Issue:April 2013

EXECUTIVE INTERVIEW – Agere: Solubilization: Accessing Broader Chemistries by Integrating Fundamental Science With Automation for Greater Predictability

Increasingly, drug targets are found to require molecular design elements that reduce the solubility of the drug candidate below historically acceptable limits. The industry as a whole can benefit significantly by further embracing drug delivery technology for poorly soluble compounds, thereby accessing new chemical space. However, to be effectively applied to a broad spectrum of compounds, advances in formulation technology are needed. Driven by this growing need for improving the oral bioavailability of BCS II-IV compounds through solubilization technologies, Agere Pharmaceuticals is creating a new approach to meet the challenge. Borrowing from other industries dealing with similar complexities, Agere has focused on learning best practices and is beginning to apply similar techniques to overcome bottlenecks and accelerate growth. One analogous business segment is electronic design automation that supports the semiconductor industry. Electronic design automation emerged in the 1960s out of the necessity to automate integrated circuit design and prototype and analyze functionality, performance, and manufacturability in software before manufacturing. Drug Development & Delivery recently spoke with Marshall Crew, President and CEO of Agere, to discuss how the company is taking a different approach that leverages expertise, but relies heavily on the principles of physical chemistry to enable automation.

Q: Can you provide our readers with an overview of the role you see solubility playing in the pharmaceutical industry?

A: Well, to begin, it’s important to summarize the trends we are all aware of and the direction we are going. According to the PhRMA 2012 Profile, R&D spending is continuing to increase for their member companies and was in the range of $50B in 2010 and 2011, representing a jump of more than 9% over 2009, and yet NCE (new chemical entity) approval rates don’t reflect that level of investment. That same study shows what we have seen throughout the past many years – that for every 5,000 to 10,000 compounds that begin drug discovery, only 1 receives FDA approval. While there is increasing demand for new drugs, the industry has reached a bottleneck, and in fact, some forecasts show global pharmaceutical revenues shrinking by more than $200B between 2009 and 2014.

Q: As you stated, we’re all aware the number of NCEs entering the market has been slowly declining over the past 15 years, and costs are increasing. What are your thoughts on this issue?

A: It motivates looking into the root causes for the decline. We all know that this is a very complex issue with numerous economic and technical factors contributing to clinical failures; drug metabolism and pharmacokinetics, efficacy, toxicity, and clinical safety being the broad categories. But a different cut through the data reveals that more than 40% of failures are due to the inability to overcome solubility issues. Some companies report even larger percentages.

Q: What do you believe are the reasons for this trend in low-soluble compounds?

A: The reasons are varied. For example, the diseases we are addressing today are much more complex than those in the past. There is much discussion in the literature as to the nature of the binding pockets in modern drug targets. This opic is controversial, but many believe that carefully engineered hydrophobicity is required to achieve the desired potency and selectivity. This, coupled with modern methods for designing, synthesizing, and optimizing chemical libraries has led to a large increase in the number of compounds with low aqueous solubility. It’s unfortunate, but many of these potentially promising compounds attrite very early on in development due to the perception that they will have poor pharmacokinetic properties.

Q: It seems like a lot of missed opportunities. What is being done to address discarded compounds with low solubility?

A: While technologies for delivery of poorly soluble compounds have been in development for more than 50 years, the pharmaceutical industry has only just begun to fully embrace them in the past decade or so. Notably, amorphous solid dispersions are now broadly utilized in clinical development, and a number of commercial drug products they enable are now on the market. A recent example is Vertex’s product Incivek®. However, in relative terms, we have only just begun to explore the potential for solubilization to expand the accessible chemical space for drug discovery. Significant advances in our understanding of the technology are still required. If the technology were to be further developed and fully exploited, the potential impact on the pharmaceutical industry could be significant.

Q: It’s exciting to hear about this potential. Can you expand on your thoughts about the impact solubilization can have on the pharmaceutical industry?

