Kirk Johnson - PDF document

1 Kirk Johnson 1 , Allan Gordon 2 , Ann C
Kirk Johnson 1 , Allan Gordon 2 , Ann C Neale 2 , Adrian Vella 3 , Clare Jung Eun Lee 4 , Allison B. Goldfine 5 , Helen Margaret Lawler 6 , Richard Millstein 6 , Stella Costante - Hamm 2 , Padma Bezwada 1 and Paul D. Rubin 2 1 Development, XOMA Corporation, Berkeley, CA 2 Clinical, XOMA Corp, Berkeley, CA, XOMA (US) LLC 3 Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 4 Endocrinology , Diabetes, Metabolism, Johns Hopkins University, Baltimore, MD 5 Research

2 Division, Joslin Diabetes Center, Bosto
Division, Joslin Diabetes Center, Boston, MA 6 Endocrinology, Metabolism, and Diabetes, Univ. Colorado School of Medicine, Denver, CO MONDAY APRIL 3, 2017 ENDO 2017 Single Administration of XOMA 358, an Insulin Receptor Attenuator, Improves Post - Meal and Nighttime Hypoglycemia Profiles in Post Gastric Bypass Hypoglycemia (PGBH) Patients Kirk Johnson, PhD DISCLOSURE 2 • Full - time Employee of XOMA Corp. • VP Development • Stock holder 3 X358: Targets an Allosteric Site on the Insulin Receptor t

3 o Decrease Insulin Receptor Signaling Or
o Decrease Insulin Receptor Signaling Orthosteric Site Allosteric Site Insulin Receptor Insulin Cell Interior Y X358 Desired mechanism of action of XOMA 358 is to create i nsulin resistance in hyperinsulinemic patients Reduced Signaling Mechanism of Action • IgG 2 monoclonal antibody that is a Negative Allosteric Modulator (NAM) of the Insulin Receptor (INSR) • Inhibits INSR auto - phosphorylation and signaling via Akt • Binds to both forms of INSR (A and B). • Selective to insulin receptor

4 and does not bind to the homologous I
and does not bind to the homologous IGF - 1 receptor. Congenital Hyperinsulinism (CHI) Mutations regulating insulin secretion in �1:50,000 births Neonatal and infant severe hypoglycemia which can result in neurocognitive damage. Approx. half are focal and can be PET - localized and surgically corrected, but only at a few centers in the world. The remainder are diffuse and are pharmacologically treated. Some mutations are not responsive and patients are not adequately controlled. Many chil

5 dren have near - total pancreatectomy t
dren have near - total pancreatectomy to limit the hypoglycemia. Many become diabetic. Between - meal and overnight glycemic control are major challenges. Post - Bariatric Surgery (PBS, PGBH) Chronic PBS hypoglycemia is particularly prominent after the most effective Roux - en - Y surgical procedure. 1/3 of ~200,000 bariatric surgeries (U.S.) are RnY and ~10% of those subjects have HH complications 4 . 80 - 90% are mid - aged females. Post - meal insulin secretions are multi - fold elevated beyond n

6 ormal and lead to hypoglycemic crashes
ormal and lead to hypoglycemic crashes ~2 hr later. Quality of life is severly impacted. There are no approved or generally - recognized beneficial pharmacotherapies 4 We are Developing X358 for Hyperinsulinemic Hypoglycemic Conditions with Severe Medical C onsequences and Serious Unmet Needs Phase 2 X358 Data from 27 Hyperinsulinemic Hypoglycemic Patients Total Patients n = 27 CHI n = 14 PBS n = 13 X358605 n = 4 3 + 6 mg/kg n = 4 X358602 n = 10 1 mg/kg n = 2 3 mg/kg n = 3 6 mg/kg n = 4 9 m

7 g/kg n = 1 3 mg/kg n = 4 6 mg/kg n =
g/kg n = 1 3 mg/kg n = 4 6 mg/kg n = 3 9 mg/kg n = 6 X358603 n = 13 U.S. & U.K. U.S. Germany 4 Study Design for Single IV XOMA 358 Administration to PGBH Patients 6 Day 1 Day - 1 Day 2 Day 3 Day 4 Day 5 Day 7 Day 8 Day 9 Day 10 Day 11 Day 22 Day 43 Baseline Treatment = Study Day w/o Meal Test Key = Meal Test = Dosing (Meal Test) Day - 4 Day - 5 Day - 3 Day - 2 Day - 6 Day 6 Day 12 Required confinement at r esearch facility Required stay either at research f acility or local hotel Subject may go ho

8 me o r stay at a hotel Out - patient Fol
me o r stay at a hotel Out - patient Follow - up = CGM Period = Optional Meal Test * In general, the challenge days were meal tests on Days - 3 and - 1 and Days 3, 5, 11 * CGM was implemented from Baseline through the Post - dose interval The meal test was oral Boost R administration with conventional 240 min total duration monitoring Glucose measurements included bedside glucometer, clin . lab. serum glucose, and interstitial glucose by CGM 7  12 Females + 1 Male  Aged 42 - 68  Body

9 weight 62 - 112 kg  Washed out of pr
weight 62 - 112 kg  Washed out of pre - existing drugs (e.g. diazoxide, octreotide, acarbose) and studied in - unit for 4 baseline days and 12 days post - 358 data presented is preliminary, pre - CSR Enrolled Patients were Representative of Typical PGBH Patients 8 X358 Significantly Improves Glucose Control in PGBH Patient Meal - Challenge Tests Mean + SEM Duration of Meal Tolerance and Magnitude of Improvement Increase with Increasing Dose 9 A closer look at the MTT results in the 9 mg/kg cohort

10 Subject # Time (min) to Hypoglycemia
Subject # Time (min) to Hypoglycemia at Baseline ( Avg Days - 3, - 1) Time (min) to Hypoglycemia at Day 5 Comment 1002 135 210 240 min at Day 11 4002 105 225 4003 111 220 3005 120 180 4004 122 240 1003 150 240 remained �100 mg/ dL 240 min = end of meal test 10 Nighttime Hypoglycemia is Evident in PGBH and is Meaningfully Improved in the Majority Following 358 9 mg/kg Cohort, 4 baseline days vs 4 post - 358 Days 3 - 6 Avg Glucose (mg/dL) Patient # Baseline Post - X358 1002 87 82 1003 68 79 3005

11 71 81 4002 64 76 4003 61 73 4004 68 93
71 81 4002 64 76 4003 61 73 4004 68 93 Also, the duration of hypoglycemia at nighttime was reduced ~50% in all these patients Biomarker Changes Confirm Reduced Insulin Action in Liver (Ketones) and in Fat (FFA) following XOMA 358 Treatment of PGBH Patients 11 • p0.05 Group PBS (n=13) (mean + SEM) Ketone FFA Baseline 0.23 + 0.05 mM 0.54 + 0.04 mEq /L Days 2 - 5 213 + 29* % increase 18 + 6 % increase 12 • Administration of 358 resulted in clinically meaningful improvement in glucose levels: - r

12 educed daily periods of hypoglycemia - i
educed daily periods of hypoglycemia - improved time to hypoglycemia in meal tests - correction of nighttime hypoglycemia • P ost - 358 improvement in a majority of patients at 3 - 9 mg/kg • Appears safe & well - tolerated. No clear anti - drug Ab formation. • The duration of action ranged 1 - 2 weeks • Additional serum markers in affirm attenuated insulin action following 358 treatment Now proceeding in multi - week, repeat - dosing designs Summary of Single - administration X358 Testing in