Somehow, I found myself at the boarding gate having fast-tracked through security with speed usually reserved for animals of the four-legged variety. Time for a coffee even―especially as one of the runways at Heathrow was closed causing delays to all in- and outbound flights. Not going well.

Nevertheless, I found myself stood in Frankfurt  Messe on October 24 considering my options and hoping I would still be able to make the CPhI pre-show conferences planned for the day before the main events. Success!

I was fortunate enough to attend a conference entitled “The challenges and opportunities in biosimilars and biobetters,” which offered a rare glimpse into the strategies, concerns and successes to be had in this contentious area. Moderated by Alan Sheppard of  IMS Health the conference brought together several schools of thought on the topic, which perhaps mirror the global view. Sheppard classified current thinking on biosimilars under three headings: a mirage, an opportunity with some way to go, and something just around the corner. And taking into account the presentations that followed, perhaps it is a little of all of these things.

Genentech’s (Roche Group) Gautam Ganguly gave an excellent, high level account of some of the current challenges of entering the biosimilar market, the level of uncertainty in the US regulatory framework a notable example. The big question here was “how similar is similar?” and the answer is somewhat unclear and product dependent. Ganguly pointed out that, because of complex manufacturing,  “the process is the product” with each stage conferring unique properties on the resulting biologic making biosimilars very distinct from small molecule generics. Ganguly also noted the companies entering the biosimilars space, making it seem crowded, with traditional innovators, CMOs and generics companies all vying for the same unpredictable market.

Frederico Pollaro from Richter-Helm BioTec posed the question “make or buy?” and provided some case study examples as to his group’s decision-making processes. The key message here was the importance of being aware of the timeline involved and asking if your target biosimilar will still be an attractive option 10 years down the road; new therapies, price erosion and market instability all factors to consider. Pollaro also made clear the opportunity, given the right target, to expand the market and take advantage of potential volume growth.

The final presentation in the conference was delivered by Anjan Selz of Finox Biotech and was, I suspect, inspirational to most. Describing his company as a renegade virtual biotech, Selz wowed delegates with the story of how Finox moved from cell bank to Phase III in just four years, comically noting that “we haven’t made any money yet!” Once again, choosing the target carefully was a key message. For Finox, picking a niche product with lower levels of competition was the route taken; follicle-stimulating hormone (FSH), with its specialised market and motivated, informed patients offered a strong business case further justified by its successful history. Selz said that the key to success was creating a differentiating factor, whether through improved stability, formulation, delivery or branding, because to physicians “FSH is FSH” and the word biosimilar has no meaning.

Tomorrow (today for you), the co-located events of CPhI Worldwide, ICSE, InnoPack and PMEC and a horde of attendees will descend on the Messe―the anticipation (and sawdust) is palpable.

How was the start of the show for you? Let me know in the comments box or give us your opinion in our quick survey. We’ll be publishing some of the responses anonymously in one of upcoming newsletters.

BIO’s ideas for enhancing regulatory science at the agency interest me most, and they likely would have a direct effect on the companies that the agency regulates. One suggestion relates to the independent nonprofit foundation created by Congress to support public–private partnerships that advance FDA’s mission. To help the foundation do its work, Congress should give FDA greater ability to transfer federal funds to it, according to BIO. The idea is worth discussing, but I think it would be even better in the context of an overall increase in FDA funding.

FDA has undertaken many initiatives for enhancing regulatory science, but has been slow to translate results into action. BIO suggests creating an entity within FDA that analyzes the findings from these initiatives and conducts pilot programs to try out promising scientific and regulatory approaches. I think this is an excellent idea. Establishing an office whose duty is to improve regulatory science would lessen the burden of other agency employees. It seems like an efficient way of keeping the agency abreast of current science.

Anyone can criticize FDA, but coming up with ideas for solving the agency’s perceived problems is a tougher job. BIO’s proposals should inform a discussion that involves regulators, representatives from industry, and independent scientists. A collaborative and transparent effort among these parties could help ensure that FDA upholds its reputation as a world-class regulatory agency.

