Case Studies

Successfully Waived a Thorough QT/QTc Study

Project Background and Strategic Question
The client was developing a small molecule drug for treatment of multiple different types of seizures. Phase 3 registration trials were ongoing, but the need for a thorough QT/QTc (TQT) study, as listed in the Food and Drug Administration (FDA) guidance for industry (https://www.fda.gov/media/71372/download), was not known. Because a TQT study is expensive and time-consuming, the question was whether the study could be waived based on the available phases 1 and 2 clinical data.

Our Client Support Services
To answer this question, we conducted an integrated nonclinical and clinical QT/QTc risk assessment. The overall assessment included 8+ nonclinical studies, 10+ clinical studies, and three concentration-QTc modeling analyses from single ascending dose and multiple ascending dose studies. Additionally, we also evaluated the time course of QT prolongation, the magnitude of QT prolongation, categorical analyses of outliers, and certain adverse events in patients that can signal potential proarrhythmic effects following guidance document. The totality of evidence based on the results of the integrated nonclinical and clinical QT/QTc assessment indicated that there was an acceptable safety margin for maximum plasma concentration at the therapeutic dose level and even under high PK exposure scenarios. We authored a 140-page report to support the waiver application of a TQT study.

Our question to FDA: does FDA agree with the sponsor’s position that the results of the integrated nonclinical and clinical assessments provided evidence for the lack of QT/QTc prolongation potential at the proposed therapeutic dose. Therefore, the results of those assessments could serve as an acceptable alternative to a standalone TQT study.

Outcome
The FDA answer was “Yes, Agree”. The implication was also significant savings from not conducting a TQT study

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Determination of Dose Range for the First-in-Human Study

Project Background and Strategic Question
The client was developing a molecule for the potential treatment of a pancreatic cancer and solid tumors with multiple mutations. A series of nonclinical studies were conducted to support an Investigational New Drug Application (IND). For the IND application, the client needed an investigational plan for a first-in-human study (FIH). However, the selection of starting dose and dose range in the FIH study was a challenge: choosing a narrow dose range might not identify a recommended phase-2 dose (RP2D), whereas selecting a wider dose range would be an expensive and time-consuming addition to the study objectives for the RP2D.

Our Client Support Services
First, we conducted a population pharmacokinetic (PK) modeling study across various species for allometric scaling to humans. PK exposures at various dose levels and schedules were obtained by simulation. Second, pharmacodynamic (PD) modeling was conducted to generate in vivo tumor-growth inhibition data. Linking the PK and PD models, the doses with the probability of achieving target concentrations for tumor growth inhibition were predicted, and a dose range was proposed for the FIH study. Our protocol was approved for the FIH study. During FIH trial conduct, we performed non-compartment (NCA) PK analyses for each dose cohort on an ongoing basis We found that the predicted and observed PK concentrations were in good agreement.

Outcome
The proposed dose range was adequate. The study objective for RP2D was achieved.

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Assessment of Drug-Drug Interaction Potential

Project Background and Strategic Question
The client planned to conduct two phase-3 studies to evaluate a small molecule drug being developed as adjunctive therapy for the treatment of patients with genetic defects caused epilepsies. It was essential to evaluate potential drug-drug interactions (DDIs) between the investigational drug and other commonly used anti-epilepsy drug (AEDs) in this patient population.

The sponsor conducted both cytochrome P450 (CYP)-mediated and transporter-mediated drug-drug interaction (DDI) studies in vitro. Additional in vitro DDI studies were also conducted for uridine diphosphate glucuronosyltransferase (UGT). There was an urgent need for speedy interpretation of the in vitro study results to determine the potential for clinical DDIs with commonly used AEDs.

Our Client Support Services
We evaluated 7+ in vitro DDI study reports and 4+ human PK study reports. We identified CYP enzymes as potential perpetrator to effect pharmacokinetics of the investigational drug. We also identified CYP enzymes which could be affected by the investigational drug. Further, we estimated the size of effect based on physiologically based pharmacokinetic (PBPK) assessment based on area under the curve (AUC) ratios. For CYPs, UGTs, and transporters which are unlikely to cause potential DDIs with the investigational drug, we also provided a list of drugs. We delivered a 45-page report to the client.

