New and Emerging Therapies for Gluten-Related Conditions

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1 New and Emerging Therapies for Gluten-Related Conditions Jocelyn Silvester, MD PhD FRCPC June 11, 2017

2 Disclosures Funding CIHR, NIH, Canadian Celiac Association Collaboration Biomedal SG Glutenostics

3 Overview Is a gluten-free diet enough? How do ideas become treatments? What s in the celiac disease pipeline? Where next?

4 A brief history of celiac disease therapies 100 AD Italy 250 AD Aretaeus koiliakos 1856 Adams 1888 Gee 1924 Haas 1940s Dicke 2017

5 Is a gluten-free diet enough?

6 Is a gluten-free diet enough? I really hope coconuts are gluten free! 6

7 How burdensome is a GFD? Very difficult Visual analogue scale Very easy Perceived Treatment Burden CD HTN GERD ESRD DM CHF IBD IBS Celiac High BP GERD Kidney Diabetes CHF IBD IBS Shaw et al (2014). Patient perception of treatment burden in celiac disease is high compared to other conditions. American Journal of Gastroenterology

8 How burdensome is a GFD? Very difficult Visual analogue scale Very easy Perceived Treatment Burden CD HTN ESRD DM Celiac High BP GERD Kidney Diabetes CHF IBD IBS Shaw et al (2014). Patient perception of treatment burden in celiac disease is high compared to other conditions. American Journal of Gastroenterology

Spectrum of NRCD in Children and Adults Other 8%

Veeraraghavan ACG 2015 Leffler et al, CGH 2007;

9 Spectrum of NRCD in Children and Adults Other 8% IBS 18% Gluten Exposure 35% RCD 11% SIBO 6% Eating Disorder 6% Disacchari dase Deficiency 9% Microscopic Colitis 7% Leffler et al, CGH 2007; Veeraraghavan ACG 2015 Leffler et al, CGH 2007; Veeraraghavan ACG 2015 Slide courtesy Dr D. Leffler

10 Recovery is Partial and Age Related Average Age of Celiac Diagnosis l/3 of people have a healthy intestine after 2 years 2/3 of people have a healthy intestine after 5 years Lebwohl et al. APT 2014, Rubio-Tapia AJG 2010, Leffler DA Gut 2012, Maki Gastro 2014 Slide courtesy Dr D. Leffler

11 Is a gluten-free diet enough? Frequent gluten (>1/week) Occasional gluten (1-3/month) No gluten Rare accidental gluten (<1/month) Rare intentional gluten (<1/month) Silvester et al (2016). Is it gluten-free? Relationship between self-reported gluten-free diet adherence and knowledge of gluten content of foods. Nutrition

12 How happy are you to take a glutenfree diet to treat your celiac disease? Aziz et al (2011). Are patients with celiac disease seeking alternative therapies to a glutenfree diet? Journal of Gastrointestinal and Liver Disease

13 How happy are you to take a glutenfree diet to treat your celiac disease? n = 310 Aziz et al (2011). Are patients with celiac disease seeking alternative therapies to a glutenfree diet? Journal of Gastrointestinal and Liver Disease

14 Is a gluten-free diet enough?

15 The first step

16 How do ideas become treatments?

17 How do ideas become treatments? Pre-clinical Clinical Post-marketing Phase 1 Phase 2 Phase 3 Phase 4 Toxicology Safety Efficacy Safety & Efficacy Safety Dose Toxicity Pharmacology Side effects Does it work in patients? Which patients does it work for? Surveillance Required studies q 6+ years 2 years 2 years 3 years $$$$ $50 million $60 million $70 million volunteers 100s patients 1000s patients

18 20-80 volunteers 100s patients 1000s patients IND FDA Drug Approval Process Pre-clinical Clinical Post-marketing Phase 1 Phase 2 Phase 3 Phase 4 Toxicology Safety Efficacy Safety & Efficacy Safety Dose Toxicity Pharmacology Side effects Does it work in patients? Which patients does it work for? Surveillance Required studies q 6+ years 2 years 2 years 3 years $$$$ $50 million $60 million $70 million

