Sagar Nigwekar1, James Lingeman2, Linda Easter3, Danica Grujic4, Zhiqun Zhang4, Annamaria Kausz4

1 Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA; 2 Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA; 3 Wake Forest University School of Medicine, Clinical Research Unit, Winston-Salem, NC, USA; 4 Allena Pharmaceuticals, Inc., Newton, MA, USA

Unmet Need in Enteric Hyperoxaluria: Clinical Characteristics and Stone Burden in Patients from ALLN-177 Studies

References: 1) Asplin JR. The management of patients with enteric hyperoxaluria. Urolithiasis. 2016;44(1):33-43. 2) Nazzal L, Puri S, Goldfarb DS. Enteric hyperoxaluria: an important cause of end-stage kidney disease. Nephrol Dial Transplant. 2016;31(3):375-382. Acknowledgements: This research was sponsored by Allena Pharmaceuticals, and was made possible by the valuable contributions of participating investigators and patients.

Poster 3018644 • Presented at the American Society of Nephrology Kidney Week 2018 • October 23-28, 2018 • San Diego, CA, USA

Table 4: 24-hour Urinary Stone Risk Parameters

Variable All EH (N = 33)

pH, mean (SD) 5.8 (0.5)

Total Volume (L/day) 1.9 (0.9)

Oxalate (mg/24h)a 102.0 (54.9)

Calcium (mg/24h)a 126.9 (120.2)

Citrate (mg/24h)a 495.7 (478.7)

Relative saturation ratio (RSR), mean (SD) [713 study only]n = 18

11.4 (6.8)a Test Low/High Unit: Calcium 25/300 mg/24h, Citrate 250/1500 mg/24h, Oxalate 10/45 mg/24h (UT Southwestern Medical Center, Dallas)

• Hyperoxaluria (HOx) is a serious metabolic disorder and one of the major risk factors for progression of kidney stone (KS) disease and can also lead to chronic kidney disease (CKD) and end-stage kidney disease (ESKD).

• Enteric HOx (EH) refers to excessive UOx excretion secondary to increased intestinal absorption of oxalate.1 Enteric HOx is most commonly seen as a complication of:

– bariatric surgical procedures such as Roux-en-Y gastric bypass (RYGB), jejunoileal bypass, and biliopancreatic diversion

– short bowel syndrome (intestinal resection for bowel disease or other reason) – inflammatory bowel disease such as Crohn’s disease – other conditions associated with gastrointestinal malabsorption including cystic fibrosis, pancreatic insufficiency, and celiac disease

• Although HOx is recognized as a major risk for KS, the KS burden and urinary profiles in patients with EH have not been sufficiently described.

• There are no approved pharmacological therapies for HOx. Current management consists of recommendations to restrict dietary oxalate and increase calcium and fluid intake, but these may be difficult to sustain or be of limited efficacy, especially in patients with enteric disorders associated with HOx. Allena Pharmaceuticals, Inc. is developing reloxaliase, an orally administered crystalline form of recombinant oxalate decarboxylase, for the reduction of urinary oxalate excretion in patients with EH.

• Three Phase 2 clinical trials (Table 1) have been conducted in the United States to evaluate the efficacy and safety of reloxaliase, also referred to as ALLN-177, in patients with secondary hyperoxaluria (enteric and idiopathic).

• Herein, we characterize the KS burden and clinical profiles of EH patients who participated in the reloxaliase Phase 2 program.