Outcome
Clinical studies conducted in healthy subjects confirmed the predicted DDIs from in vitro data. Results are in the proposed label for new drug application (NDA).

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PK Exposure-Response Analyses for New Drug Application

Project Background and Strategic Question
Patisiran (ONPATTRO®) is a member of a new class of drugs known as small interfering ribonucleic acid (siRNA) treatment. Patisiran is comprised of a novel siRNA, formulated in a lipid nanoparticle (LNP), and developed for treating hereditary transthyretin-mediated (hATTR) amyloidosis. The patisiran dose in the phase-3 APOLLO trial (patients with hereditary transthyretin amyloidosis) was 0.3 mg/kg, given intravenously every 3 weeks. For the new drug application (NDA), it was necessary to justify the dose per recommendations in the FDA publication, Guidance for Industry Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications (https://www.fda.gov/media/71277/download).

Our Client Support Services
We divided patients into four quartiles, based on pharmacokinetic (PK) exposures. The efficacy endpoint (modified neuropathy impairment score +7 [mNIS+7]) was analyzed for each quartile. The mean changes in mNIS+7 values from baseline to 18 months, compared with placebo, were comparable across the 4 PK-exposure quartiles, indicating that the PK exposures at 0.3 mg/kg reached the plateau of the dose-response curve. Likewise, the frequency of adverse events and serious adverse events did not increase with increasing PK exposure to patisiran and its two novel components of lipid nanoparticle (DLin-MC3-DMA and PEG2000-C-DMG), indicating that the incidence of these adverse events was independent of the PK concentrations of the three analytes. More information is available in publications, https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.1553 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972979/pdf/JCPH-60-37.pdf

Outcome
The 0.3 mg/kg intravenous infusion dose every 3 weeks was justified, and, in 2018, FDA approved this first-of-its kind targeted RNA-based therapy. This was also the first FDA approval of an siRNA. Patisiran received its first global approval in August of 2018.

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Modeling and Simulation for Subcutaneous Dose Selection

Project Background and Strategic Question
Tocilizumab is a humanized monoclonal antibody that inhibits interleukin-6 (IL-6) from binding to soluble interleukin-6 (sIL-6R) and membrane-expressed forms of its receptor, thus inhibiting the IL-6–mediated signaling cascade that brings about the proinflammatory activity of the cytokine. Tocilizumab was approved in many countries for the treatment of patients with moderate to severe active rheumatoid arthritis (RA) as an intravenous infusion (IV dose of 8 mg/kg every 4 weeks). However, this dosing schedule necessitates monthly visits to the infusion clinic. A subcutaneous (SC) formulation of tocilizumab for self-administration was important for patients. The challenge was to find 2 SC doses comparable to the 2 approved IV doses, in order that SC dosing options could be available in the approved tocilizumab label, along with the IV doses.

Our Client Support Services
We conducted a clinical study evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of tocilizumab following SC and IV administration to healthy subjects in doses ranging from 81 to 162 mg. The results showed that PK exposures following SC administration increased by more than a dose-proportional response, and that the elimination half-life after SC dosing was shorter than that following IV dosing. Further, absolute bioavailability for PK was dose-dependent, much less at lower doses than at higher doses. Thus, tocilizumab cannot be delivered by the SC route at a dose (560 mg for a 70 kg patient) similar to that given by the IV route (8 mg/kg).

We subsequently used a modeling and simulation tool to predict PK exposures following multiple dose administrations ranging from 81 to 162 mg at various dosing frequencies. The dose of 162 mg weekly and every other week were chosen for further assessment in phases 2 and 3 clinical studies in the RA population. More detailed information is available in the publications, https://pubmed.ncbi.nlm.nih.gov/23547848/ and https://pubmed.ncbi.nlm.nih.gov/23782588/.

Outcome
The proposed tocilizumab doses of 162 mg weekly and every other week were validated in the two large phase 3 studies, and 2 SC doses were added to the tocilizumab label. More detailed information is available in the publications, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276289/pdf/acr0066-1653.pdf, and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888614/pdf/annrheumdis-2013-203523.pdf

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