Intra-Target Microdosing (ITM)A Novel Drug development Approach

Proof-of-Concept in Humans

Tal Burt, MDClinical Research and Drug Development Consultant

Burt Consultancy, LLC.

Disclosure

Tal Burt is patent holder for Intra-Target

Microdosing (ITM).

ICH M3 Guidelines and Microdosing Challenges

Current Phase-0/Microdosing Challenges:1. Lack of pharmacodynamic (PD) data2. Uncertainty about extrapolation from microdose to full

dose

International Conference on Harmonization (ICH) M3 Guidelines, 2010

Intra-Target Microdosing (ITM)

Target Systemiccirculation

DrugBiomarker

Dru

g C

once

ntra

tion

Time

Target(pharmacological exposure)

Systemic(microdose exposure)

1. PD

2. PK

3. PET-imaging

Output

PD threshold

Microdose=1/100th total-body

dose

Input

ITM

Supplying 1/100th body mass

ITM

Artery

Vein

Burt et al., 2015

ITM Study Design

Primary Hypothesis (Efficacy): I F≅Secondary Hypothesis (Safety): I >> X

ObservationsIpsilateral Contralateral Systemic

Interventions

ITM I X X

Systemic Full-dose F F F Microdose X X X

Sham X X X

I – Intra-Target Microdosing (ITM); F – Full Dose; X – Inactive Comparator

Burt et al., 2015

Unpaired t-test p-value 95% CI MeaningPrimary hypothesis (ITM vs. SF) 0.7895 -0.024 to 0.029 I ≈ SFSecondary hypothesis(ITM vs. SM)(ITM vs. sham)

0.01470.0052

-0.045 to -0.0070.023 to 0.058

I > SM I >> Sham

ITM – 18F-FDG Uptake Slope Analysis

20 25 30 35 40 45 50 55 600.2

0.3

0.4

0.5

0.6

0.7

f(x) = 0.00173768858730158 x + 0.25412377559127

f(x) = 0.00614950808809524 x + 0.22202196310119

f(x) = 0.00664237998809524 x + 0.22197369235119

f(x) = − 0.00148175879365079 x + 0.396298476746032

Sham

Linear (Sham)

IAM

Linear (IAM)

SF

Linear (SF)

SM

Linear (SM)

Linear (SM)

Time After 18F-FDG Infusion (min)

Reno

rmal

ized

SUV

ITM – Intra-Target MicrodosingSF – Systemic Full-DoseSM – Systemic MicrodoseSham – no intervention or saline

Burt et al., 2015

Glucose and Insulin ITM Data

SubjectInsulin Dose

Saline Duration 5 min. TourniquetSystemic ITM

A (001) 2 IU 0.02 IU 2 ml 20 sec. -B (003) 2 IU 0.02 IU 2 ml 20 sec. -C (005) 2 IU 0.2 IU 10 ml 10 sec. +D (006) 2 IU 0.2 IU 10 ml 10 sec. +E (007) 2.5 IU 0.03 IU 3 ml 5 sec. +

Burt et al., ACCP 2016ITM ipsilateral – Intra-Target Microdosing intervention, plasma levels from the ipsilateral arm vein; CL – plasma levels from the contralateral arm vein during the ITM intervention

Proof of Mechanism – PKPD Continuum

PK – PharmacokineticsPD – PharmacodynamicsCu – Concentration unbound, in tissueO – OutcomeBM – BiomarkersSBM – Surrogate Biomarkers

I – plasma PKII – tissue PKIII – receptor bindingIV – PD, BM, outcomes

PK PD

CuI

II

IVO

III

SBM

BM

BM

BMBM

SBM

SBM

BM

SBM

Arterial PK

Venous PK

Burt et al., 2015

ITM – Modeling and Simulations

𝑉 𝑖 𝜕𝜕𝑡 𝐶𝑔𝑙𝑢

𝑖 (𝑡 )=−𝑚1𝐶𝑔𝑙𝑢𝑖′ (𝑡 )−𝑚2𝐶𝑖𝑛𝑠

𝑖′ (𝑡 )+𝑃𝑔𝑙𝑢𝑎 (𝐶𝑔𝑙𝑢

𝑎′ (𝑡 )−𝐶𝑔𝑙𝑢𝑖′ (𝑡 ) )+𝑃𝑔𝑙𝑢

𝑣 (𝐶𝑔𝑙𝑢𝑣 ′ (𝑡 )−𝐶𝑔𝑙𝑢

𝑖′ (𝑡 ) )

C - concentration; Q (black arrows) - blood flow; green arrows - vascular fluxes; blue arrow - cellular uptake of insulin or glucose.‘glu’ - glucose; ‘ins’ - insulin; Vi - interstitial volume; m1Ci’

glu - passive glucose diffusion into cells; m2Ci’

ins represents facilitated uptake of glucose via GLUT4, with GLUT4 expression mediated by insulin; prime notation denotes deviation from baseline concentration Burt et al., 2015

