Clinical Pharmacology Quiz

Clinical Pharmacology and PK/PD of Therapeutic Proteins: An Industry Perspective

• The presentation is about the clinical pharmacology and pharmacokinetics/pharmacodynamics (PK/PD) of therapeutic proteins from an industry perspective.
• The outline covers different stages of drug development, including pre-investigational new drug (IND) applications, phase 2/3 trials, and biological license applications (BLAs).
• A section on clinical pharmacology studies and concerns is included, along with considerations for PK and target assay, pediatric considerations and immunogenicity.

Introduction

• The presentation discusses the pre-investigational new drug (IND) application through first-in-human (FIH) studies and proceeding to phase 2/3 trials and biological license application (BLA).

Outline

• Part 1 covers the initial stages from introduction to IND application and FIH studies, phase 2/3 trials to BLA.
• Part 2 addresses other clinical pharmacology considerations including PK and target assay considerations, pediatric considerations, and immunogenicity.

Personal Background/Disclosure

• The presenter is a senior director of clinical pharmacology at Regeneron, with experience at AbbVie.
• They have a PhD in Pharmaceutical Sciences, a BS in Pharmaceutical Sciences, and a BA in Mathematics.
• Their research interests include clinical pharmacology, therapeutic proteins, pediatric drug development, monoclonal antibodies, and drug-drug interactions.

Experience in Clinical Development of Small Molecule and Biologics

• DUPIXENT (dupilumab), an anti-IL-4Ra mAb, is FDA-approved for atopic dermatitis, asthma, chronic rhinosinusitis, and other conditions.
• Itepekimab (anti-IL-33 mAb) is in Phase 3 for COPD and Phase 2 for NCFB.
• Vonsetamig (BCMAXCD3 bispecific Ab) is in Phase 1 for desensitization of patients needing a kidney transplant.
• Glecaprevir/pibrentasvir (Mavyret) is approved for chronic Hepatitis C Virus (HCV) infections.
• Lutikizumab is in Phase 2 for osteoarthritis, with ongoing development in other conditions.
• Rovalpituzumab-tesirine is for small cell lung cancer. (Trial terminated in Phase 2)

Finding information on Clinical Studies

• Most Phase 2/3 studies leading to drug approvals are published in peer-reviewed manuscripts.
• Many top journals include clinical study protocols as supplementary materials.
• Clinicaltrials.gov and clinicaltrialsregister.eu require registration of all Phase 2/3 studies

FDA Summary Reviews

• The BLA number 761055 is for Dupixent (dupilumab)
• Summary reviews include key documents like the approval letter, printed labeling, risk factor assessment, etc and summary of clinical pharmacology /biopharmaceutics relevant reviews.

Finding information on Pediatric Drug Approvals

• Reviews of pediatric studies under BPCA(Best Pharmaceuticals for Children Act) and PREA (Pediatric Research Equity Act) from 2012-present are usually available.

FDA Guidances and Email Updates

• FDA guidance documents outline expectations for topics in drug development, organized by functional area.
• Subscribe to email digests for updates on changing regulations, to FDA guidance documents and Clinical Pharmacology Corner.

What is Clinical Pharmacology?

• Clinical pharmacology is about getting the right drug at the right dose to the right patient at the right time.
• It addresses if the target mechanism is relevant for the patient population and right dose and frequency
• Considerations include special patient characteristics, immunogenicity, drug-drug interactions and food effect that impact the exposure of the drug.

Dose Selection

• FIH dose selection follows a process that encompasses preclinical and clinical development stages.
• The process involves multiple dosing stages and considerations for clinical use.
• The specific strategies can vary depending on the therapy.
• Various methodologies to reach a dose (e.g., 3+3, etc)

Relevant Data Package for IND/FIH Planning

• For monoclonal antibodies, essential data includes in vitro characterization (e.g., binding affinity, concentration producing 50% of maximal effect), in vivo animal studies (e.g. demonstrating mechanism of action), toxicology studies establishing safety, and allometrically scaled PK to predict human exposure.

Initial toxicology studies

• The types of toxicology studies used for small molecules as compared to therapeutic proteins.
• Non-human primates (NHPs) are a key species for some toxicology studies given their closer genetic relationship to humans.

Design concepts for general toxicology studies

• The design considerations for toxicology studies, including considerations like doses, recovery periods, and routes of administration.
• No observed adverse effect level is also included.

Selecting the First-in-Human (FIH) Population

• Factors considered when selecting an FIH population including criteria for patient screening, disease status and risk levels.

FIH Dose Selection Approaches

• Different methods (e.g., MRSD, NOAEL, HNSTD, PAD, and MABEL) for selecting initial doses during FIH trials for therapeutic proteins.