A: An analysis we have conducted at Agere shows there is a significant, unrealized market opportunity. Using a database containing data on 1,30 marketed drugs, we analyzed compound solubility and logP (water-octanol partition coefficient) and found that the (log normal) distribution is centered on a solubility of 100 micrograms/mL and logP of approximately 2.2. This distribution of compounds represented a market in 2011 of nearly $400B. If w were to shift this distribution to slightly higher logP and lower solubility, say, a solubility of 10 micrograms/mL and logP of ~4 (easily accomplished with current technology), and assume a similar density of compounds compared to historical records, we estimate that 450 new, yet-to-be-discovered compounds could be enabled on the market using solubilization.

Finally, assuming the average net present value of a compound on the market is approximately $300M, this opportunity represents $135B in today’s dollars – roughly expanding the accessible market by 35%. Given recent predictions of revenue erosion in the pharmaceutical industry through 2014, being able to expand the market with solubilization technologies seems to be an opportunity well worth pursuing.

Q: This is a significant impact. What will it take for the industry to further adopt this technology and explore this opportunity?

A: As discussed previously, there have been significant advances in the scientific understanding of solubilization. However, in order for the technology to have broad acceptance and not be thought of as “enhanced delivery,” an underlying foundation needs to evolve to make it a more predictable science. There are far too many uncertainties in the development process that are currently addressed with empiricism, an approach that can inhibit disruptive change and innovation. This is why Agere is dedicated to advancing the knowledge of the fundamental science of solubilization, which will enable a more automated and predictable process for drug formulation and development. This approach is similar to that used in other industries such as in electronic design automation.

Q: Most of our readers may not know about electronic design automation. Can you provide a brief overview?

A: The first integrated circuits were demonstrated in the late 1950s. At that time, they consisted of fewer than 10 transistors, and it was possible to design those using very manual approaches. But by the next decade, it became apparent that automation was needed to handle the rapidly increasin complexity. Design tools started appearing and these enabled designs to be captured digitally to accelerate the drafting process, and also to constrain the designs to conform to requirements such as angles required for manufacturing. But the act of encoding designs also enabled the use of computational programs to simulate and analyze integrated circuit designs for functionality, performance and manufacturabilty. Today, integrated circuit complexity can exceed 7 billion transistors, and it would be impossible and prohibitively expensive to design today’s electronics without being able to create and test virtual prototypes before manufacturing. Given the similar complexity and the cost of modern medicines, it seems that we now have an analogous situation in pharmaceuticals.

Q: Can you provide an overview of what it means to add automation to solubilization?

A: We encapsulate expertise using scientific and engineering fundamentals to develop rigorous models and then automate as much of the design and optimization process as possible. Part of being able to automate is to also have more standardized inputs and outputs for each stage. The ultimate goal is to achieve a solubilization platform to improve the predictability of formulation efforts on behalf of our clients. This approach promises to reduce cost and development time, and to greatly minimize down-stream risk. Assembling a comprehensive, modern platform is not going to be an easy task, as it requires going back to the fundamentals of physical chemistry and then building on that foundation. But we are making progress, and Agere has the vision, expertise and capabilities to get there.

Q: Are you able to tell our readers about some of the advances you are referring to?

A: We have started to put some of the pieces in place. I have conveyed what a challenge the industry faces in moving the solubilization technology forward. So, while we have made significant progress, there’s a long way to go. On the way to a comprehensive and integrated system, there are two main categories Agere is paying attention to. One has to do with standardization of inputs and outputs, which enables both automation and more effective technology transfer. The other area relates directly to technical and scientific innovations leading to better predictions.

Examples include phase diagrams that allow Agere to predict the key physical properties of a solubilized drug form. Related to the phase diagram analysis, we have developed technology to predict physical stability and enable selection of packaging configurations. Agere has also developed a free drug assay that enables better selection of excipients and prediction of in vivo performance. We think of each of these as similar to links in a chain. Right now they enhance the analysis and results for each specific targeted task. When ultimately connected with the other technologies we are developing, the entire solubilization process will be streamlined and much more accurate.