Table 1: Completed Reloxaliase Phase 2 Trials in Secondary HOx

Study Design/Population N = Total Subjects EH = with EH

396a NCT02289755

Phase 2, open-label, single-arm• Mean 24h UOx ≥ 36mg/24h• eGFR > 60 mL/min/1.73 m2 (MDRD)

N = 16 EH = 5

649 NCT02503345

Phase 2, randomized, double-blind, placebo-controlled, crossover• Mean 24h UOx ≥ 50 mg/24h• eGFR > 55 mL/min/1.73 m2 (MDRD)

N = 30 EH = 10

713b NCT02547805

Phase 2, randomized, double-blind, placebo-controlled• Mean 24h UOx ≥ 50 mg/24h• eGFR > 45 mL/min/1.73 m2 (MDRD)

N = 67 EH = 18

a Number of KS prior to enrollment was not available for study 396 b KS history was not required for enrollment in study 713

Background and Objectives

Methods

Results

ConclusionsCase Reports

• Retrospective review revealed 33 patients with EH who participated in the three Phase 2 studies of reloxaliase.

• Demography, medical history, concomitant medications, 24-hr urine parameters, kidney stone history, and dietary recall intake parameters were summarized for 33 EH participants. Dietary intake was assessed by unannounced, telephone dietary recall interviews conducted by a dietitian.

• Kidney stone burden was assessed by computed tomography (CT) scans in two of the studies: in Study 649, kidney scans captured for clinical reasons in the prior 12 months were requested to be submitted; in Study 713, kidney scans captured for clinical reasons in the prior 6 months were requested to be submitted, if available, or if not available low-dose radiation CT scans were performed per protocol. All CT images were sent to the central imaging core lab for interpretation. A diameter of 2 mm defined the minimum size for measurement of kidney stones by CT. Kidney stones ≥ 2 mm were used to estimate kidney stone burden.

Table 4: Key Urinary Risk Parameters in the EH Study Population

• Despite following standard of care hydration guidance, laboratory values illustrate that these patients still have a high 24h UOx

• Other urine parameters were within the normal range

• In a subset analysis (data not shown), Roux-en-Y patients demonstrated the highest mean UOx levels (122.2 mg/24h), and interestingly, patients with restrictive procedures also had significantly elevated mean UOx levels (67.8 mg/24h)

• Hyperoxaluria has been identified as one of the major risk factors for recurrent KS, and may also lead to progressive CKD.2

• CT images were obtained in two of the reloxaliase (ALLN-177) Phase 2 studies to delineate the burden of underlying KS disease for patients with secondary HOx, as well as to pilot the use of imaging for future Phase 3 studies.

• This analysis of the EH subset of patients with secondary HOx highlights a significant unmet need in the EH population.

• Despite being under standard of care for dietary and therapeutic KS management of hyperoxaluria including urine volume of nearly 2 L/day, most patients with EH had persistently high UOx and a substantial existing KS burden on CT.

• Many patients (80%) had at least one stone on CT, including some (20%) with larger KS that could require urological intervention.

• The current reloxaliase development program is focused on reducing urinary oxalate excretion in patients with EH, as this subset of patients with HOx is at particularly high risk given their underlying malabsorptive conditions.

Table 2: Demographics and Baseline Characteristics of EH Patients in Three Phase 2 Studies

Variable All EH (N = 33) EH with CT (N = 20)

Age (years), mean (SD) 63.5 (9.4) 65.3 (9.1)

Female, N (%) 19 (57.6) 11 (55)

White, N (%) 32 (97) 20 (100)

BMI (kg/m2), mean (SD) 34.5 (8.73) 34.8 (7.56)

eGFR or eCrCl, N (%) < 60 mL/min/1.73 m2 ≥ 60 mL/min/1.73 m2

9

24

(27.3) (72.7)

7

13

(35) (65)

Underlying Enteric disorder Bariatric Surgery, N (%) RYGB, N (%) Restrictive Surgerya, N (%) Crohn’s disease, N (%) Othersb, N (%)

24 18

6 5 4

(72.7) (54.5) (18.2) (15.2) (12.1)

15 13

2 1 4

(75) (65) (10) (5) (20)

Dietary intake from recall Water (L/day), mean (SD) Oxalate (mg/day), mean (SD) Calcium (mg/day), mean (SD)

3.5

192.1 979.1

(1.6) (142.7) (555.9)

