intact at 12-years exclusivity. Another advantageous factor for pharmaceutical companies was that the industry managed to avoid suggested restrictions on drug price and drug importation. It is easy to conclude that all these factors will provide economic drivers for private biotech innovation. Much of the health reform, however, targets - a widely discussed subject in the U.S. - which is health insurance.

By enfranchisement of the many U.S. citizens previously uninsured, not only does the health reform provide societal benefits by progressing towards universality of healthcare access - but it simultaneously expands the U.S. healthcare market with more than 30 million people. For biotech and pharmaceutical companies such a market expansion is very good news and The RPM Report industry newsletter estimates that it could result in $115 billion in new business over 10 years.

How the bill drives the demand for life science innovation

Business models of health insurers in the U.S. have - ironically - been the most profitable when these actors successfully have circumvented the difficult and expensive burden of dealing with sick people. But the new bill prevents insurance companies from excluding coverage to children with pre-existing disorders and it forbids insurance to be dropped when a person becomes ill. I don't think it is far-fetched to say that this is somewhat of a game changer for these actors since their business models now will have to bear more of the financial risk and burden of the sick and vulnerable. This - at least to me - is very interesting from a business model building perspective but perhaps more interesting is the new demand that these actors will create for reducing costs associated with life science innovation.

From an insurer's point-of-view, a number of demands are likely to result;

• Innovations to diagnose patients at an early-stage
• Innovations to effectively prevent patients falling ill in the first place
• Innovations to reverse disease
• Innovations to effectively select patients that are likely to benefit from treatment at all
• Innovations to effectively select which patients that are the most likely to benefit from which drug

To me, the bullet point list above shortly translates into some of the most common biotech products such as diagnostic tools, screening methods, drugs, and vaccinations. But it is interesting that more or less all of these have a personalized medicine touch to them and it doesn't seem unlikely that this will be of the major effects of the new health reform. Naturally this will stimulate creation of new biotech assets such as biomarkers, drug targets and candidate inhibitors/activator molecules, which in turn will lead to new life science innovation (six of the 26 FDA approved drugs during 2009 are personalized medicines).

New development towards personalized medicine in the U.S.

Against this background, Medco Health Solutions provides an interesting business model to learn from. In February, it acquired the San Francisco-based genomic medicine company DNA Direct to strengthen its commitment to personalized medicine. The acquisition has similarities to the strategic partnership that was signed between CVS Caremark of Woonsocket and Generation Health, at the end of last year. Medco's aim is to help physicians and payors better match individuals to therapeutics and improve clinical outcome while saving money, by becoming a one-stop health service shop. Nature Biotech reports that several trends help draw pharmacy-benefit companies into personalized medicine. Firstly, there has been an explosion in the number of genetic tests. Medco estimates there to be a 1000 genetic tests, which in many cases the full benefits are not extracted due to inappropriate interpretation and lack of knowledge. A second factor - closely connected to the discussion above - is a growing interest from payors. CVS Caremark states that "To our clients, the insurance companies and self-insured employers, being able to provide tests that target drugs to individuals is of great interest". Thirdly, the main driver is cost reduction. The need to cut healthcare costs is most likely behind the surge in personalized medicine. PricewaterhouseCooper estimates that the core market for personalized medicine - diagnostics and therapeutics - is already worth $24 billion and expected to grow 10% annually, reaching $42 billion by 2015.

What will big pharma say?

What I find particularly interesting in all this is the predicament that this new focus on personalized medicine creates for pharmaceutical companies. Personalized medicine will transfer the control position for how and when drugs are used, something that used to be controlled by drug-label indications and physicians (in consultation with big pharma). Will big pharma remain on the sidelines or will they enter the arena?

Tobias Thornblad

(Contact via Twitter)

RE: Abbreviated Pathways to drug development

I would just like to add some thoughts, on the money side of things, regarding Tobias' interesting thougts. As pharma is a huge ecosystem changes wont come suddenly and definately not without a noticable fight! Below I put down my thoughts on the situation, although perhaps not entirely correlated.

Sharing is caring - also in pharma ?
Almost everyone is writing about pharma collaborations with academia and how that will generate openness, speed and lower costs. Just having researchers work together and streamlining NDA's and disclosure policies lowers transaction costs for development. My question is if (when?) some BigPharmas will take it one step further and come togehter and own entire universities, paying for tuition in exhange for all research results.

I'm envisioning special purpose, e.g. gastrointestinal, (PhD) universities. These would paid for entirely by e.g. 4 bigPharma companies and would give scholars a PhD degree and the companies lots of input. My idea is that BigPharmas would focusing on getting more brainpower rather than the a selected few. Also that they would start sharing the most valuable substances that are discovered. Simple maths show that a blockbuster is needed to make up R&D costs of all non-profitable drugs, especially now when "only" the western world is buying drugs.
But what if the hit/miss ratio of drugs get's improved, by sharing knowledge and goals in the universities I envision, maybe sharing expense/income on blockbusters would be enough. And also - costs need to be cut when India and China catch on.
The natural concern for this would be on the competition-law side, as I can envision a good 'ol gentlemans agreement when dividing the markets.

Generica deteriorating Pharma innovation ?
A recent ruling in California (well commented here and here) basically says that Pharma companies are liable for side effects etc. caused by generica using the same substance.
To me the situation becomes quite perverse as generica companies would operate on a totally risk free basis if they would also be excluded from litigation. In relation to Tobias' post even shorter times before generica becomes available could turn into an interesting pricing situation.
Firstly - shorter times mean shorter times for ROI on drugs. As R&D costs likely won't drop substantially, by all laws of finance a price increase is to be expected.
Secondly - if big Pharma are liable for damages caused by the substance as such rather than the drug, this would either result in an increase of litigation costs or large insurance policies (if someone is willing to write one in these days). It would likely impose a cost on BigPharma.

Bottom line - costs go up for patients/consumers. That could create a very interesting marketplace for drugs. The high price means makes it analogous to drilling for oil in remote locations. If the price is high enough it would mean that more players could find the market feasible. I see that this could have any of the following implicatons:

1) A surge in pharma R&D as a blockbuster with the new high price could mean even higher revenues. Perhaps smaller VC-funded labs could be the way to go as splitting that large revenue could be enough to see ear-marked VC funding for drugs.
2) A more dismal scenario would be a standstill in the innovation and patenting pipeline as fewer actors would see the financial benefit.
3) Forum shopping for lower R&D costs, i.e. pharma development follows the path of heavy industry and moves production and research to remote locations.

The big question is really - when will pharma markets as we know them change?

Marcus Malek