19 20-80 volunteers 100s patients 1000s patients IND FDA Drug Approval Process Pre-clinical Clinical Post-marketing Phase 1 Phase 2 Phase 3 Phase 4 Toxicology Safety Efficacy Safety & Efficacy Safety Dose Toxicity Pharmacology Side effects Does it work in patients? Which patients does it work for? Surveillance Required studies q 6+ years 2 years 2 years 3 years $$$$ $50 million $60 million $70 million

20 20-80 volunteers 100s patients 1000s patients IND FDA Drug Approval Process Pre-clinical Clinical Post-marketing Phase 1 Phase 2 Phase 3 Phase 4 Toxicology Safety Efficacy Safety & Efficacy Safety Dose Toxicity Pharmacology Side effects Does it work in patients? Which patients does it work for? Surveillance Required studies q 6+ years 2 years 2 years 3 years $$$$ $50 million $60 million $70 million

21 20-80 volunteers 100s patients 1000s patients IND FDA Drug Approval Process Pre-clinical Clinical Post-marketing Phase 1 Phase 2 Phase 3 Phase 4 Toxicology Safety Efficacy Safety & Efficacy Safety Dose Toxicity Pharmacology Side effects Does it work in patients? Which patients does it work for? Surveillance Required studies q 6+ years 2 years 2 years 3 years $$$$ $50 million $60 million $70 million

Phase 2 Phase 3 Phase 4 Toxicology Safety Efficacy Safety &

work in patients? Which patients does it work for?

22 20-80 volunteers 100s patients 1000s patients IND FDA Drug Approval Process Pre-clinical Clinical Post-marketing Phase 1 Phase 2 Phase 3 Phase 4 Toxicology Safety Efficacy Safety & Efficacy Safety Dose Toxicity Pharmacology Side effects Does it work in patients? Which patients does it work for? Surveillance Required studies q 6+ years 2 years 2 years 3 years $$$$ $50 million $60 million $70 million

23 Therapeutic strategies for Celiac Disease

24 Therapeutic strategies for Celiac Disease

25 Therapeutic strategies for Celiac Disease

26 Therapeutic strategies for Celiac Disease

27 Therapeutic strategies for Celiac Disease

28 Race for a therapy Compound Gluten neutralizing BL-7010 Gluten digestion ALV-003 Kumamax Barrier enhancement Larazotide acetate Immunotherapy Nexvax2 Clinical Phase 1 Phase 2 Phase 3 Pharmacology Side effects Does it work in patients? Which patients does it works for? Postmarket

29 BL-7010: A gluten blocker

30 Race for a therapy Compound Gluten neutralizing BL-7010 Gluten digestion ALV-003 Kumamax Barrier enhancement Larazotide acetate Immunotherapy Nexvax2 Clinical Phase 1 Phase 2 Phase 3 Pharmacology Side effects Does it work in patients? Which patients does it works for? Postmarket

31 ALV-003 (Alvine) Phase 1 ALV003 DEGRADES GLUTEN UP TO 96% IN HUMAN STOMACH % Epitope Remaining by ELISA 100% DESIGN Gluten: 1,000 mg Dosage: 300 mg ALV003 Gluten Bread Crumbs in Complex Meal Stomach Content Analysis: 30 min Average 92% of Disease Relevant Epitopes Eliminated 8.7% ± 0.2% 11% ± 0.2% 8.8% ± 0.1% 4.1% ± 0.1% Control Placebo NO ALV003 Subject #1 Subject #2 Subject #3 Treatment with ALV003 Subject #4 Slide courtesy Dr D Leffler

ALV-003 Phase 2a: Randomized, doubleblind, placebo controlled gluten challenge 41 celiac disease patients (20 ALV003, 21 placebo) Normal baseline biopsy on GFD Gluten challenge 6 grams gluten daily

32 ALV-003 Phase 2a: Randomized, doubleblind, placebo controlled gluten challenge 41 celiac disease patients (20 ALV003, 21 placebo) Normal baseline biopsy on GFD Gluten challenge 6 grams gluten daily (~1/2 slice of bread) Primary outcome: histology at end of gluten challenge Biopsy Biopsy Lahdeaho et al Gastroenterology (2014). Glutenase ALV-003 attenuates gluten-induced mucosal injury in patients with celiac disease.