Synthetic biology came into public prominence last year with the announcement by the J. Craig Venter Institute (JVCI), a genomic-research organization founded and headed by J. Craig Venter, who helped map the human genome, that his group had successfully constructed the first self-replicating synthetic cell, which represented a significant step in the still-emerging filed of synthetic biology. At the time of their announcement in May 2010, the JVCI researchers said their work represented the construction of the largest synthetic molecule of a defined structure—almost double the size of a previously reported synthetically produced DNA molecule. With that proof of principle, JVCI is working on creating an organism that contains the minimal genome required to sustain itself and its replication to be used as a platform for analyzing the function of every essential gene in a cell. The researchers envision that the knowledge gained by constructing the first self-replicating synthetic cell, coupled with decreasing costs for DNA synthesis, will give rise to wider use of the technology in the development of a range of therapeutic products, such as pharmaceuticals and vaccines, and industrial products, including biofuels.

SBI is looking to take synthetic biology to the next level. SBI’s ultimate aim is to “create an industrial revolution in biological engineering,” said Matthew Tirrell, chair of Berkeley’s Department of Bioengineering and SBI’s founding director, in a SBI press release. “SBI seeks to bridge the gap between the small-scale, biological engineering of the present and industrial-level production by developing design tools and other infrastructure to produce synthetic biological systems reliably on a large scale.”

Agilent is SBI’s first industry member and will help initiate SBI research through a multiyear, multimillion dollar commitment, including early access to the company’s research scientists and engineers. SBI will be a link to research efforts focused on synthetic biology at UC Berkeley and the Lawrence Berkeley National Laboratory (LBNL). The leadership of SBI includes its director Adam Arkin, professor of bioengineering and director of the Physical Biosciences Division at LBNL, and associate director Douglas Clark, professor of chemical and biomolecular engineering and executive associate dean of the College of Chemistry. The institute builds on existing Berkeley research synergies with LBNL, the College of Letters & Science’s Division of Biological Sciences, the College of Natural Resources, the California Institute for Quantitative Biosciences, and the Energy Biosciences Institute. SBI is interdisciplinary, with 33 faculty and scientists from eight academic departments at Berkeley and four divisions at LBNL, spanning engineering, chemical sciences, and biology.

“Synthetic biology potentially can have as profound an impact in the 21st century as semiconductor technology had in the 20th,” said William P. Sullivan, Agilent’s CEO and president, in the SBI release. “To get there, we need to engineer biological solutions that are scalable, reliable, and safe. This is precisely what the UC Berkeley Synthetic Biology Institute is addressing, and why Agilent is enthusiastic about providing infrastructure, expertise, and funding for this new institute.”

The promise of synthetic biology is not only inducing Agilent but other companies to take notice as well, both large firms and startups. For example, the JVCI researchers used DNA units made by Blue Heron Biotechnology, a biotechnology company specializing in synthesizing DNA. Synthetic Genomics, a company cofounded by Venter, provided nearly $30 million in funding for the JVCI research. SGI has a $600-million agreement with ExxonMobil to develop biofuels from algae. SGI and ExxonMobil formed a long-term research and development alliance in 2009 focused on finding and optimizing (through synthetic genome techniques and other more traditional metabolic engineering techniques) algae to produce biological crude-oil replacements.

But as noted by SBI, the adaption of synthetic biologic into cost-effective and large-scale production systems is the key to the technology’s future. It is not yet clear, however, given the time and cost needed to design new organisms, that using synthetic biology will indeed be a better approach than conventional genetic-engineering techniques, and whether the type and range of industrial or pharmaceutical products that can be manufactured from synthetic biology will truly be an advancement over existing products using conventional production methods. Despite this uncertainty, it is likely that more companies will become engaged in research efforts in synthetic biology at some level given the possibilities of this emerging field.

Definitely, says the Hay Group, a management-consulting firm. Big Pharma’s executive-compensation plans reward compliance and short-term financial gains when they should be encouraging risk-taking, according to the firm’s research. About 80% of criteria that determine incentives are financial, and only 12% relate to drug development and commercialization. Although short-term incentives are common, they’re inappropriate for the pharmaceutical industry because of its long product-development processes, according to Hay Group.

