Don’t be fazed by phases

Mike Butler explains how Xceleron is helping its clients to answer critical clinical development questions.

“We have demonstrated value in identifying strong lead contenders, expedited late-stage asset development and helped identify drugs that would likely fail later and more expensively without out approaches.”
-Mike Butler

Remind us what you do at Xceleron.

Mike Butler. Xceleron is a small specialized development service company playing a part in helping drug companies overcome the significant challenges they face in today's environment. We have facilities in Europe and the US and we use a unique analytical platform called Accelerator Mass Spectrometry (AMS) to measure investigational drugs and their metabolites in drug development. We use a light label of ¹⁴C sometimes to distinguish from non-labeled drug and sometimes just to enhance sensitivity. Many of the clinical investigations we support would not be possible without this unique approach.

What types of clinical studies do you support and where are you seeing the greatest interest?

MB. Xceleron has conducted client studies in Phase 0, Phase I and Phase II/III clinical development. The question of client demand is fascinating and we've witnessed long-term changes, where adoption of AMS is still ongoing, and short-term, driven by clients who are comfortable with how ¹⁴C LC AMS can provide value.

The trend that unfolded over the past 12 years involved movement from traditional Phase II/III AME/mass balance studies through Phase 0 microdosing and onto Phase I absolute bioavailability and metabolism. The drivers of AME/mass balance in the early days were sensitivity (conventional techniques couldn't support the study), radio-stability of the investigative drug (the molecule wasn't stable with a high activity ¹⁴C label), and drugs where high levels of radioactivity couldn't be dosed for safety reasons. Phase 0 micro-dosing studies attracted great attention five years or so ago when European companies sponsored the CREAM and EUMAPP collaborative investigations and then the US FDA proposed microdosing as a component of their e-IND approach. Finally, pharmaceutical companies wishing to improve early developmental efficiency have driven interest in Phase I studies. Needless to say, we've consistently performed the established studies as we've developed new ones.

The shorter-term change that we've witnessed is equally fascinating. Starting two years ago, we entered into a period of high demand for studies to investigate absolute bioavailability in Phase I. This has continued through 2010 and we're now conducting an order of magnitude more of these studies than we did just three years ago. This year, we've witnessed more than normal levels of interest in Phase II/III AME/mass balance studies as larger companies usher assets through the later stages of development. We think that client demand today is based more on business need than on waves of adoption as it was in the past.

What are the advantages to running the types of studies that you're seeing increased interest in?

MB. Starting with AME/mass balance in Phase II/III, our customers talk about two distinct advantages of working with ¹⁴C LC AMS, irrespective of the need for sensitivity or to overcome radio-instability or safety issues. For small molecule drugs, ¹⁴C LC AMS offers significant time and cost savings because using a light ¹⁴C label precludes the need for GMP material and animal dosimetry and distribution studies. Also in Phase II/III we're seeing significant uptake in our innovative absolute bioavailability clinical design. Time and money is saved because there is no need for IV-specific safety data, formulation effort, or large-scale GMP manufacture of an IV dose. For instances where absolute bioavailability is required by the regulators, our approach provides an attractive option over the traditional crossover design.

In Phase I, our customers get the benefits of knowing absolute bioavailability (should the drug proceed, what is the likely down-stream cost of goods?) generated from this study design. Often in phase I, our customers also save time because they don't need to plan an entirely separate line of clinical investigation. For example, we've included light ¹⁴C doses in food-effect studies, SAD and MAD studies and have shown that we can co-administer a PET ligand and ¹⁴C and generate absolute bioavailability from an imaging study. Essentially, our customers can derive absolute bioavailability from a simple additional arm on a previously scheduled Phase I study.

The value that our clients are deriving from Phase 0 varies enormously according to their objectives. To give you some insight we've helped determine likely efficacy by confirming compound disposition in target and non-target tissues, quantified rate of conversion of pro-drug in isolated target cells and estimated the likely pharmacokinetics prior to full development. Supporting later development, we see a couple of interesting uses. Firstly, smaller companies are able to back-fill required information prior to an asset sale once safety and human efficacy are confirmed. Secondly, for portfolio management, Phase 0 microdosing has a place in establishing fast follow-on candidates.

How does Xceleron's approach to ¹⁴C LC AMS compare to LC-MS/MS and how do you ensure regulatory compliance?

MB. At Xceleron we like to think of the ¹⁴C LC AMS approach as complimentary to tried and tested platforms such as LC-MS/MS. In small molecule development, I foresee our clients using ¹⁴C LC AMS in conjunction with LC-MS/MS to enable innovative clinical study design that could not be achieved with either separately.

Xceleron is very lucky to have had the benefit of time with a number of client study types to develop a balanced and robust regulatory approach. In 2010 we took steps to share and test the lessons we had learned over the years and processes we had developed. The first thing we did was to collaborate with clients GlaxoSmithKline and Astra Zeneca and a respected expert in the regulated bioanalytical industry comparing ¹⁴C LC AMS with LC-MS/MS. From there, we developed a consensus toward an approach for analytical method validation, using the US FDA guideline as a benchmark. A white paper from this effort was published last month. Later in the year we were invited to speak at the US CPSA meeting where we discussed with Celgene, GlaxoSmithKline and Bristol-Myers Squibb those same issues. We think that this kind of collaborative approach is the best way to help everyone understand how ¹⁴C LC AMS can be used productively alongside established analytical techniques and ensure we're practicing a robust analaytical validation process.

Does Xceleron help pharmaceutical customers involved in biologics development?

MB. Yes. We've worked with mostly protein-based biologics thus far because we've shown that small proteins can be labeled with ¹⁴C with no apparent lost of structural integrity. This approach is very sensitive and provides cost-savings over ELISA testing because there is no need to generate matrix-specific methods. Thus far we've conducted most work with compounds in preclinical.

In the clinical arena, we are in discussions with a handful of large molecule innovators around potential clinical uses.

What do you think the future holds for Xceleron?

MB. Considering the challenges our customers face in the pharmaceutical industry, we expect to see even more growth in each of the areas I've described in the very near future. We have demonstrated value in identifying strong lead contenders, expedited late-stage asset development and helped identify drugs that would likely fail later and more expensively without our approaches.

If I were to gaze into the future and run the risk of being proven wrong by our customers, I'd expect to see us conducting more and more target studies that engage the platform's ability to enable investigations beyond systemic circulation. I see great potential in following disposition and localized kinetics. We've already conducted a number of such studies and I expect many more as we move toward more fit-for-purpose approaches to individual asset R&D.

About

Mike has 20 years experience in science-driven businesses in Europe, US and Asia. He has been President, Scientific Operations and Chief Scientific Officer with Aptuit, Group Vice President at MDS-PS and Group Director, Business Development for Huntingdon Life Sciences.