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<sup>14</sup>C microtracer+Accelerator Mass Spectrometry - Xceleron Case Studies

Introduction

Xceleron is a world leader in the use of Accelerator Mass Spectrometry (AMS) analytical technology in pharmaceutical, food technology, crop protection and biobased product applications.

Our primary business is in pharmaceutical research and development. Since 1998 we have been helping to design preclinical and clinical investigations around the unique analytical features of AMS, now a widely used and valuable tool in the quest for improved R&D efficiency. Smart use of AMS allows analytical challenges to be taken off the critical path by supporting time- and cost-efficient investigations.

Pharmaceutical services

Xceleron can help you to design and implement preclinical and clinical fit-for-purpose investigations. Our clients regu-larly use us to meet commercial objectives associated with:

•    Proof-of-concept
•    Asset sale
•    Asset purchase
•    Drug approval

Our approach

Xceleron employs a two-stage approach in using AMS to improve the time- and cost-efficiency of pharmaceutical research and development. First we harness the inherent selectivity, sensitivity and robustness of the AMS analytical technology through quality control procedures associated with analytical method transfer, method validation and sample handling - all captured in proprietary SOPs. Second, we help our clients to produce simple time- and cost-efficient preclinical and clinical protocols designed to provide specific investigational endpoints and achieve commercial objectives.

Study protocols are delivered using a network of long established and trusted development partners in Europe, N America and Asia, supported as required by a dedicated Project Manager from Xceleron.

Our preclinical and clinical investigations can yield an extensive range of AMS-enabled outputs which support a number of important commercial applications.

AMS analytical robustness and sensitivity

AMS is analytically very specific, highly sensitive, free from biological matrix interferences and independent of test compound structure. These unique analytical characteristics result from the 14C microtracer and from the tightly controlled three-stage process used by Xceleron to turn the sample under investigation into graphite that is ultimately loaded onto the AMS detector. The unique sensitivity of AMS enables very small samples to be analyzed - a few µL or mg and even down to a few thousand cells.

The inherent process and instrument robustness is strengthened by Xceleron’s quality control procedures. Client samples can be analyzed as total 14C (all drug derived material) or fractionated using an appropriate separation technique (commonly HPLC) in order to measure specific analytes of interest. Quantitative and qualitative methods are designed for every investigation.

Improved R&D efficiency

Xceleron’s customers are using AMS to improve the efficiency of R&D through a combination of reduced development time and reduced expense

•    Analytical method development and validation is off the critical path
•    Intelligent preclinical and clinical designs are inherently shorter in duration and require less resource
•    Rich data set: all drug derived material, specific analyte and metabolite profiling measurement

Trusted partners that deliver

Xceleron has developed a tried and tested network of partners over time. This network is used to provide all of the components necessary to complete an AMS-enabled investigation

•    14C labelling of the asset under investigation
•    Preclinical development to support clinical investigations
•    Clinical pharmacology units in Europe and N America to conduct volunteer studies
•    Clinical pharmacology and out-patient centers in Europe and N America to conduct patient studies
•    Matrix and tissue preparation centers
•    Complimentary LC-MS/MS analyses
•    Specialized PK analyses and report writing

Enriched Phase I Clinical Investigations

This is our most popular and fastest growing area of investigation. Xceleron has helped develop clinical protocols to support proof of concept investigations, asset sales, asset purchases and regulatory submissions. This approach is very cost- and time-effective because we leverage your Phase I investigations to gain additional endpoints. We do not require additional safety or dosimetry data over traditional Phase I clinical trials. As a result, we can generate valuable human disposition, bioavailability, or metabolism data within existing drug-development timelines and at incremental cost.

Xceleron’s enriched Phase I Studies inform Phase II-readiness as we:

•    Obtain human absolute bioavailability data
•    Gain vital PK data on high potency drugs in sensitive populations
•    Quantify drug distribution in target tissues such as biopsy samples, cerebral spinal fluid or skin blisters
•    Gain a first view of human metabolites for safety assessments

Xceleron has used AMS to deliver early insight to human metabolite exposure. We incorporate a 14C microtracer into an existing Phase I SAD, MAD, or Food Effect study. We combine the clinical plasma samples to form a single representative pool across all subjects / time-points and analyze this

pool to give a single metabolite profile. From this we can establish the presence of human specific, significant and/or disproportionate metabolites.