In light of Hay Group’s research, the compensation package for former Pfizer CEO Jeffrey Kindler makes no sense at all. The company was facing distinct problems when its board gave Kindler the boot in December 2010. Not only had Pfizer’s share prices languished for four years, several promising drugs had failed in late testing, including a potential replacement for Lipitor. Despite these problems, Kindler got a 60% raise over his 2009 compensation. A performance-related bonus brought his compensation to $4.9 million. Kindler seems to have been rewarded for failure, which, to my mind, is even worse than being rewarded for short-term gains.

To overcome its current challenges, Big Pharma will have to change how it defines, measures, and rewards performance, according to Hay Group’s research. Fortunately, Big Pharma can use mid-sized drugmakers and biopharmaceutical firms as models. These companies “have been much more creative in weaving pipeline and R&D measurements into their incentive strategies,” said Hay Group in a press release. By learning from these firms’ compensation strategies, Big Pharma might match their level of innovation.

It’s easy to blame circumstances for our failings, and harder to admit our own missteps. If it took Hay Group’s recommendations seriously, Big Pharma might reclaim its reputation for innovation. And achieving this goal naturally would be good for the world’s patients as well as for industry.

In a press statement, Myriad Genetics specified that a federal district court ruled that certain claims covering isolated DNA sequences in seven of the company’s 23 patents covering the company’s genetic test, BRACAnalysis, were invalid. The lawsuit was brought by the American Civil Liberties Union (ACLU) and the Public Patent Foundation (PUBPAT), a not-for-profit organization affiliated with Benjamin N. Cardozo School of Law. According to Myriad, the plaintiffs were seeking a declaratory ruling that 15 claims under the seven BRCA patents owned or exclusively licensed to Myriad were invalid and unenforceable. Myriad Genetics said it will appeal the ruling.

“While we are disappointed that Judge Sweet did not follow prior judicial precedent or Congress’s intent that the Patent Act be broadly construed and applied, we are very confident that the Court of Appeals for the Federal Circuit will reverse this decision and uphold the patent claims being challenged in this litigation,” said Peter Meldrum, president and CEO of Myriad Genetics, in the company’s statement. “More importantly, we do not believe that the final outcome of this litigation will have a material impact on Myriad’s operations due to the patent protection afforded Myriad by its remaining patents.”

The Biotechnology Industry Organization (BIO) issued a statement questioning the ruling, but added that the ruling was only a preliminary step in a legal process, and reasserted the association’s position on the patentability of DNA-based inventions. “The District Court’s determination is only a preliminary step in the legal process that does not affect how the US Patent and Trademark Office (PTO) evaluates patent applications relating to DNA-based inventions,” said BIO president and CEO Jim Greenwood in the statement. “…From the mass production of life-savings medicines by cell cultures to the screening of our blood supply for life-threatening viruses, patented DNA molecules have been put to countless uses that have benefited society. Preparations of isolated and purified DNA molecules, which alone can be put to use in these ways, are patentable because they are fundamentally different from anything that occurs in nature,” he said.

However, the ACLU, one of the plaintiffs in the Myriad Genetic case, pointed to the significance of the ruling. “The precedent-setting ruling marks the first time a court has found patents on genes unlawful and calls into question the validity of patents now held on approximately 2000 human genes,” according to an ACLU statement.

In their lawsuit against the US PTO, Myriad Genetics and the University of Utah Research Foundation, which hold the patents on the BRCA genes, the ACLU and PUBPAT asserted that the patents were illegal and restricted scientific research and patients’ access to medical care, and that patents on human genes violate the First Amendment and patent law because genes are “products of nature,” according to the ACLU statement. “[The] ruling is a victory for the free flow of ideas in scientific research,” said Chris Hansen, a staff attorney with the ACLU First Amendment Working Group, in the statement. “The human genome, like the structure of blood, air or water, was discovered, not created. There is an endless amount of information on genes that begs for further discovery, and gene patents put up unacceptable barriers to the free exchange of ideas.” Daniel B. Ravicher, executive director of PUBPAT and co-counsel in the lawsuit added: “The court correctly saw that companies should not be able to own the rights to a piece of the human genome,” he said. “No one invented genes. Inventions are specific tests or drugs, which can be patented, but genes are not inventions.”

