upcoming drugs in IBD 2019

1. RECENT ADVANCES:
PHARMACOTHERAPY OF
INFLAMMATORY
BOWEL DISEASE
SHREYA GUPTA

2. INTRODUCTION
• Inflammatory bowel disease includes Crohn’s disease and
Ulcerative colitis
• Environmental, genetic and microbial factors interact with
the immune system, resulting in dysregulated immune
responses responsible for chronic intestinal inflammation
• In the past decade, inflammatory bowel disease has
emerged as a public health challenge worldwide
• In 2015, estimated 1.3% of US adults (3 million) reported
being diagnosed with IBD (either Crohn’s disease or
ulcerative colitis)
https://www.cdc.gov/ibd/data-statistics.htm

3. INFLAMMATORY BOWEL DISEASE
CROHN'S DISEASE ULCERATIVE COLITIS
Location Any portion of GIT, usually
terminal ileum and colon
Colitis = Colon inflammation
Involvement Skip lesions, rectal sparing Continuous involvement,
rectum always involved
Gross
morphology
Transmural inflammation Mucosa and submucosal
inflammation only
Microscopic
morphology
Noncaseating granulomas
seen, lymphoid aggregates,
Th1 mediated
Crypt abscesses, ulcers,
bleeding. No granulomas,
Th2 mediated
Manifestation
s
Diarrhea, may or may not be
bloody
Bloody diarrhea
Complication
s
Fistulas, abscess, strictures
causing obstruction, perianal
disease
Fulminant colitis, toxic
megacolon, perforation

5. SYMPTOMS OF IBD
• Abdominal pain
• Mouth/stomach ulcers
• Diarrhea
• Rectal bleeding /bloody stools
• Loss of appetite, weight loss
• Fever, fatigue
• Change/loss of menstrual cycle

6. PATHOGENESIS OF IBD

8. PATHOGENESIS OF IBD

9. Alteration of gut microbiota and
impairment of intestinal epithelial barrier
function, in genetically predisposed hosts,
influenced by environmental factorsConsequent exposure of intestinal
mucosal immune system to altered
microbial antigens triggers a dysregulated
immune response that results in
inflammation of the intestinal wall
Microbial antigens activate APCs which
migrate to secondary lymphoid tissues, in
particular to mesenteric lymph nodes
They present antigens to resident naive T
lymphocytes, inducing their differentiation
into Th cells, proliferate and secrete ILs and
other cytokines responsible for intestinal
inflammation.

10. CURRENT TREATMENT OF IBD

11. GROUP DRUG SIDE EFFECTS
Amino
Salicylates
Sulfasalazine
Olsalazine
Balsalazide
Mesalamine
• Hypersensitivity reactions
• Agranulocytosis
• Hypersensitivity pneumonitis
• Pancreatitis
• Folic acid deficiency
Gluco-
Corticoids
Prednisone 40–60 mg/d
Budesonide 9 mg/d
Hydrocortisone enemas
• Fluid retention, Abdominal striae
• Fat redistribution, hyperglycemia
• Osteonecrosis, osteoporosis
• Myopathy
• Emotional disturbances
• Withdrawal symptoms
Antibiotics Metronidazole
Ciprofloxacin
• Nausea, Metallic taste
• Disulfiram-like reaction
• Peripheral neuropathy
• Achilles tendinitis and rupture
Anti-folate Methotrexate im/sc 25
mg/week
• Mucositis
• Leukopenia
• Peripheral neuropathy
• Hypersenstivity pneumonitis

12. GROUP DRUG SIDE EFFECTS
Thiopurines Azathioprine
6-MP
• Nausea, fever, rash
• Hepatitis
• Bone marrow suppression
• Risk of lymphomas
Calcineurin
inhibitors
Cyclosporine
Tacrolimus
• Nephrotoxic
• Hypertension
• Gingival hyperplasia
• Hypertrichosis,
• Paresthesias, tremors
• Electrolyte abnormalities
Biologics Anti TNF alpha
Adalimumab
Infliximab
Certolizumab
Golimumab
• Infusion reactions
• Antibodies formation
• NHL
• Reactivation of latent TB
• Opportunistic fungal infections
Anti Integrins
Natalizumab
Vedolizumab
• Progressive multifocal
leukoencephalopathy (PML)

