A Double Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MK-7240/ PRA023 in Subjects with Systemic Sclerosis Associated with Interstitial Lung Disease (SSc-ILD)

Prometheus Biosciences a subsidiary of Merck & Co.,Inc. has developed MK-7240/
PRA023, a humanized IgG1 kappa (IgG1N) monoclonal antibody that binds human
tumor necrosis factor-like cytokine 1A (TL1A) with high affinity and
specificity. PRA023 binds to both membrane-bound and soluble forms of TL1A and
blocks the binding of TL1A to its functional death receptor 3 (DR3).
TL1A is a cytokine which is part of the tumor necrosis factor (TNF) superfamily
protein and is secreted by both innate and adaptive immune cells as well as by
endothelial cells. TL1A occurs as both membrane-bound and soluble forms
(Ferdinand 2018).
TL1A binds to DR3 that is found primarily on T cells, natural killer (NK) and
NK-T cells, innate lymphoid cells (ILC), and epithelial cells (Valatas 2019).
TL1A potently drives inflammation through Th1, Th2, Th9, and Th17 responses
(Prehn 2007).
Systemic Sclerosis with Diffuse Cutaneous Scleroderma and Interstitial Lung
Disease (SSc-ILD) is characterized by fibrosis and a broad inflammatory profile
(Mirsaeidi 2019). This profile is consistent with a role for the TL1A and its
receptor DR3, which contribute to inflammation and fibrosis in inflammatory
bowel disease (IBD) (Takedatsu 2008; Hsu 2011). The pleiotropic effects of TL1A
include many effects directly implicated in the pathogenesis of SSc from direct
effects on fibroblasts to Th2 and Th17 immune responses. In addition to their
roles in driving inflammation, TL1A and DR3 have been implicated in driving
fibrosis independent of inflammatory mechanisms by direct stimulation of
fibroblasts (Jacob 2020). TL1A also drives fibrosis by directly activating
fibroblasts as well as up-regulating cytokines, such as transforming growth
factor-beta (TGF-E), leading to collagen disposition and fibrosis. In fibrotic
skin and lungs of patients with SSc, expression of TGF-*-regulated genes
correlates with disease activity, which points to this cytokine as a mediator
of pathogenesis (Lafyatis 2014). Higher serum values of TGF-* were also
observed in SSc patients compared to those in healthy subjects with a positive
correlation with the disease severity (e.g., digital ulcers, more extensive
skin fibrosis)

For more information please refer to background page 27 of the protocol

This study has been transitioned to CTIS with ID 2023-509743-27-00 check the CTIS register for the current data.

x To assess the safety and tolerability of MK-7240/PRA023 in SSc-ILD
x To compare the annual rate of change from Baseline in forced vital capacity
(FVC), in mL, of MK-7240/PRA023 vs. placebo over 50 weeks


For more information please refer to objectives page 35 of the protocol

This is a multi-center, double-blind, randomized, placebo-controlled study
designed to assess the safety, tolerability, and efficacy of MK-7240/PRA023 in
subjects with SSc with diffuse cutaneous disease and ILD. This study will be
conducted under the aegis of a DMC.
The study has 4 periods (Screening Period, Treatment Period, Open-Label
Extension [OLE] Period, and Follow-Up [FU] Period).
Following the Screening Period, approximately 100 eligible subjects will be
randomized in a 1:1 fashion to receive 1000 mg of MK-7240/PRA023 or placebo via
intravenous (IV) administration on Week
0/Day 1, followed by 500 mg or placebo IV on Week 2, then every 4 weeks (Q4W)
until Week 46. Randomization on Week 0/Day 1 will be stratified by presence of
anti-topoisomerase antibody (+/-) and CDx status (+/-).


For more information please refer to study design page 38 of the protocol

A placebo arm is needed to allow for a true assessment of the effects of
MK-7240/ PRA023 on the rate of decline in FVC. In this study, the placebo arm
will be commercially available 0.9% normal saline solution which will be
sourced locally by the study sites. To address current practice, patients
without immunosuppressive background therapy as well as patients on a stable
background therapy of mycophenolate mofetil (MMF), methotrexate (MTX),
azathioprine, or corticosteroid will be eligible for the trial. Rescue
treatment is allowed in case of clinical deterioration of SSC either in the
lungs FVC decrease >= 10% compared to Baseline), in the skin (mRSS increase of
> 25% and > 5 points compared to Baseline) or in any other organ system
(Section 4.4.5). By implementing these measures, the inclusion of a placebo arm
is considered to be ethically justifiable.

Patients with the rare condition of SSc-ILD with diffuse cutaneous disease will
be included in this trial. Placebo-controlled randomized trials provide the
most robust results and are thus considered the most appropriate design,
especially in rare patient populations, where multiple trials are not possible
due to lack of patients

establishing medical history, use of medication and side effects
-collect urine
- smoking history/behaviour
-physical examination
-blood pressure, height, weight and BMI
-ECG
-questionnaires QoL,SSPRO,L-PF,HAQ-DI,UCLA-SCTC

Infusion of MK-7240/PRA023 or placebo 13x outpatient in OLE every 4 weeks and
every 12 weeks HH visit
lung function test (PFT)
blood samples
DCLO assessment
PK genetic testing (blood and saliva)

All drugs can cause unwanted effects. Pain at the injection site
and anaphylaxis, rash wheezing and difficulty breathing dizziness and fainting
swelling around the mouth, throat, or eyes a fast heartbeat sweating

You may experience side effects or adverse effects
You may be bothered by the measurements during the examination. For example:
blood draw may hurt a little. Or you could get a bruise as a result