The crux of the case and the significance of the ruling in assessing the patentability of genes is the determination of the point at which the application of genomic information transforms from broad scientific knowledge, to which there should be unlimited access, to an “invention,” and therefore enforceable by patent protection. BIO filed an amicus brief outlining case law and statutory provisions in support of patentability and the significance of this case to the biotechnology industry. “Plaintiffs’ unprecedented constitutional and statutory challenges to the patenting of isolated DNA molecules go far beyond the BRCA1 and BRCA2 genes at issue in this case; consequently, they are of tremendous concern to the Biotechnology Industry Organization and its membership,” said BIO in the brief. “For almost a century, jurisprudence originating in this Court has recognized the patent-eligibility of isolated substances that differ in kind, and not merely in degree of purity, from their natural counterparts.”

It is not yet clear what the repercussions will be from the Myriad ruling. The Myriad ruling concerned the patentability of human genes for diagnosis, but raises the question, if the ruling stands through the appeal process, how it might be applied not only in molecular diagnostics but in the legal framework for genomic information as it relates to drug discovery and development. As the pharmaceutical industry increasingly adapts it drug-development efforts to more specialized treatments for patient-specific populations, which include the use of molecular diagnostics and potentially personalized medicine, the legal framework for intellectual property protection of genomic information is significant and will be an important issue to watch in the coming months.

They could do worse than follow the example of Medivation, a Californian company that has more than doubled its workforce, albeit from an extremely low base, from 28 in 2007 to 59 in 2008. Founded by a group of experienced professionals, its business model tries to bridge the gap between early-stage development and product launch. It finds promising compounds in markets with significant unmet needs, adds a bit of value and then sells them on to big pharma in record-breaking deals. In that sense, it is doing precisely what a team of analysts at Morgan Stanley said in January that Big Pharma should be doing, moving away from internal R&D and focus more on in-licensing. To move, in other words, from research and development to search and development.

While well-argued, it is not a particularly original proposal and forecast data from EvaluatePharma shows that while Big Pharma is certainly up for in-licensing, it is also not that keen to give up its central defining activity. Indeed, it is actually spending more on internal R&D as a percentage of sales. In 2008, it spent $69.8 billion, a figure that had grown by 9.3% annually since the turn of the century. And while it is set to slow quite radically to 1.5% CAGR from 2008–2014, when expressed as a percentage of sales, the figure is actually rising, from 15.6% in 2000 to an expected 18.5% in 2014.

Medivation, meanwhile, has done spectacularly well from buying in and partnering on. It had just two pipeline candidates in 2008, both of which have since been bought up by Big Pharma in record-breaking deals. The first was in September 2008, when a $225 million upfront fee from Pfizer for its Alzheimer’s candidate Dimebon was the largest for a single pipeline product that year. The second, in October 2009 with Astellas Pharma, brought in another $110 million upfront for the prostate cancer drug, MDV3100. That was the fourth largest upfront fee in 2009.

A reason for its success may be to do with its size and focused business development team that would confirm another suggestion on how pharma might revamp its ailing R&D model. This comes from the consultancy firm McKinsey & Co, which brought out a report in February that said scientific innovation is only part of pharma’s R&D problem. Better management could also play a part. “Increased attention to costs, speed of development and decision making,” it said, “could increase the internal rate of return (IRR) of an average small molecule from around 7.5% — less than the industry’s cost of capital — to 13%.”1

Without knowing the IIRs on Dimebon and MDV3100, investors are certainly impressed. Shares in this small company initially rose to $27.92 after the deal with Astellas Pharma, giving the company a market capitalization of $935 million, which is not bad for an outfit that has a payroll of just 59 and demonstrating there is life after Big Pharma.