14. IMMUNOMODULATION IN IBD

15. NEED FOR NEW DRUGS
• Management of patients with IBD remains a great challenge
for health professionals
• Currently available drugs show limited efficacy
• No identified predictors of drug response
• Long-term use of immunomodulatory drugs has several
safety concerns for potential risk of infections and
malignancies

16. RECENT ADVANCES
1. JANUS KINASE INHIBITORS
2. SPHINGOSINE-1-PHOSPHATE RECEPTOR MODULATORS
3. PDE 4 INHIBITORS
4. ORAL INTEGRIN ANTAGONISTS
5. BIOLOGICS

17. UPCOMING THERAPIES
• Conventional = “small
molecules”
Synthesized by organic
chemistry
Potentially cheaper
Usually can be oral (pills)
Usually short half life (take
daily)
• Biologics = Biologicals =
Biopharmaceuticals
Very expensive
Cannot be oral: must be IV
or SC
Long half life (weeks to
months)

18. JANUS KINASE INHIBITORS

19. JANUS KINASE INHIBITORS
• JAK proteins (JAK1, JAK2, JAK3, and tyrosine kinase 2 [Tyk2])
are implicated in inflammatory pathways through
associations with intracellular domains of surface cytokine
receptors
• Inflammatory cytokines such as IFN-γ, IL-2, IL-4, IL-7, IL-9,
IL-15, IL-12, IL-21, IL-22, and IL-23 depend on this pathway,
inhibiting JAK might result in their downregulation
• JAK1 and JAK3 are implicated in pathogenesis of IBD

20. TOFACITINIB
• Pan-JAK inhibitor that primarily targets JAK1 and JAK3
• Current status: Approved (2018) by USFDA as First oral
therapy for UC
• Trials: OCTAVE 1
OCTAVE 2
OCTAVE SUSTAIN
• 10mg twice daily → 5mg twice daily (typically after 8 weeks)
• Symptom improvement can be seen in as little as 3 days

22. TOFACITINIB
• In contrast to the observed efficacy of tofacitinib in UC,
results in CD have been less favourable and inconsistent
• 2 placebo-controlled, multicentric phase II randomized 280
patients to 5 mg, 10 mg, tofacitinib BID or placebo
• At week 8, no significant difference in clinical remission
rates among patients assigned to 5 mg tofacitinib (43.5%),
10 mg tofacitinib (43.0%), or placebo (36.7%)
• No further trials planned as of now

23. TOFACITINIB
• Most common side effects:
1. Nasopharyngitis
2. Arthralgias, headache
3. Herpes zoster (shingles) risk 5% with 10mg twice daily
dosing
4. Risk of non-melanoma skin cancer
5. LDL and HDL increase within first 1-2 months
6. Elevated liver enzymes
• Should not be combined with azathioprine, Methotrexate,
biologics

24. TOFACITINIB
WARNING: SERIOUS INFECTIONS AND MALIGNANCY
• Patients are at increased risk for developing serious infections
leading to hospitalization or death.
• Patients at risk include those taking concomitant
immunosuppressants such as methotrexate or corticosteroids.
• Reported infections include: • Active tuberculosis. • Invasive fungal
infections, including cryptococcosis and pneumocystosis. •
Bacterial, viral, including herpes zoster, and other opportunistic
infections.
• MALIGNANCIES Lymphoma and Epstein Barr Virus-associated
lymphoproliferative disorder has been observed

25. UPADACITINIB
• JAK1-selective inhibitor
• CURRENT STATUS FOR UC: PHASE III, Study of the Efficacy
and Safety of Upadacitinib (ABT-494) in Participants With
Moderately to Severely Active Ulcerative Colitis (U-
Accomplish)
• Results expected in 2021
• Approved in 2019 by USFDA for treatment of adult patients
with moderate to severe rheumatoid arthritis.

