Recent advances in management of Inflammatory bowel diseases

Subhash Nandwani

Aminosalicylates

FOR CROHN’S DISEASE

• Sulfasalazine – useful for inducing remission

• Mesalamine – role uncertain

• For maintenance – 5-ASA compounds not useful

Aminosalicylates

• FOR ULCERATIVE COLITIS

• Sulfasalazine and Mesalamines – useful in inducing remission and maintenance of it

Glucocorticoids• Effective both in CD and UC for inducing

remission

• They are not effective for maintenance of remission.

Budesonide• Preferred over prednisolone in localised mild

ileocaecal crohn’s

• Less effective than conventional steroids in severe disease

• Not effective for maintenance of remission

Thiopurines • Azathioprine and 6-mercaptopurine

FOR CROHN’S DISEASE

• 50 % patients respond and 1/2 -2/3 of them will maintain that response

FOR ULCERATIVE COLITIS

• use of azathioprine is largely based on its estabilished efficacy in CD rather any proven benefit in UC

methotrexate

FOR CROHN’S DISEASE

• MTX 25 mg/wk IM, induced remission in 40% vs 20% in placebo at 8 weeks

• MTX 15 mg/wk IM / SC for 1-4 yrs. 65% maintenaned remission vs 40% in placebo group

• Oral MTX was not found effective

• Used as alternative to thiopurines

methotrexate

FOR ULCERATIVE COLITIS

• Not effective

antibioticsFOR CROHN’S DISEASE

• Metronidazole – useful in healing perinealfistulas. Benefit not seen in active luminal crohn’s disease.

• Ciprofloxacin –showed benefit in perianalfistula and in treatment of luminal disease.

• Rifaximin 800 mg bd Vs placebo : 62% vs 43% remission at 12 wks (p=0.005)

antibiotics

FOR ULCERATIVE COLITIS

• Antibiotics not effective in UC except in suppurative complications

cyclosporineFOR CROHN’S DISEASE

• Only high doses are effective at unacceptably high cost of side effects. Other less hazardous medications are preferred.

FOR ULCERATIVE COLITIS

• Only 1 study showed response in 9 of 11 patients in 7 days with IV cyclosporine 4mg/kg/day

• 50% patients required colectomy in 6 months

cyclosporine

• Cyclosporine can be considered as bridge therapy in steroid refractory UC while waiting for elective surgery or onset of action of azathioprine

Mycophenolate mofetil

• Pharmacodynamics similar to azathioprine, but more rapid onset of action

• Efficacy inferior to azathioprine, < 50% remission rate

TacrolimusFOR CROHN’S DISEASE

• Preliminary data suggest benefit in steroid resistant disease.

• Also may be effective as topical agent for oral and perianal ulcerating disease.

FOR ULCERATIVE COLITIS

• Limited data

• Not accepted as standard therapy

Thalidomide

• Efficacy seen in small studies in CD

Biological therapy

Biological therapy for IBDBiological therapy is the use of biological agents, which are so termed because of their protein origin (e.g., antibodies and cytokines)

Anti- TNF antibodies

Infliximab

Adalimumab

Golimumab

Certolizumab pegol

Biological therapy - indications

• steroid refracory

• Steroid dependent

• Steroid intolerant

Biological therapy

• All have similar response rate of 60% and 40% of responders maintain that for 1 year

• Infliximab and cyclosporine showed similar efficacy in severe UC

• serious infections in 2-4% patients

• Pyogenic complications of crohn’s should be treated first

• Screen for TB before starting therapy

Biological therapy• Anti TNF therapy is more effective when

treatment is initiated early in the disease

• Clinical remission rates approached 60% in patients who had CD for <2 years, compared to 40% in patients who had a longer duration of disease

• Combination therapy with infliximab and azathioprine is more effective than either alone

Adalimumab

Ref: - Triantafillidis et al. Drug Design, Development and Therapy 2011; 5: 185- 210

Adalimumab

• Advantages over infliximab:

– induces remissions more frequently than placebo in adult patients with CD who cannot tolerate IFX or are symptomatic despite receiving IFX therapy

– Less immunogenic

• Prospective, randomized head to head studies comparing IFX to ADA required.

Ref: - Triantafillidis et al. Drug Design, Development and Therapy 2011; 5: 185- 210

Golimumab

• Latest approval, May 2013

• Moderate to severe Ulcerative colitis (UC) with an inadequate response or intolerant to prior treatment or requiring continuous steroid therapy

Golimumab

Ref: - Full Prescribing information. Drugs at FDA.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125289s094lbl.pdf

Golimumab

• Resembles adalimumab

• Not a huge advance, but offers another option in its class

• ?? May be superior to other anti-TNF-α antibodies in terms of its ability to inhibit both TNF-α-mediated cytotoxicity and TNF-α-mediated endothelial cell activation.

Ref: - Gastroenterology & Hepatology 2012; 8 (8)

Certolizumab pegol

• Approved in April 2008

• Reducing signs and symptoms of Crohn’s disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Certolizumab pegol

• Approved in April 2008

• Reducing signs and symptoms of Crohn’s disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Stu

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CD

1St

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y C

D2

Ref: - Full Prescribing information. Drugs at FDA.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125160s215lbl.pdf

Induction therapyChronic maintenance

therapy

Infliximab5 mg/kg i.v. infusion, at 0, 2 and 6 weeks

5 mg/kg i.v. infusion every 8 weeks

Adalimumab160 mg s.c. at week 0, then 80 mg at week 2

40 mg s.c. every 2 weeks

Golimumab200 mg s.c. at week 0, then 100 mg at week 2

100 mg s.c. every 4 weeks

Certolizumab pegol400 mg s.c. at 0, 2 and 4 weeks

400 mg s.c. every 4 weeks

Anti- TNF antibodies: Treatment protocol

- Treatment should be given as a planned course of treatment until treatment failure

(including the need for surgery), or until 12 months after the start of treatment,

whichever is shorter.