Phase II and Phase III Clinical Investigations

Xceleron provides essential absolute bioavailability and mass balance data for late-stage studies. Our data support regulatory submissions to the EMEA and FDA and have contributed to numerous filing packages for marketed drugs. In 2013 six out of 27 new drugs approved by FDA were supported by AMS data.

We have established specialized validation packages to support the bioanalytical requirements of late-stage studies, an important consideration when the study is being used for regulatory submission.

Phase 0 Microdosing Clinical Investigations

For Confident Decision Making in Early Drug Development

Drug-development teams turn to us for Phase 0 microdosing studies when they need to select the most promising compounds for full drug development or to confirm that their compound reached its target site of action.

In microdosing studies, the dose administered is very small, 1/100th of the predicted pharmacologic dose to a maximum of 100 µg. At Xceleron, we are able to detect those minute drug traces in the blood, tissue, and body fluids using AMS analysis.

Because these small doses are inherently safer than pharmacologically active doses, regulatory authorities accept a much reduced safety toxicology package. Consequently, Phase 0 clinical trials can allow drug developers to obtain human data earlier and with less expense compared to a Phase I clinical study.

Proof-of-concept

We have conducted proof-of-concept studies for a range of small and large pharmaceutical companies. The following case studies demonstrate how simple study design combined with the AMS platform may be applied to your development program. Our customers have saved years and significant expense by using a microtracer and AMS in either a pharmacological-dose or microdose setting.

Arpida

Clinical indication

Anti-infective AR-709 to treat MRSA in the upper respiratory tract

Objective

Obtain early evidence of drug disposition in lungs to determine the optimal clinical route of administration prior to starting full-scale preclinical toxicology studies

Service

•    Helped to design a Phase 0 microdose study using an oral/iv crossover design, followed by an IV microdose with tissue biopsies of the lung to determine amounts of drug getting to the target
•    Full project management of compound 14C labelling, preclinical toxicology and clinical dosing
•    Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analyzed by AMS

Outcome

•    AR-709 attained concentrations appreciably higher within the lung than in plasma
•    Low oral bioavailability however oral administration
•    No expensive oral formulation required for clinical study
•    Pursued inhaled formulation with two-year saving in development time

Lundbeck

Clinical indication

CNS

Objective

De-risk late-stage clinical investigations by investigating potential for unexpected human metabolites. Regularly use early microtracer studies to guard against late-stage discovery of human-specific metaolites

Service

•    Helped to design adaptive Phase I studies with oral microtracer to investigate metabolism and mass balance
•    Chromatographic separation of parent and metabolites plus analysis of total and fractionated 14C by AMS
Outcome

Lundeck adopted AMS as part of early development strategy

Astra Zeneca

Clinical indication

Various, including oncology

Objective

Various including;

•    Early estimate of formulation resource for development plans
•    Assess backup compound PK to compare to poorly performing leads
•    Assess compound developability with better dose-dependent PK Service
•    Helped to design a series of concomitant oral/IV dosing study designs to generate absolute bioavailability data and other PK data
•    Chromatographic separation of parent and metabolites plus analysis of total and fractionated 14C by AMS

Outcome

Objectives achieved

Incyte

Clinical indication

Unknown

Objective

Determine relative abundance of human metabolites

Service

•    Helped design PI healthy human volunteer investigation to identify major metabolites of Compound “X”. Used a microtrace amount of 14C labeled material co-administered with a pharmacologically relevant dose of ‘cold’ compound during the course of a phase I clinical study
•    Transferred HPLC chromatography method
•    Analysed all samples using HPLC + AMS

Outcome

•    Early assessment of major human metabolites compared to traditional drug development. This in turn enabled the determination of safety margins for the major metabolites in nonclinical toxicology studies.
•    Using AMS, the plasma concentration of metabolite M5 (cleavage product of parent compound) was determined to be 13.8% of total 14C (35.1% of parent present), compared to ~1% of parent when based on qualitative LC-MS analysis
•    Concluded that quantitation of metabolites based solely on mass spectral response (in the absence of synthetic standards) can be misleading and should be avoided for the purpose of establishing the relative abundance of metabolites
 
US biotech company

Clinical indication

Acute Myeloid Leukemia (AML)

Objective

Determine preclinical concentrations of highly potent parent cytotoxic and metabolites in two preclinical species as part of an antibody-drug conjugate IND submission

Service

Chromatographic method development and analysis using HPLC + AMS for quantitative metabolite profiling

