ACG22_JAKi_2_faces_Higgins.pdf

October 21-26, Charlotte, NC
The Janus Kinase Inhibitors: Two
Faces for Efficacy and Safety?
Peter D.R. Higgins, MD, PhD, MSc
University of Michigan

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Agenda
• JAK inhibitors are highly efficacious, multi-pathway inhibitors
of immune function
• JAK inhibitors are small molecules that act intracellularly, so
intestinal leak/trough levels are not a problem
• JAK inhibitors are effective, act quickly, and are not at risk for
anti-biologic antibodies
• JAKi do appear to weaken defenses against infection & cancer,
appear to increase risk of VTE, & may increase the risk of
MACE (Major Adverse Cardiac Events) in combination Rx

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JAK (and Tyk2) Multi-Pathway Signaling
Nature Reviews Rheumatology volume 18, pages 133–145 (2022)
In vitro JAK
specificity
testing may
not reflect
in vivo
effects
INSIDE THE CELL

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JAKs Act Intra-cellularly
• Drug binds and largely stays inside of
cells
• Not as susceptible to leak as
monoclonals
• Not as susceptible to low troughs in
severe UC
• Not at all susceptible to anti-biologic
antibodies
• The leaky bucket (leaky colon)
problem is not an issue BIOLOGICS
LEAKY COLON

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Upadacitinib Efficacy in UC – Induction
Delta 29
4
33
0
5
10
15
20
25
30
35
Percent Clinical Remission at Week 8
U-ACCOMPLISH

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Upadacitinib Efficacy in UC – Maintenance in
Randomized Responders
12
42
52
0
10
20
30
40
50
60
Percent Clinical Remission at Week 52
U-ACHIEVE
Delta
30
40

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Tofacitinib in Hospitalized, Biologic-
Experienced Acute Severe UC
Tofa 10 tid + IVCS
Tofa 10 bid + IVCS
IVCS
Berinstein, Higgins, et al., CGH, 10: 2112-2120, 2021

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Upadacitinib Data in Crohn's
(not yet peer-reviewed nor FDA approved)
13%
29%
46%
49%
0% 10% 20% 30% 40% 50% 60%
Endoscopic Remission
Clinical Remission
Upadacitinib 45 mg po qd for CD Remission at Week 12
Upa 45 Placebo
https://news.abbvie.com/news/press-releases/news-type/rd-news/second-phase-3-induction-study-confirms-upadacitinib-rinvoq-improved-clinical-and-endoscopic-outcomes-in-patients-with-crohns-disease.htm
Delta
20
33

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Speed of Onset of JAKi
• Tofacitinib 10 mg po bid induction
• Significantly reduced stool frequency vs PBO by day 3
• Significantly reduced rectal bleeding vs PBO by day 3
• Upadacitinib 45 mg po qd induction
• Significant improvement in symptoms of UC vs PBO on day 1
• Achieved abdominal pain=0 and the absence of bowel urgency
within 3 days at significantly higher rates than PBO
Hanauer, et al. Gastroenterol Hepatol. 2019 Jan;17(1):139-147.
Vermeirere, et al. Journal of Crohn's and Colitis, Volume 16, Issue Supplement_1, January 2022, Pages i087–i088

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2 JAK Inhibitors That Stumbled
Filgotinib
(JAK1)
Promising Data in
UC and CD,
Including fistulas
Evidence
of Sperm
Toxicity
Approved in Europe
Development Halted in US
Deucravacitinib
(TYK2)
Promising Data in
Psoriasis
Completely Failed in
UC
(Placebo Better)
Development Recalibration
for IBD
Lancet. VOLUME 389, ISSUE 10066, P266-275, JANUARY 21, 2017
https://www.biospace.com/article/galapagos-touts-positive-post-hoc-data-but-likely-won-t-gun-for-us-approval-/
Journal of Crohn's and Colitis, Volume 16, Issue Supplement_1, January 2022, Pages i091–i092
https://www.fiercebiotech.com/biotech/bristol-myers-deucravacitinib-flunks-midphase-ibd-trial-raising-questions-about-potential

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2 JAK+ Inhibitors at early Stages
0% 0%
11%
5%
26%
24%
36%
24%
0%
5%
10%
15%
20%
25%
30%
35%
40%
Ritlecitinib Brepocitinib
Delta 36
Delta 24
Hung, et al. VIBRATO study, UEGWeek 2022.
JAK3/TEC JAK1/TYK2
Clinical
Remission
At Week 8
In mod-severe
UC

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Network Meta-analysis of Approved
UC Therapies
• Upadacitinib 45 mg qd ranked 1st for clinical
induction of remission in naïve and bio-
experienced UC patients
• Followed at #2 by IFX 10 mg/kg
• IFX 10 mg/kg ranked 1st for endoscopic remission
in all UC patients
• Followed at #2 by Upa 45 mg once daily
Burr, Ford, et al. Gut. 2021 Dec 22;gutjnl-2021-326390.

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Network Meta-analysis of UC Therapies
• Upadacitinib 45 mg qd induction had
• higher rates of all adverse events
• but not serious adverse events
• nor withdrawals due to AEs.
• Tofacitinib 10 mg was associated with
• higher rates of infections (RR 1.41 vs. Placebo)
Burr, Ford, et al. Gut. 2021 Dec 22;gutjnl-2021-326390.