3.6

179.7 945.9

(1.6) (107.5) (579.3)

Number of kidney stones prior to enrollment, mean (SD) 6 (6.6) 5.3 (4.9)

Number of patients taking any medication or supplement for stone managementc, N (%)

19 (57.6) 11 (55)

a Restrictive surgery includes adjustable band gastric bypass and sleeve gastrectomyb Others includes pancreatic insufficiency, celiac disease, and irritable bowel syndrome (IBS) with diverticulosisc Any medication or supplement for stone management including calcium or magnesium supplement, thiazide, citrate, pyridoxine, bicarbonate, allopurinol and bile acid binder

Table 2: Key Demographic and Baseline Characteristics in the EH Study Population

• There were no substantive differences in the baseline characteristics of all 33 EH subjects and the 20 EH subjects who had CT available

• The majority of patients were white, and there was an even gender distribution

• Overall, the population was obese, with mean BMI 34.5 kg/m2

• A subgroup of 9 (27.3%) patients had moderate CKD (Stage 3)

• Most patients had EH associated with bariatric surgery (N = 24, 72.7%) and Crohn’s disease (N = 5, 15.2%)

• According to dietary recall, mean dietary oxalate intake was 192 mg/day and water intake was 3.5 L/day

Table 3: Kidney Stone Burden on CT in EH Patients

Variable EH with CT (N = 20)

Patients with at least one stone, N (%) 16 (80)

Patients with multiple stones in one kidney, N (%) 9 (45)

Patients with stones in both kidneys, N (%) 8 (40)

Total number of stones, mean (SD) 2.9 (3.7)

Maximum stone diameter (mm), mean (SD) 8.6 (5.4)

Table 3: Key Kidney Stone Findings on CT

• Most patients had at least one stone detected at enrollment by CT

• Patients had a stone in both kidneys and/or had multiple stones in a single kidney, both of which are risk factors for kidney damage

• Many patients had large KS indicating a potential need for urological intervention

Case 1Demographic: 82-year-old white female

Medical History: Pancreatic insufficiency (Whipple’s procedure), chronic diarrhea

Relevant Concomitant Therapies for Stone Management:

Pancrelipase, Colestipol, calcium carbonate, supplementation with cranberry extract

Stone History: 14 stones prior to enrollment

Average Dietary Intake:

Ox 54.71 mg/day, water 2.5 L/day

24h Urine: TV 1.9 L/day; UOx 115.2 mg/24h; Ucitrate 397.5 mg/24h; UCa 63 mg/24h; RSR 9.1

CT image: 16 stones total

Right Kidney: 15 stones, with largest diameter at 7.94 mm

Left Kidney: 1 stone, with largest diameter at 8.75 mm

Case 2Demographic: 73-year-old white male

Medical History: Roux-en-Y bypass jejunal surgery, gout

Relevant Concomitant Therapies for Stone Management:

Allopurinol

Stone History: 3 stones prior to enrollment

Average Dietary Intake:

Ox 86.06 mg/day, water 1.9 L/day

24h Urine: TV 1.4 L/day; UOx 107.5 mg/24h; Ucitrate 369 mg/24h; UCa 82.5 mg/24h; RSR 10.4

CT image: 5 stones total

Right Kidney: 2 stones, with largest diameter not recorded

Left Kidney: 3 stones, with largest diameter at 3.89 mm

Case 3Demographic: 80-year-old white male

Medical History: Celiac disease

Relevant Concomitant Therapies for Stone Management:

None

Stone History: 3 stones prior to enrollment

Average Dietary Intake:

Ox 343.83 mg/day, water 2.6 L/day

24h Urine: TV 1.1 L/day, UOx 68.2 mg/24h; Ucitrate 475.5 mg/24h; UCa 30 mg/24h; RSR 3.9

CT image: 4 stones total

Right Kidney: None

Left Kidney: 4 stones, with largest diameter at 9.83 mm