- Should only be continued if there is clear evidence of ongoing active disease as

determined by clinical symptoms, biological markers and investigation, including

endoscopy if necessary.Ref:- NICE technology appraisal guidance 187, 2011

Anti adhesion molecules

Anti- integrin therapy

Gut-homing

effector memory

cell

Natalizuma

b

Anti adhesion molecules

• Natalizumab : inhibits lymphocyte trafficking into site of inflammation

• Vedolizumab : gut selective, no effect on CNS

natalizumab

• Humanized monoclonal antibody against α4-integrin, Inhibits leukocyte migration into inflammed tissue

• it also inhibits lymphocyte trafficking into CNS

• Risk of progressive multifocal leukoencephalopathy (PML) caused by infection with John Cunningham virus (JCV)

• Check anti JCV virus antibodies before treatment

natalizumab

• Approved by FDA in 2008 for moderate to severe crohn’s refractory to prior treatment, including anti-TNF

• However, it should not be used in combination with immunosuppressants or inhibitors of TNF-α.

vedolizumab

• Gut selective anti adhesion molecule

• Anti integrin molecule, similar to natalizumab, but no effect on brain so no risk of PML

• Approved by FDA in 2014 for Crohn’s disease and ulcerative colitis

Anti interleukins

Anti interleukins : ustekinumab

• Human anti IL-12/IL-23 monoclonal antibody

• Study in severe crohn’s disease: 40% response rate at 6 wks vs 24% in placebo

Janus Kinase (JAK) inhibitor

Janus kinase (JAK) signal inhibitors • As most of the available biological therapies

are directed at the blockage of only one cytokine, it seems reasonable to believe that the modulation of a common cytokine downstream pathway could represent an attractive therapeutic approach.

J Med Chem. 2010;53:8468–8484

Janus Kinase (JAK) inhibitor

• JAK family of kinases mediate signal transduction activity for multiple cytokines

• Tofacitinib: oral JAK inhibitor showed promise for UC and CD with response rates 30-80%

Epidermal growth factor (EGF)

Stimulates cell proliferation in GIT

EGF enema – effective in left sided mild to moderate UC

rosiglitazone

• Peroxisome proliferator receptor agonist

• 44% response vs 23% in placebo in UC at 12 weeks

• Use restricted to patients who have failed or cannot tolerate standard medical therapy

Probiotics

• To modulate intestinal immune response in IBD

• Disappointing results in CD

• Mixed results in UC

Fecal microbiota transplant

• Extreme form of probiotic treatment

• Few reports

• Good results

Porcine whipworm

• Trichuris suis: promising effect, 43% vs 17% in placebo at week 12 in UC

• good safety and toleralability

Nutritional therapy

• Defined enteral or polymeric diets useful in children with CD in whom steroids are undesirable, no role in adults.

Nutritional therapy

• Dietary pattern has effect on intestinal microbial enterotype

• Alteration of microbiome with diet may be a strategy to prevent or manage crohn’s disease

Cytapharesis

• To reduce peripheral blood leukocytes

• Not effective

• Autologous hematopoietic stem cell transplantation (HSCT) as a therapy for experimental colitis shows that immunosuppressive therapy followed by cell transplantation might be an efficient approach for IBD control.

• In those HSCT studies, cyclophosphamide or total body irradiation were used as immunosuppressive therapy, followed by bone marrow transplantation to restore the immune compartment and, presumably, self-tolerance.

Cellular therapy for IBD

Braz J Med Biol Res. 2015 Feb; 48(2): 96–107.

Out of 12 patients , 5 achieved a clinical and endoscopic remission within 6 months after HSCT.

Impact of Autologous HSCT in crohn’s disease

Gut. 2008;57:211–217.

Mesenchymal stem cells (MSC) infusion therapy

• Injection of MSC into fistulas secondary to CD results in closure of the lesions in most cases.

• It also showed complete fistula closure

Gut. 2011;60:788–798.

IBD: Pathogenesis & targets

Novel agents….

ᵡ Apilimod

mesylate

(IL-12, IL- 23)√ Ustekinumab

(p40 subunit of IL-

12/23)

ᵡ Briakinumab

(p40 subunit of IL-

12/23)

√Basiliximab

(CD25 of IL-2)ᵡDacilizumab

(CD25 of IL-2)√Fontolizuma

b(IFN-γ)

Sirukumab (IL-6);

Tocilizumab (IL-

6R)

Anrukinzumab (IL-

13)ᵡSecukinumab (IL-

17)√Vidofludimus

(release of IL-

17)

ᵡIL-10, IL-11,

IFN-β

√Visilizumab

(CD3 TCR)

ᵡRituximab

(CD20)

ᵡSargramostim

(GM-CSF)

Filgrastin

(rGSF)

Thiazolidinedion

es

√GED-0507-

34

ᵡAlicaforsen (ICAM-1)

√ Alicaforsen enema

Etrolizumab (α4β7)

PF-547659 (MAdCAM )

Anti-

adhesion

(anti-

integrin)

Anti-

ILJAK3

inhibitors

Anti-

inflamm

-atory

cytokine

s

Inductio

n of T-

cell

apoptos

is

Growth

factors

PPAR-γagonists

III

II

I

Conclusion

A number of new drugs and technologies are at various stages of development and investigation.

Of these, few will prove to be effective or safe enough to make a major impact.

Thank you