Download - Intra-Target Microdosing (ITM) POC in Humans ACCP 2016 Poster

Intra‐TargetMicrodosing(ITM),ANovelDrugDevelopmentApproach:Proof‐of‐ConceptinHumans

Burt, Tal1;MacLeod, David2; Lee, Kihak3; Hawk, Thomas4; Turkington, Timothy4; Borges‐Neto, Salvador4; Santoro , Antoinette2; DeMasi, Daniel K.2; Feinglos, Mark5; Noveck, Robert6; Rowland, Malcolm7

1. Corresponding Author: Burt Consultancy, LLC, Durham, NC, United States [email protected]. 2. Anesthesiology, Duke University, Durham, NC, United States. 3. RSC Clinical Education , Siemens Medical Solutions USA, Inc. , Knoxville, TN, United States. 4. Radiology, Duke University, Durham, NC, United States. 5. Endocrinology, Duke University, Durham, NC. 6. Duke Clinical Research Institute, Duke University, Durham, NC. 7. Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom.

ABSTRACT

BACKGROUND

OBJECTIVES

Table 3. Insulin and Glucose Plasma Levels and 18F‐FDG SUVs (Standard Uptake Values). IL –ipsilateral (i.e., samples obtained from the same arm that received the intra‐arterial insulin); CL –contralateral; IU – international units n/a – not available. PET data were not available for subject C due to excessive movement during the scanning. ______ ‐ insulin and glucose plasma levels consistent with the primary hypothesis (hypoglycemic effects after intra‐arterial insulin).

METHODS

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. +

RESULTS

RESULTS

Glucose SystemicGlucose ITM Ipsilateral

Glucose ITM CL

Insulin Systemic

Insulin ITM Ipsilateral

Insulin ITM CL0

50

100

150

200

250

300

350

400

0 5 10 15 30 60

mg/dL

for g

lucose; ng/dL

for insulin

Figure 3. Subject C (005). Insulin and glucose plasma levels.

CONCLUSIONS

Subject Visit Data typeBaseline

(10 minutes from FDG to Insulin)

InsulinTime post insulin administration (= FDG+10)

5(FDG+15)

10(FDG+20)

15(FDG+25)

30(FDG+40)

60

A (001)

Sysglucose 74

2 IU77 68 57 55 n/a

Insulin 1.4 242.8 27.9 12.3 4.3 4.618F‐FDG 0.156 .226 .239 .252 .275

ITM (IL)glucose 97

0.02 IU(1/100th of therapeutic

dose)

94 101 92 87 78insulin 3.3 3.7 3.2 3.5 2.7 2.418F‐FDG 0.163 .268 .291 .308 .320

ITM (CL)glucose 86 86 85 85 87 82insulin 3.8 3.7 3.9 3.3 2.7 2.318F‐FDG 0.135 .260 .261 .295 .318

B (003)

Sysglucose 85

2 IU79 66 52 54 83

insulin 3 131 36.6 15.8 10 9.418F‐FDG 0.132 .273 .291 .299 .307

ITM (IL)glucose 101


dose)

99 104 105 103 96insulin 1.7 10.9 9 11 9.8 6.918F‐FDG 0.380 .437 .470 .484 .524

ITM (CL)glucose 110 120 109 114 111 95insulin 3.7 8.8 9.8 11.9 9 6.818F‐FDG 0.402 .503 .541 .567 .617

C (005)

Sysglucose 107 2 IU

+ 5 min. tourniquet (IL)

105 105 92 83 76insulin 32.1 162.6 77.3 29.9 19.8 1318F‐FDG

ITM (IL)glucose 107


dose)

65 110 108 117 93insulin 35.7 366 76.5 65 63.9 56.918F‐FDG

ITM (CL)glucose 99 103 110 115 115 93insulin 34.8 38 40.4 49.8 60.1 45.518F‐FDG

D (006)

Sysglucose 103 2 IU


101 90 75 59 78insulin 7.8 115.5 31.9 17.1 4.7 2.818F‐FDG 0.309 .478 .493 .520 .521

ITM (IL)glucose 77


dose)+ 5 min. tourniquet (IL)

70 66 71 70 63insulin 1.3 261.7 250.2 18.2 5.4 4.418F‐FDG 0.164 .195 .270 .293 .376

ITM (CL)glucose 80 86 78 76 79 82insulin 1.2 1.4 4.9 2.9 1.3 218F‐FDG 0.136 .231 .268 .279 .328

E (007)

Sysglucose 83 2.5 IU


86 59 56 n/a n/ainsulin 10.1 257.7 59.2 21.4 19.1 10.918F‐FDG 0.106 .215 .213 .241 .252