Outcome

IND approved and ADC is now in a phase 1 clinical trial designed to assess its safety and anti-leukemia activity in AML

Organon

Clinical indication

Female health (birth control)

Objective

Develop fast-follow backup leads for lead with toxicology risk

Service

•    Helped to design a comparative 56-d, three-compound microdose study of highly potent compounds
•    Compare lead compound microdose with pharmacological dose PI study to validate approach
•    Full project management of compound 14C labelling, preclinical toxicology and clinical dosing
•    Measured compounds concentrations out to 56 days

Outcome

Original lead compound microdose PK scaled perfectly with pharmacological dose providing confidence in reliability of backup compound microdose information

Asset sale

Asset sale strategies are pursued predominantly by smaller drug developers seeking to generate income from their early pipelines. For this reason, many of our asset sales case studies are similar to those for proof-of-concept. The same principles of simple investigational design and robust analytical insight are used in this context to show value to a potential buyer.

Speedel

Clinical indication

Hypertension renin inhibitors

Objective

Improve bioavailability of lead compound by investigating microdose amounts of different congeners in the clinic

Service

•    Helped to design iterative microdose clinical approach
•    Managed project including partner preclinical and clinical organizations
•    Conducted all AMS analyses

Outcome

Increased lead compound bioavailability (2.6%) to >30%. Formed the basis of Speedel’s renin inhibitor series. Speedel subsequently bought by Novartis for $880MM in 2008 on the basis of this and other compounds in their development pipeline. Speedel highlighted:

•    Need only grams of API - can be produced under less demanding manufacturing conditions
•    Reduced preclinical toxicology and ADME package
•    Duration of 4 to 6 months, compared with 12 to 18 months for standard Phase I safety and tolerability trial

US biotech company

Clinical indication

Prostate Cancer

Objective

Determine absolute bioavailability and routes and rates of clearance with full quantitative metabolite profiles in urine and feces

Service

•    Helped to design Enriched Phase I study with 2 parallel cohorts – IVPK arm for absolute bioavailability and oral arm for mass balance and metabolite profiling.
•    Chromatographically separated parent from metabolites and conducted full quantitative analysis using AMS

Outcome

Company recently acquired by one of Xceleron’s European large pharma clients for $750M US in order to obtain Phase II compound. The acquiring company appreciated the value of this data and are now discussing with Xceleron how to adopt the approach in their early clinical development programs. This drug, an androgen receptor antagonist, is now on Phase III in non-metastatic prostate cancer patients.

US biotech company

Clinical indication

CNS (Alzheimer’s)

Objective

Determine blood-brain barrier penetration of two novel drug candidates by measuring drug CSF levels

Service

•    Helped to design a microdose study
•    Full project management of partner companies conducting drug labelling, clinical dosing and CSF collection

Outcome

Lead candidate was eventually sold to a Japanese Pharma in a deal worth $760MM

Idenix

Clinical indication

Anti-HIV-1 (NNRTI)

Objective

Use a microdose investigation of two non-nucleoside reverse transcriptase inhibitor to select a lead candidate on the basis of clinical PK and metabolism

Service

Helped to design a human microdose investigation

Outcome

IDX899 was taken into Phase II by Idenix before being licensed to GSK for an upfront payment of $34MM

Asset purchase

Asset purchase is the other side of the coin from asset sale in today’s pharmaceutical development world. Consequently, most of our case studies feature larger companies seeking to enrich their later-stage pipelines. AMS is a useful tool for quickly gaining additional information on clinical metabolism, IV pharmacokinetics and ADME mass balance where this is not fully understood due to lack of investment in these areas by drugs developed by biotech organizations on a tight budget.
 
European pharmaceutical company

Clinical indication

Oncology

Objective

Back-fill data package for oral anti-cancer asset in early clinical development acquired from a US biotech company

Service

•    Helped design enriched PI clinical investigations intended to investigate absolute bioavailability, metabolism and mass balance
•    Transferred and validated chromatographic HPLC methods prior to clinical start-up
•    Conducted al analyses using AMS

Outcome

•    Time and expense saved on acquiring absolute bioavailability information by conducting enriched PI as part of a planned formulation investigation
•    All clinical objectives satisfied

Shire Pharmaceutical

Clinical indication

GI – accelerate gastric emptying and stimulate gastrointestinal motility

Objective

Back-fill regulatory package for asset from small company and exhibiting strong melanin binding. Conduct mass balance and metabolite profile using a microtracer