33 Histologic outcomes in celiac disease trials Villous height (Vh) Normal Vh:Cd > 2ish Normal IELs <20/hpf Crypt depth (Cd) Normal Marsh 1 Marsh 3a Marsh 3c Adapted from Ludvigsson et al Gut (2014).

ALV-003 Phase 2a: Randomized, doubleblind, placebo controlled gluten challenge ALV-003 Placebo Normal Vh:Cd > 2ish Normal IELs <20/hpf Normal Marsh 1 Marsh 3a Marsh 3c Baseline End

34 ALV-003 Phase 2a: Randomized, doubleblind, placebo controlled gluten challenge ALV-003 Placebo Normal Vh:Cd > 2ish Normal IELs <20/hpf Normal Marsh 1 Marsh 3a Marsh 3c Baseline End of gluten Baseline End of gluten challenge challenge Lahdeaho et al Gastroenterology (2014). Glutenase ALV-003 attenuates gluteninduced mucosal injury in patients with celiac disease.

35 ALV-003 Phase 2b: Randomized, doubleblind, placebo, symptomatic on GFD 494 patients Murray et al Gastroenterology (2017). No difference between Latiglutenase and placebo in reducing villous atrophy or improving symptoms in patients with symptomatic celiac disease.

36 ALV-003 Phase 2b: Randomized, doubleblind, placebo, symptomatic on GFD Normal Vh:Cd > 2ish Normal IELs <20/hpf Normal Marsh 1 Marsh 3a Marsh 3c Increase in villous height (Vh:Cd) 100 mg 300 mg 450 mg 600 mg 900 mg Murray et al Gastroenterology (2017)..

37 ALV-003 Phase 2b: Randomized, doubleblind, placebo, symptomatic on GFD Normal Vh:Cd > 2ish Normal IELs <20/hpf Increase in villous height (Vh:Cd) Normal Marsh 1 Marsh 3a Marsh 3c mg 300 mg 450 mg 600 mg 900 mg Placebo Murray et al Gastroenterology (2017). No difference between Latiglutenase and placebo in reducing villous atrophy or improving symptoms in patients with symptomatic celiac disease.

5 0 100 mg 300 mg 450 mg 600 mg 900 mg Placebo Murray et al Gastroenterology (2017).

38 ALV-003 Phase 2b: Randomized, doubleblind, placebo, symptomatic on GFD 3 Symptom improvement (CDSD) mg 300 mg 450 mg 600 mg 900 mg Placebo Murray et al Gastroenterology (2017). No difference between Latiglutenase and placebo in reducing villous atrophy or improving symptoms in patients with symptomatic celiac disease.

39 Race for a therapy Compound Gluten neutralizing BL-7010 Gluten digestion ALV-003 Kumamax Barrier enhancement Larazotide acetate Immunotherapy Nexvax2 Clinical Phase 1 Phase 2 Phase 3 Pharmacology Side effects Does it work in patients? Which patients does it works for? Postmarket

Computational Design to Increase Activity 3.

Alicyclobacillus sendaiensis Theoretical

40 KumaMax Developed Using Computational Protein Design 1. Select Template Protease 2. Computational Design to Increase Activity 3. Test Designed Enzymes Kumamolisin from Alicyclobacillus sendaiensis Theoretical Mutation Intended to Increase Enzyme Activity Against Gliadin Substrate 4. Combine Promising Mutations Courtesy of Ingrid Swanson Pultz KumaMax Lead

41 KumaMax Efficiently Reduces Gluten In Foods and in Gastric Conditions EPB2/SCPEP KumaMax 10,000 ppm 84.8% 20 ppm >99.97% Courtesy of Ingrid Swanson Pultz

42 Race for a therapy Compound Gluten neutralizing BL-7010 Gluten digestion ALV-003 Kumamax Barrier enhancement Larazotide acetate Immunotherapy Nexvax2 Clinical Phase 1 Phase 2 Phase 3 Pharmacology Side effects Does it work in patients? Which patients does it works for? Postmarket