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TURNING TO SAFETY

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Shingles (Herpes Zoster)
• A consistent risk across JAK inhibitors
• Appears dose-dependent
• Rates ~ 5% per year on drug
• Likely increases with age / time since chickenpox/vaccine
• Largely preventable with recombinant vaccine
• Use Shingrix early, particularly if over 30 years old
• 2 doses, highly effective, recombinant, non-live vaccine
• 97% effective in study of immunocompetent patients under
70 years old
• 68% effective in stem cell transplant recipients
• 87% effective in hematologic malignancies
• Recommended by ACIP & CDC for immunocompromised
and immunosuppressed patients
https://www.cdc.gov/mmwr/volumes/71/wr/mm7103a2.htm

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Other Infections
• Boxed warning includes
• Tuberculosis (pre-test
with QFTB or PPD)
• Fungal infections,
including
cryptococcosis and
pneumocystosis
• Bacterial, viral, and
opportunistic infections

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Malignancies
• Malignancies, including lymphoma and solid tumors, are
seen with tofacitinib and upadacitinib
• Higher rates of lymphoma and lung cancer in RA were
seen on tofa/MTX vs. TNF/MTX
• Higher rates of EBV-associated PTLD in transplant patients
on tofacitinib combination therapy with other
immunosuppressants
• Think twice about JAKi
• After prior malignancy
• In smokers
• Elderly / high risk for malignancy
• Think twice about JAKi combo therapy with other IS

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Major Adverse Cardiovascular Events (MACE)
• Post-marketing study with tofacitinib in RA
patients (combo with MTX)
• ≥50 years old
• with at least one CV risk factor
• Saw a higher rate of major adverse
cardiovascular events (MACE)
(defined as cardiovascular death,
myocardial infarction, and stroke)
• Current and past smokers at higher
risk
• Avoid JAKi in smokers, or prior CAD over
50 years old
• Stop JAKi after MI or stroke

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Thrombosis
• DVT, PE, and arterial thrombosis have
been seen with JAK inhibitors
• Post-marketing study with tofacitinib
in RA patients (combo with MTX)
• ≥50 years old
• with at least one CV risk factor
• Saw a higher rate of thrombosis
in these patients
• Avoid JAKi in prior VTE if NOT
adherent to long-term
anticoagulation
• Stop JAKi if thrombotic event occurs
CONSIDER
Comorbid risk factors for VTE:
- Inflammation
- Immobility
- Corticosteroids
- Oral contraceptives
- Estrogens
- Pregnancy
- Cancer
- Surgery
- Bone fractures

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ORAL SURVEILLANCE STUDY
Tofacitinib/MTX in RA vs. TNF/MTX
• Patients were over 50 with at least one CV risk factor plus
RA (a risk factor)
• Tofa/MTX is not a combination used in IBD
• Over 4 years, more MACE in 3.4% vs 2.5%
• Over 4 years, more cancer in 4.2% vs 2.9%
• Higher rates of zoster, NMSC with tofa/MTX vs IFX/MTX
N Engl J Med 2022; 386:316-326

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The Problem with Methotrexate
• MTX has failed to produce a measurable benefit in 2 RCTs in
UC (METEOR, MERIT-UC)
• MTX had benefit for induction in CD in one trial, but no
measurable benefit for MTX + IFX in CD
• Lots of adverse events, no benefit as combination therapy
with MTX/IFX in Crohn's
• NO ONE should be using MTX in UC, nor combo in CD
• No good evidence for combining small molecules in IBD
Gastroenterology, 2016 Feb;150(2):380-8, Gastroenterology. 2018 Oct;155(4):1098-1108,
N Engl J Med 1995; 332:292-297, Gastroenterology. 2014 Mar;146(3):681-688.

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In Which Patients to Use
JAK Inhibitors?
Favors Use of JAKi
• Severe Inflammation
• Rapid Response Needed
• Younger patient
• Few comorbidities
• No CAD, cancer, VTE
• Nonsmoker
• Biologic-experienced
• Prior anti-drug antibodies
• Never thrombosis or very adherent to life-long
anticoagulation
• Willing to take Shingrix, test for TB
Against the Use of JAKi
• Mild Inflammation
• Older patient
• Prior malignancy, CAD
• Former or current smoker
• Using MTX or other immunosuppressant
• Biologic-naïve
• Prior VTE without long-term anticoagulation
• Unwilling to take Shingrix, test for TB

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Risk and Benefit Perceptions Change
• Severe UC, failed biologic, at risk of colectomy
• Willing to take short-term risk
• Desires rapid efficacy & high efficacy
• Same patient, in deep remission 1 year later
• Less willing to take risk
• May want to transition to different maintenance medication
• Won't develop antibodies – can re-induce with JAKi if needed

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JAK Inhibitor Take Home Points
• JAK inhibitors are not for every patient
• Very high efficacy, rapid, great for biologic-failed
• May reduce colectomy in Acute Severe UC (TBD)
• May be less attractive as maintenance
• Select patients and the time point in disease carefully
• Balance risks and benefits

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Thank You
Questions?

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I will consider the risk of shingles with JAK inhibitors, and advise patients to get
vaccinated with a recombinant shingles vaccine (Shingrix)
Consider
I will consider JAK inhibitors when my patients need rapid control of inflammation
and are at risk of leaking biologics through an inflamed intestine (and low trough
and anti-biologic antibodies).
Consider
I will consider the risk of VTE with JAK inhibitors, and discuss additional risk
factors with my patients, including immobility, inflammation, steroids, oral
contraceptives and estrogens, cancer, surgery, and bone fractures.
Consider

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ACG22_JAKi_2_faces_Higgins.pdf

ACG22_JAKi_2_faces_Higgins.pdf

Peter Higgins

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