Overcoming early clinical development hurdles

Clinical trials are part of a staple diet for pharmaceutical companies. They provide priceless information that pushes the right drugs and inhibits the hemorrhaging of money to drugs that would fail at market. Michael Butler walks NGP through how to overcome clinical trial problems and get the right drugs to market.

Unprecedented thinking is emerging in early clinical drug development – driven by the need to understand compound-specific challenges in humans before committing to large sums for full clinical development. Critical early human data that cannot be obtained solely by traditionally methods can now be generated using 14C tracers coupled with exquisitely sensitive Accelerator Mass Spectrometry (AMS) analysis. Large pharmaceutical companies and smaller innovators are employing this unique application in different ways.

“We hope to obtain an early read of human drug metabolites instead of relying on animal models. This will allow us to make knowledge-based, strategic decisions that foster our cost-effective and prudent drug-development decisions,” said Jerry Brisson, Associate Director of Clinical Pharmacology at Otsuka Pharmaceutical Development & Commercialisation, Inc.

The need to reduce late stage failure

Reducing the rate and high cost of drug compound failure in phase II clinical trials is a high priority for Xceleron’s clients. Paradoxically, high phase II attrition has developed because of advances in scientific innovation. For example, automated combinatorial techniques can produce more promising and closely related analogs than can be accurately discriminated by existing preclinical methods used to predict human pharmacokinetics (PK).

Additionally, new post-genomic targets have required novel chemistries that interact with the new target space. Drug candidates with unprecedented chemistry are now estimated to comprise 60 to 70 percent of candidates entering first human trials. These compounds have a high rate of failure because they lack predictive models and human PK data. As a result, there is great interest in rapidly promoting high-value candidates and identifying failures before entering phase II.

Early clinical discrimination

Recently, the area of greatest client interest in Xceleron’s approaches has been an enrichment of phase I clinical studies. Adopting the 14C/AMS approach provides invaluable human metabolism and PK insight to a candidate drug with minimal additional expense and effort.  Understanding human PK early helps to identify selection criteria and allows informed decisions about candidate choice, reduces the uncertainty associated with PK prediction and can guide the development of follow-up candidates where improved PK compared to the primary candidate is important. On the regulatory front, gaining early quantitative metabolite information allows the team to address potential metabolite safety issues, as emphasized by MIST and ICH M3 guidance, before embarking on long-term safety studies. Finally, rather than following a wholly pre-defined development strategy, our customers are increasingly opting for fit-for-purpose programs that address the particular needs and problems of each molecule in question. 

Innovative phase I clinical development

The increase in interest we have recently witnessed in phase I is driven by multinational pharmaceutical innovators who want to gain an early insight into human bioavailability, clearance, distribution and systemic metabolism, especially to identify potential BCS class II liabilities. In one approach, development teams administer a very small dose of 14C-labelled experimental compound intravenously concomitantly with an oral, pharmacological dose. The specificity and exquisite sensitivity afforded by the 14C tracer/AMS combination results in the acquisition of critical data very early in human development and at pharmacologically relevant doses.

This data is used by clinical pharmacology and CMC groups to inform subsequent development decisions that can influence the overall cost/candidate, time-to-market and even PIII probability of success. AstraZeneca has used this approach as a ‘bolt on’ to existing phase I programmes (e.g. as part of a food interaction study) to make go/no go decisions – as recently described in a presentation made at the 2010 Exploratory Clinical Development conference in London. We’re also seeing increased interest in addressing human metabolite safety much earlier in the development process and specifically in phase I. Initially driven by the Metabolites In Safety Testing (MIST) FDA guidelines, such investigations yield advantageous intelligence when conducted cost-effectively.

By obtaining human metabolite profiling at this early stage, development groups can make sense of their preclinical species results and make sound decisions about potential toxicity liabilities. The data also helps to focus metabolite identification work, saving time and cost.
Large pharmaceutical companies have traditionally addressed these issues in phase III, due in part to the cost and time associated with manufacturing the 14C-drug and the associated dosimetry testing to gain radiation approvals. 

Now, however, the lower radiation levels in the 14C- micro-tracer/AMS study approach overcome these constraints and enable valuable investigations in phase I. With only incremental cost to a SAD/MAD study, a 14C- micro-tracer can be added to the pharmacological dose and the pooled plasma and excretory samples analyzed by AMS. In the majority of cases, major metabolites in most sample types can be quantified up to several days post dose, although the limits of detection depend on the molecule under study.
The phase I study designs and the technical reasons for their adoption are becoming increasingly well understood. Such progress is possible because micro-tracer enriched studies provide important early asset-specific information in humans whilst adding only 10-20 percent to the cost of the committed programme.

Application of 14C Microtracer Approaches in Early Clinical Drug Development : Presentation at ECD 2010 London, Dr Andy Gray, AstraZeneca
FDA MIST Guidance : February 2008

Putting The Best Candidate Forward: Phase 0 Development

Phase 0 clinical studies have become synonymous with so-called microdose studies which in turn have been the subject of sometimes heated debates about the correlation between microdose PK and pharmacological dose PK. This is a shame because pre-conceived ideas can close minds to the potential of very early access to human data in pharmaceutical development. 

“Our innovative approach with the use of human microdosing has allowed us to fast-track these compounds to a stage where we expect to select the best candidate to continue classical phase I studies,” said Alice Huxley, CEO of Speedel.

Let’s review a few examples in the public domain 

Idenix conducted a microdose investigation of two non-nucleoside reverse transcriptase inhibitor (NNRTI) leads being developed for the treatment of HIV-1. The data showed for the first time that both exhibited favorable human PK, including high mean absolute bioavailability and long half-life. IDX899 was considered the stronger candidate and subsequently in-licensed by GSK. 

Corcept investigated their GR-II antagonist in a phase 0 study and determined that it was well absorbed, demonstrated good bioavailability and possessed a half-life consistent with once-daily oral administration. The phase 0 study also guided phase I dosing and it has been estimated that savings of US$400K and 6 to 8 weeks were realised as a result.

Speedel used phase 0 investigations to ‘screen in’ the most promising renin inhibitors for the treatment of hypertension. Speedel used this early human data to select the best of three candidates and eventually sold their enhanced portfolio back to Novartis. These are just three examples in the public domain; we have many more that are proprietary. The point is that phase 0 studies provide very valuable and cost-effective insight when used appropriately.

Drivers of Change in Early Clinical Development

Xceleron’s experience suggests that larger, multi-national innovators are driving interest in enhanced phase I investigations enabled by 14C/AMS technology. Smaller innovators continue to drive most of the interest that we see in phase 0 and much of that information enables out-licensing attention. We are actively engaged in discussions of novel clinical designs that could be characterised as screening or one-off investigations. 

However, two themes prevail throughout all discussions. Irrespective of client or study type, the 14C/AMS approach is best applied early in asset development and must be done so cost-effectively.

Biography

Michael Butler is CEO of Xceleron. He has 20 years of experience in science-driven businesses in Europe, US and Asia. Butler 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.