26. UPADACITINIB
• CURRENT STATUS FOR CROHN'S : PHASE III, Study of
the Efficacy and Safety of Upadacitnib (ABT-494) in Subjects
With Moderately to Severely Active Crohn's Disease Who
Have Inadequately Responded to or Are Intolerant to
Conventional and/or Biologic Therapies
• Phase II showed clinical and endoscopic benefit seen early
on and continue to progress with time
• Serious side effects may be greater with higher doses

27. PEFICITINIB
• Oral pan-JAK inhibitor with increased selectivity for JAK3
• Phase II dose-ranging trial, patients of UC were randomized
to receive placebo or peficitinib at doses of 25 mg, 75 mg,
or 150 mg daily or 75 mg BID.
• Results showed no significant dose-response relationship
• No further studies are underway

28. FILGOTINIB
• JAK1-selective inhibitor for moderate-to-severe UC and
Crohn’s disease
• Once daily medication
• CURRENT STATUS FOR UC: PHASE III trial evaluating the
Efficacy and Safety of Filgotinib in the Induction and
Maintenance of Remission in Subjects With Moderately to
Severely Active Ulcerative Colitis
• CURRENT STATUS FOR CD: PHASE III trial for the
treatment of moderate-to-severe CD (Diversity1) and
PHASE II trial in fistulizing CD (Divergence2)
• Phase 2 study in CD showed clinical benefit but not
endoscopic

29. SPHINGOSINE-1-PHOSPHATE
RECEPTOR MODULATORS

30. SPHINGOSINE-1-PHOSPHATE RECEPTOR
MODULATORS
• Widely expressed on lymphatic endothelial cells across
many organs and tissues
• S1P receptors involved fundamental inflammatory
processes, including immune cell trafficking and
modulation of vascular barrier function
• 5 S1P receptor subtypes (S1P1–S1P5)
• S1P1, S1P2, and S1P3 are ubiquitously present

31. SPHINGOSINE-1-PHOSPHATE RECEPTOR
MODULATORS
• S1P4 predominantly found in lymphoid, hematopoietic, and
lung tissue,
• S1P5 primarily restricted to CNS, skin, and spleen
• S1P receptor agonists induce S1P receptor internalization
and degradation, thereby preventing lymphocyte egress
from the lymph nodes to the bloodstream
• FINGOLIMOD was first S1P modulator developed for MS,
but showed multiple ADRs: bradycardia, AV blocks,
disseminated VZ and HSV infections, elevated liver
enzymes, ILD

32. OZANIMOD (RPC1063)
• Modulator of S1P1 and S1P5 receptors
• Designed to reduce trafficking of activated lymphocytes to
the GIT with an improved safety profile relative to
fingolimod
• Approved in 2019 for MS
• CURRENT STATUS FOR UC: PHASE III, To Evaluate
Efficacy and Long-term Safety of Ozanimod in Japanese
Subjects With Moderately to Severely Active Ulcerative
Colitis (1 mg dose for up to five years)

33. OZANIMOD
• CURRENT STATUS for CD: PHASE III, Ozanimod in
patients with moderately to- severely active CD is currently
enrolling
• Consists of two 12-week studies in which patients are
randomized to either ozanimod 0.92 mg, for 48 weeks or
placebo

34. ETRASIMOD (APD334)
• Modulator of S1P1, S1P4, and S1P5 receptors
• CURRENT STATUS for UC: PHASE III, ELEVATE UC 52
trial, Etrasimod Versus Placebo for the Treatment of
Moderately to Severely Active Ulcerative Colitis (2 mg
tablet, OD for 52 weeks)
• Also being evaluated for MS