Service

•    Helped to design a regulatory hADME study
•    Transfer and fine-tune chromatographic method from Shire
•    Transferred chromatographic methods to Covance for use in metabolite ID
•    Perform all MB and metabolism profile 14C analyses using AMS detection

Outcome

•    Overcame regulatory melanin binding concerns by using microtracer
•    Good adoption and transfer of methods allowed for very efficient data acquisition
•    Expanded into US market

Drug approval

Xceleron has been supporting drug approvals since its inception in 1998. We have helped to remove simple hADME studies from the critical path by using a microtracer and AMS sensitivity to save time and expense in 14C manufacture and dosimetry determination. More recently, we have employed novel clinical pharmacology designs to save valuable time when regulatory authorities request, for example, last-minute absolute bioavailability data. We are aware of 13 marketed drugs which have benefitted from one or more of these approaches. In 2013, six of the 27 drugs approved by FDA included AMS-generated data in their regulatory submissions. The case studies which follow show some of the ways in which our clients have worked with Xceleron to gain product registration.

Genentech – Vismodegib

Clinical indication

Advanced basal cell carcinoma (hedgehog signaling pathway inhibitor)

Objective

Understand previously observed non-linear PK

Service

•    Helped to design enriched PI IVPK investigation in healthy post-menopausal women
•    Transferred and validated fully quantitative HPLC methodology
•    Analyzed 14C tracer samples using HPLC + AMS
•    Supported a Phase 1 open-label mass balance study in healthy female subjects of non-childbearing potential using AMS to determine routes of excretion, mass balance and extent of metabolism following a single oral dose

Outcome

•    Genentech achieved accelerated FDA approval for Vismodegib in 2013
•    Provided insight to the complex and multifactorial mechanism for time-dependant PK observed with Vismodegib.
•    Specifically identified differential plasma protein binding, solubility-limited absorption and slow metabolic elimination
•    Removed investigation off the critical path by saving Genentech 18 – 24 months of IV formulation design and IV toxicology studies

Japanese pharmaceutical company

Clinical indication

Oncology

Objective

Minimize radiation burden to patients during conduct of a regulatory mass balance/metabolism investigation of antineoplastic combination therapy

Service

•    Full project management of 14C re-purification, patient dosing, LC-MS/MS analysis and PK analysis
•    Chromatographic separation plus 14C analysis

Outcome

Accelerated the hADME without delay of new 14C manufacture and dosimetry testing

US biotech company

Clinical indication

Secondary Hyperparathyroidism (SHPT) in patients with Kidney Disease

Objective

Conduct regulatory mass balance and metabolism studies in renally impaired patients to support NDA for drug in Phase III

Service

•    Help design clinical protocols
•    Coordinate with specialist clinical research site
•    Conduct all total radioactivity measurements using AMS in all clinical samples including hemodialysate
•    Transfer and validate metabolite profiling methods using HPLC + AMS for quantitative metabolite profiles

Outcome

•    Determined rate and routes of radioactivity excretion by

measurement of radioactivity related to [14C] in excreta over time.

•    Measure radioactivity concentrations in whole blood, plasma, and excreta over time.
•    Determined biotransformation product profiles in selected matrices
•    Assessed the impact of hemodialysis on drug elimination
•    Reduced the radiation burden to chronically sick patients
•    Allowed patients to be released from clinic after initial excreta collection period with further excreta collections during routine clinical visits used to follow slow excretion over several weeks
 
GSK – Dabrafenib

Clinical indication

BRAF mutation-positive solid tumor oncology

Objective

Satisfy regulator request for absolute bioavailability data for their late stage development compound

Service

•    Transfer and validate analytical methodology
•    Conduct all analyses using HPLC + AMS

Outcome

•    Efficiently conduct critical path investigation to meet regulatory need
•    Remove the need for any IV toxicology
•    Reduce cost and time of IV formulation development as the IV dose was only 100 μg and could be developed by the clinical CRO
•    Reduce number of patients by collecting oral and IV PK data in the same individuals concurrently
•    Conduct study in patients without need for wash out between oral and IV doses
•    Gain information on circulating metabolites by measuring total 14C in plasma

Discover how we can create preclinical and clinical investigations that will improve time- and cost-efficiency and help you achieve your commercial objectives;

Visit    www.xceleron.com

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