Reference
1. The Road to Positive R&D Returns, Eric David, Tony Tramontin and Rodney Zemmel, McKinsey & Co Pharmaceutical and Medical Products Practice, February 2010.

This blog post was written by Jacky Law.

Combination of a drug with a medical device could allow medicines to be delivered locally and thus maximize therapeutic effect and minimize side effects. But many manufacturers — particularly in Europe — are not fully aware of the benefits that combination products offer.

After chairing a session at the recent Pharmapack meeting in Paris (France) about the regulatory framework and procedures for combination products in Europe, Yves Tillet, Director at White–Tillet Consultants & Experts, spoke exclusively to Pharmaceutical Technology Europe to provide further insight. According to him, many companies do not yet realize the opportunities presented by combination therapies.

“The firms have their projects — and in the largest companies these projects are still tuned towards the search for blockbusters. Companies are under the influence of a culture they cannot dismiss overnight; however, the landscape is changing little by little,” he said. “For the moment, there is little noise about combination products, but as soon as the firms see the dangers and opportunities, they will jump on them.”

This changing landscape is partly due to the arrival of generic products and new competitors with biologic products, cell therapy and gene therapy products, which may require the development of new medical devices. “Thanks to new medical devices, there will be a revolution; that of drugs placed in situ with much lower amounts, thus protecting targeted tissues, as well as the liver and the kidney,” said Tillet. “Pharmacology will be changed.”

Combination products clearly offer a lot of promise for the future, but many manufacturers in Europe still lack a thorough understanding of the European regulations that govern these products. Some companies may even have been manufacturing combination products, such as asthma inhalers, for a while without realising it. In Europe, a combination product can be either a drug or a medical device, but the rule is less clear for certain borderline products and different EU member states may have different positions. However, there are plans to form a European Commission committee that will comprise representatives from member states. This committee will, in the absence of a consensus, take a supranational decision.

“The regulation on combination products was born with the regulation on medical devices and, in particular, with the 93/42/CEE directive applied in 1998. Previously, drug delivery devices were very few and inadequately assessed (only according to pharmaceutical standards). The devices were an accessory to the drug — hardly better than an excipient,” Tillet explained.

However, medical devices have now been developed, the functions of which are assisted by drugs. In some instances, for drug eluting stents for example, the European Medicines Agency (EMA), has published guidelines to assess drugs that assist the stents in their functions, however Tillet also added: “But in another way, except for some isolated cases, little progress has been made in the field of drug delivery devices. We are at the beginning of innovative in situ drug delivery concepts using sophisticated medical devices. The regulatory framework and project assistance provided by registration agencies should favor the emergence of new combination products.”

So should we expect a massive overhaul of the European regulatory system? “The current regulation should not evolve so much in the future — at least in its current framework,” said Tillet. “Rather, I see the creation of many guidelines to frame and standardize the development of these new combination products, with major actions taken to provide information and training on their good use.”

In its press release about the amicus brief, BIO says the Court of Appeals “created a new test under which a method or process is only patent-eligible if it is tied to a specific machine or if it transforms a particular article or substance to a different state or thing.” The test is known as the machine-or-transformation test.

Is the test new? Au contraire. The Court of Appeals based its reasoning in Bilski on three Supreme Court decisions made between 1972 and 1981. Several judges on the Court of Appeals argued that these criteria can be traced to the framers of the Constitution. Rather than being novel, the test seems to rely on an established precedent.

“In 1980, the Supreme Court defined patent-eligible subject matter in a flexible and inclusive way that has fostered the tremendous growth of biotechnology for the benefit of millions of patients, farmers, and consumers around the world,” said Tom DiLenge, BIO’s general counsel, in the press release. He went on to say that Bilski “would negatively impact investment in biotechnology, and thus stifle future growth of this remarkably beneficial industry.”

I believe that Bilski establishes prohibitions that will benefit the industry rather than stifling its growth. In my reading, Bilski would prevent biomarkers from being patented. It also would prevent someone from patenting the understanding that particular biomarkers are associated with particular diseases or conditions.

