Reduces Fasting and Postprandial Glucose in a Multiple-Dose Clinical - - PowerPoint PPT Presentation

The Glucagon Receptor Antagonist LGD-6972 Reduces Fasting and Postprandial Glucose in a Multiple-Dose Clinical Trial

Eric G Vajda1, Douglas Logan2, Kenneth Lasseter3, Danielle Armas4, Diane J. Plotkin5, J.D. Pipkin1, Yong-Xi Li2, Rong Zhou2, David J. Klein2, Xiaoxiong Wei2, Stacy Dilzer3, Lin Zhi1, and Keith B. Marschke1

1Ligand Pharmaceuticals Incorporated, La Jolla, CA 2Medpace, Inc., Cincinnati, OH 3Clinical Pharmacology of Miami, Miami, FL 4Celerion, Phoenix, AZ 5Diane Plotkin Clinical Development Consultation Services, San Diego, CA

ENDO 2016 April 2, 2016 Boston, MA

DISCLOSURE

EGV, JDP, LZ, and KBM are employees and shareholders of Ligand Pharmaceuticals DL, KL, DA, DJP, YXL, RZ, DJK, XW, and SD were contracted by Ligand Pharmaceuticals to perform the studies described

• Excessive hepatic glucose production is a common feature in type

2 diabetes mellitus (T2DM)

• Inappropriate elevations in postprandial glucagon concentrations

further exacerbate hyperglycemia in T2DM patients

• Multiple preclinical models have demonstrated that blockade of

the glucagon receptor with antibodies, antisense

• ligonucleotides, or small molecule glucagon receptor antagonists

leads to reductions in plasma glucose

Background

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• Orally bioavailable small molecule that potently binds to the

glucagon receptor in vitro and competitively antagonizes the actions of glucagon

• LGD-6972 reduces plasma glucose in animal models of type 1

and type 2 diabetes1,2

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LGD-6972: Overview

1American Diabetes Association (ADA) 72nd Scientific Sessions; Philadelphia, PA, USA; June 8-12, 2012 2American Diabetes Association 73rd Scientific Sessions; Chicago, IL; June 21-25, 2013

STZ Injected Mice db/db Mice

• Double-blind, placebo-

controlled, randomized single ascending oral dose study evaluating safety, tolerability, PK, and PD in healthy individuals and type 2 diabetes subjects

• Dose-dependent

decreases in fasting plasma glucose after a single dose

• Favorable safety profile

LGD-6972: Clinical Data

Positive Phase 1a Clinical Data

5 Vajda, et al., American Diabetes Association 74th Scientific Sessions; San Francisco; June 13-17, 2014

Type 2 Diabetics Healthy Individuals

Phase 1b Study Design

• Phase 1b multiple ascending dose trial in normal healthy volunteers (NHV)

and T2DM subjects

• Randomized, double-blinded, placebo controlled study conducted at 3 sites
• T2DM subjects were on a stable dose of metformin throughout the study
• Once daily oral administration for 14 days, evaluated in 4 cohorts:

— 15 mg per day in NHV — 5, 10, and 15 mg per day in T2DM subjects

• 48 subjects

— n = 12 per cohort (9 active + 3 placebo)

• Primary Endpoints: Safety and tolerability of LGD-6972
• Secondary Endpoints: Pharmacokinetics and plasma glucose influence

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Baseline Characteristics and Demographics

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Volunteers Healthy Diabetics Placebo 15 mg Placebo 5 mg 10 mg 15 mg Number of subjects 3 9 9 9 9 9 Age (years) (%) 47.3 (8.7) 42.3 (10.8) 52.2 (6.2) 55.1 (6.0) 58.9 (6.7) 53.6 (8.7) Gender (n) Female 6 2 4 5 Male 3 9 3 7 5 4 Ethnicity (n) Hispanic/Latino 1 3 7 5 6 6 Not Hispanic/Latino 2 6 2 4 3 3 Race (n) White 1 4 8 8 7 6 African American 2 5 1 1 2 3 BMI (Kg/m2) (%) 27.4 (1.7) 24.4 (2.9) 31.0 (4.7) 33.6 (4.2) 32.0 (4.9) 31.3 (5.1) Baseline HbA1c (%) Not taken Not taken 8.5 (0.9) 8.2 (0.7) 8.2 (1.1) 8.5 (0.9)

Safety and PK

• There were no serious adverse events or adverse events that required study

discontinuation

• LGD-6972 was well tolerated with no clinically significant or dose dependent

changes in:

— Hematology — Clinical chemistry — Urinalysis — ECG — Vital signs

• Adverse events were generally mild to moderate (most common AEs were

nausea and headache)

• LGD-6972 was well absorbed with a long half life (t½ ≈50 hours) and steady

state PK was achieved within 7-10 days with once daily oral administration

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• LGD-6972 reduces fasting plasma glucose after a single dose and the effect

persisted throughout 14-day dosing period

LGD-6972 Reduces Fasting Plasma Glucose

Normal Healthy Volunteers

LGD-6972 Reduces Fasting Plasma Glucose

Type 2 Diabetics

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• Dose dependent decreases in fasting plasma glucose after treatment for 14

days with LGD-6972

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Glucose is Reduced Throughout the Day

Type 2 Diabetics

• 7 point glucose measurements performed on Day -1 and Day 14
• LGD-6972 decreased glucose in both fasting and post-prandial states
• 15 mg dose decreased weighted mean glucose by -53 mg/dL; estimated to

be approximately 1.5% reduction in HbA1c at steady state1

Rohlfing, et al., Diabetes Care; 25:2, 275-278, 2002

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HbA1c decreased from baseline

Type 2 Diabetics

• Decreases from baseline in HbA1c were observed for all cohorts after only

14 day treatment

• Longer term studies will be needed to determine the magnitude of this

effect

Hormonal Effects

Type 2 Diabetics

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• LGD-6972 increased plasma glucagon and total GLP-1

Oral Glucose Tolerance Test

Type 2 Diabetics

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• 10 mg LGD-6972 increased insulin excursion and decreased glucagon

excursion after oral glucose load

• In a multiple ascending dose study, LGD-6972 was well tolerated in NHV and

T2DM subjects treated for 14 days

• LGD-6972 substantially improved glycemic control with a rapid onset of effect

in T2DM subjects

• Dose dependent decreases in fasting plasma glucose were observed in NHV

and T2DM after a single dose and the effects persisted throughout a 14 day dosing period

• Glucose reductions were observed in both fasting and postprandial states
• In an OGTT, insulin excursion was increased while glucagon excursion

decreased

• The favorable safety and efficacy profile of LGD-6972 supports further clinical

development

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Summary