ITM (IL)glucose 107


dose)+ 5 min. tourniquet (IL)

88 124 108 112 87insulin 15.5 61.6 18.8 16.1 15.9 9.518F‐FDG 0.132 .272 .286 .324 .386

ITM (CL)glucose 109 121 118 119 108 95insulin 15.8 17.4 13 16.8 15.3 8.918F‐FDG 0.145 .306 .337 .366 .400

Primary Hypothesis (Efficacy): ITM ≅ SF

Secondary Hypothesis (Safety): ITM >> SM

Observations

Ipsilateral Contralateral Systemic

Inte

rven

tions

ITM ITM SM SM

Systemic

Full-dose SF SF SF

Microdose SM SM SM

The objective of the study was to demonstrate that ITM is associated with local full-dose exposure and systemic microdose exposure. Table 1 outlines the study hypotheses and respective outcomes.

Table 1. Intra-Target Microdosing (ITM)Proof-of-Concept Study DesignInterventions in the rows are matched withobservations in the columns to test theprimary and secondary hypotheses. ITM –Intra-Target Microdosing intervention andipsilateral (target) effects; SF – Systemic Full-dose comparator; SM – Systemic Microdose(including systemic and contralateral effectspost-ITM);

Figure 1. Intra‐Target Microdosing (ITM): Schematic of input and output. By generating concentrations higher than the pharmacodynamic (PD) threshold, ITM allows the capture of local PD data relevant to full (pharmacological, therapeutic‐level) exposure, in addition to systemic PK data. Multiple infusion profiles are possible depending on desired exposure‐response profiles.

The study demonstrated the ethical and operational feasibility and scientific proof‐of‐concept of ITM. The approach, to which we coined the term ‘in‐humano’ in a recent publication (2) to indicate pre‐clinical testing in humans, enabled simultaneous target measurement of drug (insulin) and biomarker (glucose) plasma levels as well as imaging another biomarker (18F‐FDG). Target exposure post ITM was similar to systemic full dose administration resulting in local effects but with minimal systemic effects. Small numbers and variability in the execution of the PET component may have led to the inconclusive nature of the PET results. ITM could enable safe, inexpensive, and early testing of novel drugs at the FIH stage. Findings should be validated in larger, controlled studies using a range of targets and classes of drugs.

Figure 2. Slope Analysis of 18F‐FDG Uptake. Each slope represents data from each of the 4 experimental groups: (1) IAM – Intra‐Arterial Microdosing; (2) SF – Systemic Full‐dose administration; (3) SM – Systemic Microdose; (4) Sham – no insulin. Slopes are the mean of Standard Uptake Values (SUV)‐based Time‐Activity Curves (TAC)

The safe and efficient translation of biological insights into human applications is a major public health challenge. Safety concerns are associated with substantial pre‐clinical developmental costs, delaying entry into First‐in‐Human (FIH) testing. We introduce a novel drug development tool, Intra‐Target Microdosing (ITM), combining features of ‘microdosing’, the systemic subpharmacological testing of drugs, and intra‐target drug delivery (Figure 1). We previously reported the results of a rodent ITM study using similar methodology (Figure 2) (1).

References: (1). Burt, T., D. C. Rouse, K. Lee, H. Wu, A. T. Layton, T. C. Hawk, D. H. Weitzel, B. B. Chin, M. Cohen‐Wolkowiez, S. C. Chow and R. J. Noveck (2015). "Intraarterial Microdosing: A Novel Drug Development Approach, Proof‐of‐Concept PET Study in Rats." J Nucl Med 56(11): 1793‐1799. (2). Burt, T. et al.Microdosing and other Phase‐0 Clinical Trials: Facilitating Translation in Drug Development. Clinical and translational science 9, 74‐88 (2016).

Sham slope = ‐0.0015

IAM slope = 0.0066

SF slope = 0.0061

SM slope = 0.0018

0.2

0.3

0.4

0.5

0.6

0.7

20 30 40 50 60

Reno

rmalized

SUV

Time After 18F‐FDG Infusion (min)

ShamIAMSFSMLinear (Sham)

Linear (IAM)

Linear (SF)

Linear (SM)

Glucose Systemic

Glucose ITM Ipsilateral

Glucose ITM CL

Insulin Systemic

Insulin ITM Ipsilateral

Insulin ITM CL0

50

100

150

200

250

300

0 5 10 15 30 60

mg/dL

for g

lucose; n

g/dL

for insulin

Figure 4. Subject E (007). Insulin and glucose plasma levels.