To patent the association of a biomarker with a disease, or to patent any other diagnostic method, would be to patent basic science, which would have the effect of restricting knowledge. Bilski ensures that science is no one’s exclusive property and thus fosters the development of new biopharmaceuticals, which are BIO’s bread and butter. I hope the Supreme Court acknowledges the sound reasoning and long precedent behind Bilski.

In his plenary address, Jim Thomas, PhD, vice-president of the process and product development group at Amgen, spoke about the benefits and challenges of QbD principles in biologicals. He set the scene by quoting a recent article that predicted that in 2014, 7 of 10 top selling drugs will be biologicals. Moreover, biotechnology drugs will account for 50% of the top 100 drugs in 2014, compared with 11% in 2000 (versus conventional drugs). But, said Thomas, the challenges were many. The costs of drug development and treatment are high. Intellectual property issues and the growth of follow-on biologics will have to be addressed. In addition, he listed at least 25 major attributes of molecules that, if modified, would have an effect on a molecule’s pharmacokinetics. “We need to pay attention to these attributes because of concerns over safety, efficacy, and stability,” said Thomas. The long-term solution, he said, is innovation, specifically in formulation, better production methods, and in deliverying protein therapeutics. “Innovation will be key to future success,” said Thomas, who then discussed in detail Amgen’s work in antibodies, peptibodies, and avimers as examples.

Amgen is working with the US Food and Drug Administration and other companies to understand how to apply the philosophies of QbD in they way they develop protein therapeutics, particularly “based on a fundamental understanding of the science of building quality into the molecule.” The process, said Thomas, starts with a core design knowledge (”what works and what doesn’t”), which must then incorporate what he referred to as “systematic learning” or “buckets of information” that include analytics (including top-down mass spectrometry), biological aspects, and the process itself. The keys are trying to link an knowledge of the molecule with analytics and then linking the analytical characterization of the molecule to the biology to define the critical quality attributes.

The main challenge in doing this, says Thomas, is that there will be a significant initial investment to apply QbD to biologics, but these costs should decrease for platform modalities. The application of QbD to nonplatform molecules will be much more costly. An investment in high-throughput technologies is necessary, he said. Other challenges include the need for sophisticated knowledge of antigen systems, linking molecular structure to biological attributes, and applying risk-management tools to help define the design space. Thomas said Amgen is taking “gradual steps” in applying QbD in it’s processes and will “soon” have evidence of QbD in its regulatory filings.

An afternoon session in process analytical chemistry echoed much of these challenges and future benefits of implenting QbD. In a session titled “What can the Biopharmaceutical Industry Learn from the Use of QbD in Small Molecule Production,” Mel Koch, PhD, of the University of Washington’s Center for Process Analytical Chemistry (CPAC) reviewed the fundamental principles of QbD and how the advancements in measurement science (miniaturization, new materials, data processing, etc.) have helped trigger the need for implementing these principles in bioprocessing. Areas of interest, said Koch, include the characterization of media, nutrient quality, sampling, and microfermentation for optimizing bioprocesses.

A keen eye on science and built-in quality … biotechnology is indeed on the verge of great innovation.

The grants will be used to fund 15 broad areas of health science, including translational science, genomics, enhancing clinical trials, and regenerative medicine. According to NIH, applicants will be notified of their status in August.

In the meantime, the biotechnology industry is applauding an NIH announcement last week of two new grant programs, also supported by the AARS act, specifically for small R&D firms. Alan Eisenber, executive vice-president for emerging companies and business development at BIO (Biotechnology Industry Organization) pointed out in a prepared statement that many emerging biotech companies are struggling to raise the necessary capital to take their innovative research forward and therefore must leave promising work on the shelf and lay off scientists. Both grants were developed to help alleviate this problem. They are: RC3, “Recovery Act Limited Competition: Biomedical Research, Development, and Growth to Spur the Acceleration of New Technologies”; and R43, “Recovery Act Limited Competition: Small Business Catalyst Awards for Accelerating Innovative Research.”

Here’s to the restart of innovation.