Pharma Innovation

"Innovation." This word is at the heart of bio/pharmaceutical development and manufacturing, whether innovators are targeting a new cell line or formulation, a drug delivery target or method, an analytical or packaging approach, or a quality system. As FDA Commissioner Margaret Hamburg said in April of this year at the Boston NEHI conference on "Bridging the Innovation Gap," innovation "is an issue that is important to us all, whether you come from industry, from academia, from clinical practice, or from government." She spoke about the challenges facing R&D and product pipelines, including patent-cliff implications, stating that, "The trend lines for innovative products relative to investments in research and development are not what any of us would like."

(IMAGE: DAN WARD; BUENA VISTA IMAGES/GETTY IMAGES)

As an example, Hamburg pointed to the current "golden age" of biomedical discovery in which the industry has sequenced the human genome to reveal potential drug targets and made gains in high throughput screening and nanotechnology, and yet has not necessarily translated these developments into therapies or cures. Hamburg proposed in her speech that a potential solution to this innovation gap requires a "comprehensive, integrated strategy that engages the full 'eco-system.'"

Such a strategy would include "new and strategic investments in research," and "true collaboration by stakeholders," including "strong leadership from business, academia, and government," she said.

Here, Pharmaceutical Technology looks at some of the collaborative efforts taking place among these stakeholders to continue to advance innovation in drug development and manufacturing. The following pages highlight honors given to graduate students and professors as well as bio/pharmaceutical R&D and manufacturing teams throughout 2012. As we prepare to enter the year 2013, we hope these individuals and their hard work will provide inspiration for further pharma innovation.

DRUG-PRODUCT INNOVATION STRATEGIES AMONG BIG PHARMA

Every year, our sister publication Pharmaceutical Executive publishes a report on the top 50 pharmaceutical companies based on global sales of prescription drugs. These companies have managed to stay ahead of the game as the industry faces multiple patent expiries and a changing landscape that includes new outsourcing models, capacity-sharing, and consolidation strategies.

As we look ahead to 2013, Pharmaceutical Technology asked the top companies in this list to talk about their innovation strategies, with a specific focus on drug development and manufacturing. These companies include, in order: Pfizer (New York) with 2011 global prescription sales of $57.7 billion; Novartis (Switzerland) with sales of $54 billion; Merck (New Jersey) with sales of $41.3 billion; and Sanofi (France) with sales of $37 billion. Below are their responses.

Pfizer

Kevin Nepveux, vice-president, Global Technology Services, Pfizer Global Supply

"Innovation is a mindset, not a process that can be turned on and off. Organizational strategists tell us that behaviors eat process for breakfast, yet the tendency to separate 'hard' technical skills from the 'softer' communicative skills that drive global workforce interaction persists. Technical-based organizations continue to place great value on the 'hard' skills. We instead need to better understand how our technologists interact with each other, our businesses and their environmental challenges to inspire the everyday innovations as well as breakthroughs.

"In 2010, Pfizer Global Supply (PGS) reexamined its approach to innovation. We'd designed our tactics to inspire creative thinking, but our follow-up metrics included chasing after projects' monetary value. We began to see the categorization of projects as innovative to meet the fiscal metrics, rather than the unleashing of a mindset to derive truly creative solutions. It was time to reinvigorate our innovation methodologies.

"We conducted a year-long listening tour at our manufacturing locations and with our technical groups. We formed a diagonally hierarchical global team to steer the development of the new approach, with executive team sponsorship and participation, a manufacturing mechanic operator, technologists, and the organizational levels in between—all with equal seats at the strategy table.

"Today, our deliberately small headquarters' innovation office trains innovation coaches around the world. This 200-plus global network has responsibility to build local innovation ecosystems and to adapt innovation tools to local needs and cultures. Rather than being in the business of innovation, innovation is instead employed at the needs of the local business.

"The ideas need to come from everywhere within our global organization, but innovation must be nurtured from the top. Sure, we still need to show the fiscal value of all of this effort. However, we have seen significant payback in a short time by shifting our focus to changing the innovation mindset first, and to allow value to emerge as an outcome of a new way of thinking and behaving. The PGS technologists of tomorrow are not the same mold as the past, and neither is our business."

Novartis

Timothy Wright, global head of development

"There is a consensus in the pharmaceutical industry that we need to accelerate the pace of drug development. If we fail to do so, we won't keep up with the rising health challenges facing our society. Novartis has made good progress with some strong shifts in our approach to drug development. One shift is to invest in developing multiple indications simultaneously (rather than serially), where we advance compounds in more than one clinical setting in parallel, thereby increasing the likelihood that drugs get to patients faster. Once you understand the disease biology and the molecular pathways involved, then each compound can be tested simultaneously in multiple diseases that share the same pathway. An example is our mTor inhibitor everolimus, which is now approved in the US for five cancer indications (under the tradename Afinitor) and renal transplantation (under the tradename Zortress), and our orphan drug Ilaris, originally approved in a very rare genetic disease and now continues to be developed in larger disease populations, including gouty arthritis and heart disease.