43 AT-1001/Larazotide Acetate: a tight junction regulator Lumen Lumen Larazotide Acetate Lamina propria TTG TTG T

44 Larazotide Phase 2a: Randomized, doubleblind, placebo controlled gluten challenge Screening (21 days) 86 Patients 494 patients Randomization Treatment (14 days) Placebo/Gluten Placebo/Placebo gluten 8 mg/placebo gluten 0.25 mg/gluten 1 mg/gluten 4 mg/gluten 8 mg/gluten Follow-up (7 days) Primary outcome Lactulose:mannitol ratio Secondary outcomes Symptoms Gluten-related adverse events Intestinal permeability Intestinal permeability Leffler et al. American Journal of Gastroenterology (2012) A Randomized, Double-Blind Study of Larazotide Acetate to Prevent the Activation of Celiac Disease during Gluten Challenge

45 Larazotide Phase 2a: Randomized, doubleblind, placebo controlled gluten challenge Total GSRS Score Change from Day 0 to Day Symptoms Score (GSRS) p = p = % Subjects with Gluten Toxicity Gluten-Related Adverse Events p = p = Disease Control Negative Control Active Treatment 0 Disease Control Negative Control Active Treatment No differences in primary endpoint of LA:MA Prevention of immunologic changes in PBMc (B cells) Daily diary: Reduction in frequency of bowel movements, abdominal discomfort & pain Safety comparable to placebo Leffler et al. American Journal of Gastroenterology (2012) A Randomized, Double-Blind Study of Larazotide Acetate to Prevent the Activation of Celiac Disease during Gluten Challenge

46 Larazotide Phase 2c: 12 week trial in patients with persistent symptoms Leffler DA et al. Gastro 2015

47 Race for a therapy Compound Gluten neutralizing BL-7010 Gluten digestion ALV-003 Kumamax Barrier enhancement Larazotide acetate Immunotherapy Nexvax2 Clinical Phase 1 Phase 2 Phase 3 Pharmacology Side effects Does it work in patients? Which patients does it works for? Postmarket

48 Nexvax (Nexpep) Peptide library: 18,117 12mers Dominant peptides 2,922 20mers 3 16AA Proteins Treatment shifts T cells from pro-inflammatory to tolerant response to gluten Induces tolerance in a celiac mouse model Phase 2a trials underway Nexvax administration symptoms mimicking oral gluten exposure

49 What else is in the pipeline?

50 What have we learned? Patients need more than a GFD Outcome measures matter Most could be more adherent to a glutenfree diet (if somebody were watching)

51 Another Approach: Gluten Detection

52 Gluten as a biomarker of gluten ingestion LQLQPFP QPQLPYP QPQLPYP QPQLPYP QPQPF Gluten In Gluten Out

53 Gluten as a biomarker of gluten ingestion LQLQPFP QPQLPYP QPQLPYP QPQLPYP QPQPF LQLQPFPQPQLP YPQPQLPYPQP QLPYPQPQPF LQLQPFP QPQLPYP QPQLPYP QPQLPYP QPQPF Gluten In Gluten Out

54 188 CeD (60 children) HLADQ2/DQ8 + villous atrophy + serology GFD > 12 months 84 controls Celiac ruled out No GI condition anti33mer sandwich ELISA Comino et al (2016) American Journal of Gastroenterology 111;

55 188 CeD (60 children) HLADQ2/DQ8 + villous atrophy + serology GFD > 12 months 84 controls Celiac ruled out No GI condition anti33mer sandwich ELISA Comino et al (2016) American Journal of Gastroenterology 111;

56 188 CeD (60 children) HLADQ2/DQ8 + villous atrophy + serology GFD > 12 months 84 controls Celiac ruled out No GI condition 29.8% gluten immunogenic peptides detected in stool anti33mer sandwich ELISA Comino et al (2016) American Journal of Gastroenterology 111;

57 GIPs in stool age of patient v v Comino et al (2016) American Journal of Gastroenterology 111;

58 GIPs in stool GFD duration GFD Duration Comino et al (2016) American Journal of Gastroenterology 111;

59 Our next project

60 DOGGIE BAG

61 Where next?

62 How do we get there?

63 How do we get there?

64 Thank you!

Novita In Tema Di Alternative Alla Dieta Aglutinata

Novita In Tema Di Alternative Alla Dieta Aglutinata Alessio Fasano, M.D. W. Allan Walker Chair in Pediatric Gastroenterology and Nutrition Professor of Pediatrics Harvard Medical School Mucosal Biology