35. TYPE-4 CYCLIC NUCLEOTIDE
PHOSPHODIESTERASE
INHIBITORS

36. PDE4 INHIBITORS
• Cyclic nucleotide phosphodiesterases (PDE) are group of
enzymes that catalyse intracellular breakdown of cAMP and
cGMP
• PDE4 family is predominantly expressed in macrophages
and T cells
• Inhibition of PDE4 has been demonstrated to reduce
nuclear factor κB-mediated gene transcription with
downstream reduction in TNF-α, inhibit nitric oxide
production, attenuate IL-17 produced by Th17 T
lymphocytes, and augment anti-inflammatory IL-10 and IL-
6 expression

37. APREMILAST (CC-10004)
• Oral PDE4-specific inhibitor
• Indicated for treatment of moderate-to-severe plaque
psoriasis and psoriatic arthritis
• CURRENT STATUS: Completed Phase II, Randomized,
Placebo-controlled, Multicenter Study to Investigate the
Efficacy and Safety of Apremilast (CC-10004) for Treatment
of Subjects With Active Ulcerative Colitis
• Patients were randomized 1:1:1 to treatment with placebo,
apremilast 30 mg BID or 40 mg BID

38. APREMILAST (CC-10004)
• Linear dose-response relationship not observed and no
significant differences in clinical remission, endoscopic
remission, histologic remission, or mucosal healing rates
when patients treated with apremilast were compared to
those who received placebo
• Phase III trial for apremilast in UC not currently registered

39. ORAL INTEGRIN ANTAGONISTS

40. ORAL INTEGRIN ANTAGONISTS
• Lymphocyte infiltration into intestinal lamina propria is
mediated by binding to mucosal addressin cell adhesion
molecule-1 (MADCAM1) on endothelial surface and
dependent on the expression of lymphocyte α4β1 or α4β7
integrins
• Gut selective blockade of lymphocyte trafficking with
vedolizumab, a monoclonal antibody antagonizing α4β7,
has been demonstrated to be an effective therapeutic
approach in both UC and CD

41. AJM300
• Novel oral small-molecule phenylalanine derivative that
targets α4 integrin
• In in vitro IL-10 deficient CD4+ T-cell mouse model, it
inhibited lymphocyte homing to intestinal Peyer’s patches
and prevented development of experimental colitis
• CURRENT STATUS: PHASE III Study to Evaluate the Safety
and Efficacy of AJM300 in Participants With Active
Ulcerative Colitis

42. AJM300
• Primary concern with its mechanism of action is risk of John
Cunningham virus-mediated progressive multifocal
leukoencephalopathy (PML), as α4-integrin antagonism is
not gut-specific
• Additional data regarding the safety of AJM300 is needed

43. BIOLOGICS

44. ETROLIZUMAB
• Anti-adhesion Humanized antibody against α4β7 and αEβ7
• MECHANISM: “Gut specific”
1. Inhibit leucocyte trafficking to the gut (by blocking of
α4β7- MAdCAM-1 interactions)
2. Inhibit retention of leucocytes in the intraepithelial lining
of the gut (by blocking αEβ7- E-cadherin interactions)

46. ETROLIZUMAB
• Subcutaneous injection
• CURRENT STATUS FOR UC: PHASE III, Randomized,
Double-Blind, Placebo-Controlled, Multicenter Study to
Evaluate the Efficacy (Maintenance of Remission) and Safety
of Etrolizumab Compared With Placebo in Patients With
Moderate to Severe Active Ulcerative Colitis Who Are Naive
to TNF Inhibitors
• CURRENT STATUS FOR CD: Phase III, Randomized, Double-
Blind, Placebo-Controlled, Multicenter Study to Evaluate the
Efficacy and Safety of Etrolizumab as an Induction And
Maintenance Treatment For Patients With Moderately to
Severely Active Crohn's Disease

47. RISANKIZUMAB
• Anti-cytokine antibody, targets cell signalling molecule IL-
23
• Subcutaneous injection
• Promising short- and long-term outcomes
• No increased adverse side effects compared to placebo
• CURRENT STATUS FOR UC: PHASE III, Multicenter,
Randomized, Double-Blind, Placebo Controlled 52-Week
Maintenance and an Open-Label Extension Study of the
Efficacy and Safety of Risankizumab in Subjects With
Ulcerative Colitis