"Another solution to tackling the innovation drought is collaboration and knowledge-sharing. The cost of developing a drug has risen exponentially. Currently, it takes an average of 10 years and costs on average $4 billion to bring a new therapy to market. This model is not sustainable. We need to work together across industry, academia, and government to make our innovation dollars work harder. Only by working together can we make sure new and innovative treatments get to the patients who need them the most."

Merck

Rich Tillyer, senior vice-president, Discovery & Preclinical Sciences, Merck Research Laboratories

"The opportunities for Merck and the pharmaceutical industry to impact human health are real and numerous given the continuing rapid evolution of biomedical science, but this rapid evolution will not happen without a continued investment in R&D and emphasis on innovation. Innovation in R&D is a critical success factor and Merck understands that this requires a long-term commitment.

"At Merck, our focus lies in developing first- and best-in-class medicines that will make a meaningful difference for patients. To realize this goal, we need to establish a culture of innovation fueled by collaborations with internal and external partners, and with a focus on growing talent. We will continue to drive these initiatives in 2013 and beyond to ensure that our pipeline of candidates remains strong and continues to advance toward the patients who need our medicines."

Sanofi

Marc Bonnefoi, head of the Sanofi North America R&D Hub

"Sanofi is evolving its R&D approach to be able to access the best ideas, science, and people in research. This requires a combination of both internal and external innovation and is implemented through the creation of geographically focused integrated research hubs in which Sanofi scientists increasingly partner with external teams. R&D hubs have been created in North America, with a special emphasis in the Boston area, as well as in Germany and Asia, and a project for implementing a hub in France is being discussed.

"For many years, the pharmaceutical industry designed drugs from biological targets that were not always well validated and in areas where the path to clinical proof-of-concept and ultimate validation in patients was uncertain. We screened scores of molecules to see whether they had any effect on different disease models that were often incompletely qualified. There were too many assumptions regarding the biology of diseases. Today, we seek to begin with an understanding of the underlying cause(s) of a given disease and work to develop a solution to interfere with that process.

"We are trying to integrate a translational approach to these efforts, applying the knowledge from patient populations and medical experience much earlier in the R&D processes. To make these translational research efforts a reality, Sanofi is using the ability to translate to the patient situation as a yardstick to judge the quality of projects. None of this can be done by Sanofi R&D alone: we have great people and fantastic ideas, but no one organization can single-handedly tackle the complexity of human chronic diseases, which remain beyond our reach at the moment. By effectively implementing open innovation and raising the bar for projects to be accepted into development and reach further investment milestones down the road, Sanofi expects to create one of the best portfolios in the industry."

STUDENT INNOVATION ACROSS THE PHARMA SCIENCES

At the 2012 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting in Chicago, graduate students across the country were honored for their research and work in bio/pharmaceutical innovation. Symposium awards were given to graduate students in the areas ranging from analysis and pharmaceutical quality to ocular drug delivery and disposition. Pharmaceutical Technology had the chance to talk with a few of the recipients about their work.

Biotechnology category winner David W. Woessner noted that his team's work at the University of Utah on "Synthetically Lethal Combinations for Chronic Myeloid Leukemia (CML) Therapy-Disrupting Dimerization of Bcr-Abl and Secondary Leukemia Specific Pathways" demonstrates the first development of a protein/peptide-based therapeutic for CML.

"While current therapies in the clinic (tyrsosine kinase inhibitors [TKIs]) act on the ABL portion of the protein, we are demonstrating efficacy by targeting the BCR portion, necessary for oligomerization and activation of the tyrosine kinase. Additionally, this work also exploits a combination therapy approach early in development," he said. Future research in this area has already moved towards combination therapy approaches, explained Woessner. "There are now essentially five TKIs that effectively treat CML. Combinations with other small molecules that target leukemic stem cells, but not normal/healthy hematopoietic stem cells are highly valued. We will continue to see trials for drug combinations," he said.

Mamta Kapoor of the University of Connecticut also won in the biotechnology category. Her research, "Elucidation of Cellular Uptake Mechanism of Novel Ternary Anionic-siRNA Lipoplexes," aimed to obtain an understanding on formulation-cell interaction that may facilitate faster formulation optimization to achieve efficient delivery. "This research area is interesting because it involves a mechanistic approach to comprehend the rate-limiting steps to proficient intracellular delivery of therapeutic agents," Kapoor explained. The mechanistic studies "have helped in understanding the contribution of formulation components in the uptake process and consequent bioactivity." Looking ahead, Kapoor's team intends to repeat the studies with other novel formulations.