Table 2. Insulin administration schedule in Visit 2 (‘Systemic’, intravenously) and Visit 3 (‘ITM’, intra‐arterially)

In subjects C, D, and E (Figures 3 and 4; Table 3) there was an increase in ipsilateral insulin levels and a corresponding drop in glucose levels after intra‐arterial administration in the ipsilateral arm but not the contralateral arm. Consistent with the primary hypothesis, systemic FDG‐uptake was not statistically different from ipsilateral ITM (IL) (p = 0.117). However, lack of observed statistical difference between ITM (IL) and contralateral (CL) (p = 0.143) did not reject the secondary null hypothesis.

ITM ipsilateral – Intra‐Target Microdosing intervention, plasma levels from the ipsilateral arm vein; CL – plasma levels from the contralateral arm vein during the ITM intervention

Disclosures: T. Burt holds a patent for Intra‐Target Microdosing (ITM). Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001117.

Tourniquet5 min. ipsilateral

Tourniquet5 min. ipsilateral

The protocol was approved by the Duke University Medical Center (DUMC) IRB. 5 healthy male volunteers (A‐E), age 21 – 34, weight 84.28 ± 6.55 kg, underwent informed consent process, and entered a 3‐visit protocol over 3 weeks. In Visit 1 the minimal insulin dose necessary to generate systemic reduction in glucose levels was determined. In Visit 2 the minimum full dose was systemically administered and in Visit 3 the ITM dose was administered intra‐arterially into the non‐dominant radial artery (Table 2) Insulin administration in visits 2 and 3 was followed by PET imaging of 18F‐FDG uptake. Tourniquet placement: Subjects C, D, and E had a tourniquet placed for 5 minutes ipsilaterally to increase local exposure time to insulin. The tourniquet was applied during the corresponding ‘Systemic’ visit too, as control, to ensure comparable conditions.PET Imaging: Image analysis was performed using the Inveon Research Workplace 4.2 package (Seimens Medical Solutions, USA). Regions of interest were drawn on the CT images with a soft tissue threshold applied (Houndsfield units ‐300 to 300). Right and left hand ROIs were drawn to cover the area of metacarpals (wrist to 1st knuckle), circular ROIs in addutor pollicis and hamstring muscles. ROIs were applied to dynamic PET dataset and time activity curves were generated.

Statement of Purpose, Innovation or Hypothesis: Intra‐Target Microdosing (ITM) is a novel drug development approach combining intra‐target (e.g., intra‐arterial) drug delivery and ‘microdosing’, the sub‐pharmacological systemic exposure to a novel drug. We hypothesized that, when the target is small enough (about 1/100th of the body mass) ITM can lead to target exposure equivalent to systemic full‐dose administration but with minimal (microdose) systemic exposure. We previously reported the first animal ITM proof‐of‐concept (POC) study. Here we report the first human ITM POC study using a similar methodology.Description of Methods and Material: Each of 5 healthy male volunteers (A‐E) had 3 visits separated by at least one week. The first visit determined the minimal insulin dose. In the second, insulin was administered systemically IV in therapeutic‐level doses. In the third, insulin was administered in microdose intra‐arterially (radial artery). Blood sampling for insulin and glucose plasma levels and 60‐minute dynamic 18F‐FDG uptake PET imaging of ipsilateral and contralateral hand muscles followed. The same slope method used in the rodent study for 18F‐FDG‐uptake analysis was used.Data and Results: Subjects A and B received 2 IU of insulin systemically during the second visit, and 0.02 IU intra‐arterially during the third. Subjects C, D, and E had a tourniquet inflated for 5 minutes over the ipsilateral arm (the arm receiving the intra‐arterial insulin) in order to prolong tissue exposure to insulin. Subjects C and D received 2 IU during the second visit and 0.2 IU during the third. Subject E received 2.5 IU in the second visit and 0.03 IU in the third. In subjects C, D, and E, there was an increase in ipsilateral insulin levels and a corresponding drop in glucose levels after intra‐arterial administration in the ipsilateral arm but not the contralateral arm. Consistent with the primary hypothesis, systemic FDG‐uptake was not statistically different from ipsilateral ITM (IL) (p = 0.117). However, lack of observed statistical difference between ITM (IL) and contralateral (CL) (p = 0.143) did not reject the secondary null hypothesis.Interpretation, Conclusion or Significance: The study demonstrated the ethical and operational feasibility and scientific proof‐of‐concept of ITM. The approach enabled simultaneous target measurement of drug and biomarker (glucose) plasma levels as well asimaging another biomarker (18F‐FDG). Target exposure post ITM was similar to systemic full dose administration resulting in local effects but with minimal systemic effects. ITM could enable safe, inexpensive and early testing of novel drugs at the FIH stage. Findings should be validated in larger, controlled studies using a range of targets and classes of drugs