Drug Organ / Tissue BiomarkerNitrates, inotropes, adrenergic, muscarinic, PDE5 inhibitors, neutral endopeptidase (NEP) inhibitors, natriuretic peptides

Peripheral vascular Vasodilation, vasoconstriction, cGMP spillover measurement

Anesthetics, analgesics (e.g., Nav1.7 inhibitors)

Peripheral organ / tissue Anesthesia, analgesia

Triptans Blood vessels Analgesia, substance P and CGRP levels

Neuromuscular blocking agents Skeletal muscles Muscle relaxation/paralysis

Chemotherapy Liver, kidney, brain, breast Receptor binding (with PET imaging of radiolabeled drug)

Anticoagulants, antiplatelet Blood Coagulation parameters, platelet aggregation

Immune modulators, antihistamines Blood Cytokines, allergic symptoms Hypoglycemics, sodium glucose cotransporter-2 (SGLT-2) inhibitors, diuretics

Kidney Glucose levels, reabsorption in proximal tubule (by 18F-FDG)

Antiarrhythmics Heart ECGCNS stimulants and depressants (e.g., hypnotics, sedatives, anxiolytics), NMDA antagonists

CNS Neuronal activity (e.g., Wada Test)

PDE5 - phosphodiesterase type 5; cGMP - cyclic guanosine monophosphate; CGRP - Calcitonin Gene-Related Peptide; SGLT - Sodium-glucose transport; ECG - electrocardiogram; NMDA - N-methyl-D-aspartate; CNS - Central Nervous System.

Use of ITM to study pharmacological effects (in addition to systemic PK, tissue PK, and receptor binding) will be feasible in drug classes that allow collection of biomarkers (or surrogate biomarkers) in the time frame of seconds to minutes

ITM Applications

Burt et al., 2015

ITM Application Examples

DrugOrgan / Tissue (artery)

Biomarker Value to Drug Development

Chemotherapy HCC

(Hepatic artery)

Tissue binding; Venous

biomarkers; Tumor PK;Histology;

Displacement

Proof-of-concept that the chemotherapeutic agent reaches, penetrates and binds to cellular

targets in the tumor (and metastases); biomarkers of safety and efficacy;

tissue PK/PD and systemic PK

SGLT-2 inhibitors

Kidney (Renal artery)

Glucose excretion;18F-FDG

reabsorption

Biomarker of efficacy / MOA;tissue PD and systemic PK

Natriuretic peptides

Hand (Radial artery)

Vasodilation;cGMP levels

Physical and chemical biomarkers of efficacy;tissue PD and systemic PK

Neuromuscular blocking drugs

(NMBDs)

Hand (Radial artery)

Muscle strength

Efficacy in muscles is generalizable to all skeletal muscles; No risk of systemic paralysis

and general anesthesia;tissue PD and systemic PK

1) PD Data.

2) Systemic Safety.

3) Short exposure.

4) Control in the same individuals in real time.

5) Ability to model and extrapolate microdose data using real human full-dose data.

Intra-Target Microdosing (ITM) Advantages

1) Risk of the intra-arterial (and intravenous) procedure. Use will depend on benefit/risk assessment (e.g., favorable in patients already cannulated for therapeutic purposes (e.g., chemotherapy) or during surgery).

2) Identifying, quantifying, and validating the biomarkers relevant to drug efficacy or safety within the short window of seconds to minutes of local exposure that ITM would provide.

3) Validation

4) Regulatory Perspective. Animal toxicology using the ‘intended route of administration” ICH M3, 2009

Intra-Target Microdosing (ITM) Challenges & Limitations

Acknowledgements

Co-PI:Robert J. Noveck, MD, PhD

Co-investigators:Bennett Chin, MDDouglas C. Rouse, DVMDouglas H. Weitzel, PhDThomas HawkSalvatore Borges-Neto, MDTimothy Turkington, PhDMark Feinglos, MDSein-Chung Chow, PhDHuali Wu, PhDAnita T. Layton, PhD

Staff at the Duke Division of Laboratory Animal Resources (DLAR), Duke Clinical Research Unit (DCRU), and Duke PET

Collaborators:Malcolm Rowland, PhD (UK)Graham Lappin, PhD (UK)Yuichi Sugiyama, PhD (Japan)Kenta Yoshida, PhD (Japan)Le Thuy Vuong, PhD (USA)Christy John, PhD (USA, FDA)Lakshmi Putcha, PhD (USA, NASA)Saskia de Wildt, PhD (The Netherlands)Jon Ruckle, MD (USA)Antoinette Santoro, BSRT, CRC (USA)David MacLeod, MB (USA)Michael Cohen-Wolkowiez, MD, PhDKihak Lee, PhD

Tal Burt, MD Burt Consultancy, LLC