Traditional FIH Single Ascending Dose Study

• An overview of the study designs implemented to assess immunogenicity, safety and efficacy of monoclonal antibodies, and small molecules in healthy human subjects.

3+3 Dose Escalation Design

• A description of the 3+3 design used in clinical trials, particularly in oncology and similar conditions
• The methodology and steps in choosing the next dosing level in terms of the dosing scheme

MABEL Case Study: Teclistamab (BCMAxCD3)

• Overview of a specific MAB case showing usage and process of choosing a starting dose.
• Data are presented that show both functional drug and total target molecules being measured.

Phase 2/3 to BLA

• The transition from Phase 2/3 trials to subsequent biosimilar license applications (BLAs)

Is your program ready for Phase 2?

• Considerations about costs, patient selection and how these trials can vary for oncology studies compared to other conditions

The Phase 2 study landscape

• An overview of several scenarios of phase 2 studies, from Proof of Concept to Dose-Ranging (DR).

Therapeutic index (TI) and protein therapeutics

• Explaining the therapeutic index and its significance in relation to the safety and efficacy of protein therapeutics.

Dose selection and injection volume limits

• Factors to consider for dose and volume limits for subcutaneous therapeutic proteins.

Normalizing doses and exposure across patients

• Considerations about methods for standardizing dosages and exposures across different patient populations, and the pros/cons of different approaches

Characterizing the impact of body size on PK

• Discussing the methods for normalizing drug dosages according to body weight and other relevant characteristics.

Simulating different body-size normalization algorithms

• Different approaches are presented that can provide suitable exposure for both larger and smaller subjects for the same compound.

Commercial examples of body size normalization

• Showing examples of how different companies have adapted dosing schemes based on body size and other factors.

The rush to pivotal studies

• Issues of time pressures and economic considerations.

FDA's "Project Optimus"

• The goals of this project are to improve how dose-finding is conducted for oncology treatments.

Phase 3, BLAs, and clinical pharmacology

• Overview of the role of clinical pharmacology in providing supportive analyses after Phase 3 trials.
• It relates the drug's exposure and efficacy/safety relationships

Exposure-response

• Analyzing how drug exposure relates to the clinical outcome, or surrogate endpoints, using plots.

Exposure-Response Case Study

• Case study example showing exposure-response analyses for a drug in children.

Hysteresis plots

• Explanation on how these plots are used to relate declining drug concentration with target saturation.

Pediatric Considerations

• How pediatric development studies should leverage information gained in adult studies.
• The consideration of the development/ontogeny aspects when extrapolating PK from adult studies to children
• Pediatric approval considerations for drugs.

Immunogenicity

• Overview of the challenges of immunogenicity in therapeutic proteins, and approaches taken to address them.
• A case study on the immunogenicity profile of certain compounds.

PK and Target Assay Considerations

• Overview of assays used to measure PK (and considerations around which form of the drug is measured).
• Discussion around what is being measured in drug PK assays that are used in human subjects.

Measuring PK of mAbs to Cellular Targets

• Many cellular targets also have soluble versions, which must be considered.

Bispecific antibodies

• Discussion on how bispecific antibodies require additional considerations relative to standard monoclonal antibodies.

Soluble target can act as a drug sink

• The potential role of soluble targets in affecting the exposure of therapeutic proteins or monoclonal antibodies

Measuring total target for antibodies against soluble antigens

• Analyzing the concentrations of total target and how they are associated with the exposure of a compound in a clinical context.

Modeling maturation of clearance

• How the clearance of monoclonal antibodies in children differs from adults and the different models that have been used to understand the time-dependent clearance

Pediatric Development

• How to leverage existing information from adult studies when evaluating the pharmacokinetics of the same drug in children..

Pediatric PK/Safety Studies of Dupilumab in Patients

• Presenting different experimental plans, as well as examples of PK/safety studies conducted.
• Detailing of particular cases that involved children

Dupilumab Pediatric AD Phase 3 Dose Selection

• Discussion on how dose selection for pediatric clinical trials was informed by the available dosage forms, convenient dosing intervals and body weights.

Dupilumab 200/300 mg (<60/≥60 kg) Q2W

• Discussing how 200/300 mg Q2W dupilumab regimens were statistically better or superior to 300 mg Q4W in adolescents.

Ontogeny and Pediatric PK Considerations

• Discussing how antibody pharmacokinetics can differ in young children due to factors such as developmental status.

Conclusions

• The goal of clinical pharmacology is to identify the right dose of the right drug.
• Encourage collection of dose-ranging PK and PD data at an early stage.
• Clinical pharmacology for therapeutic proteins involves new technologies continually evolving from new technologies.
• Certain aspects of clinical pharmacology for protein therapeutics are simpler than traditional small molecule drugs, like immunogenicity, but there are different challenges

Questions?

• QnA session about the presentation content and related topics.