Lakshmi Prasanna Kolluru, who won in the drug design and development interface category, focused on the "Design and Development of Albumin-based Theragnostic Nanoparticles for Tumor Targeted Drug Delivery." Based at Mercer University, the PhD candidate was inspired as a teenager by a cousin, a cancer patient suffering from the side effects of chemotherapy. "She was disturbed psychologically when she had lost her hair due to side effects and this spurred the interest in me to focus on cancer research. So, when my professor gave me the freedom to design a project, I opted to work on development of a delivery system that targets anti cancer drugs to tumor and reduces the side-effects of chemotherapy," said Kolluru. Looking ahead, the grad student says the university team is "planning to decorate this delivery system with dual-targeting probes to examine the efficacy of the targeting ligands in vitro and in vivo for selective localization of the drug in the tumor region."

Jiban Jyoti Panda of the International Center for Genetic Engineering and Biotechnology in New Delhi and of the FM University of Balasore, Odisha, India, won in the category of formulation design and development for the paper, "Self-Assembled Dipeptide Nanotubes, Nanovesicles and Nanogels: Potential Vehicles for Targeted Tumor Drug Delivery." The research focused on testing the potential of nanotechnology in cancer therapy. "Different types of polymeric, inorganic, and metallic nanoparticles have been investigated for their potential for effective tumor delivery and therapy. However, there are many factors which prevent the development of these nanoparticles for safe human use," Panda explained. "We tried to develop peptide-based nanoparticles, which are expected to be highly biocompatible due to their peptidic origin. Moreover, because the greatest problem with peptide-based drugs or systems is their low in vivo stability, we tried to develop nanoparticles from designed small peptides with the modified amino acid a, -dehydrophenylalanine (?Phe), residue, which is unique and would provide the nanostructures with enhanced assembling behavior and resistance to enzymatic degradation leading to better stability."

Panda's next goal is to demonstrate the efficacy of these systems in other tumor models and to prove their broader application potential, such as peptide-based nanosystems that may target tuberculosis, AIDS, and other global diseases.

University of California–San Francisco student Rachel Jean Eclov won for her research into "In Vivo Characterization of ABCG2 Enhancers," in the category of pharmacokinetics, pharmacodynamics, drug metabolism, clinical pharmacology and translational research. "Previous research on MXR functionality has been mostly aimed at functional (coding) variants of MXR. My research is unique in that it looks for how other types of genomic variations can alter MXR expression and thus drug disposition. I utilize epigenetic tools to unravel how MXR expression can be tissue specific or transiently increased or decreased," she explained.

"I then consider how genetic variation in identified regulatory elements can alter the transcriptional properties of that element. Although other epigenetic research has been published, the majority of it is on variations in regulatory elements that cause developmental defects. My research uses epigenetics to identify genetic variations that impact the more subtle world of drug disposition where the effects of these variations are not as obvious but can be just as severe." In terms of how Eclov's research may affect future industry work, she says, "Even though my research is only at the initial edges of understanding of the genetic regulation of an ADME gene, it can be used as a general template for others to research the genetic regulation of their own gene of interest. It shows that there are many ways a gene's expression can be epigenetically regulated and thus deregulated in cancers or by drug treatment. It is also important for scientists to realize that noncoding genetic variants found in large screens, like a GWAS, could be very relevant 'hits' and that there are tools out there to help develop epigenetic models for the function of these variants."

Another University of Connecticut student, Ekneet K. Sahni, won in the category of manufacturing science and engineering for "Contact Drying in an Agitated Filter-Dryer: Experiments and Simulations." Says Sahni about the research, "Despite recent advances made towards understanding the drying phenomena, intricacies involved in the process not only due to the coupled nature of the process involving heat, mass, and momentum transport but also from their dependence on the material properties and drying conditions, do not allow quantitative predictions with extreme accuracy. The penetration model has been long known and considered as the industrial standard for contact drying. Nevertheless, it has disadvantages in the consideration of granular mechanics due to its continuous nature. Until recently, most of the DEM-based heat transfer work was either two-dimensional or in static granular beds." Sahni explains that the winning work was the first study employing 3D-DEM "to better understand the granular behavior in an agitated filter-dryer by investigating the effect of process variables on the drying performance. Major consideration has been given to the effect of speed, which has not been clearly understood in literature."

In terms of the work's relevance to future studies, Sahni says, "Along with improving our confidence for the use of DEM as an emerging tool, it fills the gap in the literature for discrete approaches. The benefits are also seen in reduced developmental resources and manufacturing costs without any production delays. Hence, process-modeling based on product development can reduce the time required to get products to market as well as the healthcare costs by saving resources. Takeaways for the scientists are that a priori performance predictive tool is developed that can help in predicting the final outcome even for the process parameters outside the range studied and for any material which gives it an edge over other designs as well as models which are mainly restricted to the parameters and/or material studied."

Brief PowerPoint presentations from each of the above graduate students appear on PharmTech.com/AAPSstudents2012. For a full list of all the AAPS 2012 Symposium Graduate Student awards, visit www.aaps.org.