48. RISANKIZUMAB
• CURRENT STATUS FOR CD: PHASE III Multicenter,
Randomized, Double-Blind, Placebo Controlled Induction
Study of the Efficacy and Safety of Risankizumab in Subjects
With Moderately to Severely Active Crohn's Disease

49. MIRIKIZUMAB
• Targets IL-23 (p19 subunit)
• Subcutaneous injection
• Most effective dose and frequency of maintenance doses not
yet certain
• Similar rates of response for CD and UC
• CURRENT STATUS FOR UC: PHASE III, Study to Evaluate the
Long-Term Efficacy and Safety of Mirikizumab in Participants
With Moderately to Severely Active Ulcerative Colitis (LUCENT
3)

50. MIRIKIZUMAB
• CURRENT STATUS FOR CD: PHASE III, Multicenter,
Randomized, Double-Blind, Placebo- and Active-
Controlled, Treat-Through Study to Evaluate the Efficacy
and Safety of Mirikizumab in Patients With Moderately to
Severely Active Crohn's Disease

51. PF-04236921
• IL-6 is pro-inflammatory cytokine involved in IBD
pathophysiology
• PF-04236921 is fully human IgG2 anti-IL-6 monoclonal
antibody
• Use in clinical development for anti TNF-α refractory
moderate-to-severe CD patients (50mg, 200mg)
• CURRENT STATUS: PHASE II COMPLETED Randomised
trial and open-label study of an anti-interleukin-6 antibody
in Crohn's disease (ANDANTE I and II)

52. PF-04236921
• Clinical remission rate at week 12 was significantly greater
in 50-mg group compared to placebo (27.4% vs. 10.9%,
respectively, p < 0.05
• 200-mg arm was interrupted early due to safety concerns
• Side effects: Gastrointestinal perforation and abscess

53. CHALLENGES & FUTURE
CONSIDERATIONS
• Greatest challenge is personalizing medication
• Finding the right medication for the right patient
• Multimodal treatment algorithms needed, including
combination of medical therapies, as well as surgical
intervention
• Need cheap and quick diagnostic tools to identify
inflammatory pathway in patients
• Better understanding of development of IBD including,
Microbiome’s role, Host factors (genetics, diet) and
Environmental factors

54. SUMMARY
CROHN'S DISEASE
DRUG CLASS STATUS
Tofacitinib (JAK
1/3)
JAK kinase inhibitor APPROVED
Upadacitinib
(JAK 1)
JAK kinase inhibitor PHASE 3
Filgotinib (JAK 1) JAK kinase inhibitor PHASE 3
Ozanimod S1P receptor
modulator
PHASE 3

55. ULCERATIVE COLITIS
DRUG CLASS STATUS
Tofacitinib (JAK 1/3) JAK kinase inhibitor APPROVED
Upadacitinib (JAK 1) JAK kinase inhibitor PHASE 3
Peficitinib (pan JAK) JAK kinase inhibitor PHASE 2
Ozanimod S1P receptor
modulator
PHASE 3
Etrasimod S1P receptor
modulator
PHASE 3
Apremilast PDE4 Inhibitor PHASE 2
AJM300 Oral α4 integrin
antagonist
PHASE 3

56. SUMMARY
BIOLOGICALS IN IBD
DRUG CLASS STATUS
Etrolizumab Anti-adhesion
antibody
PHASE 3
Risankizumab Anti-cytokine
antibody
PHASE 3
Mirikizumab Anti-cytokine
antibody
PHASE 3
Pf-04236921 Anti IL6 antibody PHASE 2

57. THANK YOU

58. REFERENCES
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17:1-5.
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Hisamatsu T, Hibi T, Rogler G. Mechanism-Based Treatment Strategies for
IBD: Cytokines, Cell Adhesion Molecules, JAK Inhibitors, Gut Flora, and More.
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