Diffusion Imaging

Efficacy of Apremilast on Whole-Body Inflammation Indices in Patients With PsA :Assessments by Whole-Body MRI in the Ph4 MOSAIC Study

Efficacy of Apremilast on Whole-Body Inflammation Indices in Patients With Psoriatic Arthritis: Assessments by Whole-Body Magnetic Resonance Imaging in the Phase 4 MOSAIC Study

Background:

Psoriatic arthritis (PsA) is characterized by various patterns of inflammatory arthritis, enthesitis, dactylitis, and spondylitis. Apremilast is an oral immunomodulating phosphodiesterase-4 inhibitor that is indicated for treatment of PsA. Whole-body magnetic resonance imaging (WB-MRI) allows assessment of joints and entheses of the entire body in one examination when using the Outcome Measures in Rheumatology Clinical Trial (OMERACT) MRI whole-body scoring system for inflammation in peripheral joints and entheses (MRI-WIPE), which has not previously been applied in a clinical trial. Here we evaluate the efficacy of apremilast 30 mg BID (APR) on peripheral inflammation indices as measured by WB-MRI.

Objectives:

To evaluate how APR affects inflammation in peripheral joints and entheses of patients with PsA as assessed by WB-MRI.

Methods:

The phase 4 MOSAIC study was a multicenter, single-arm, open-label study evaluating APR (either as monotherapy or in combination with stable methotrexate) in patients with active PsA (diagnosis ≥3 months but ≤5 years, meeting the CASPAR criteria for PsA) for treatment up to 48 weeks. WB-MRI was performed at baseline, Week 24, and Week 48. Images were read and adjudicated by 2 experienced readers who were blinded to time of acquisition and clinical information. From WB-MRI, changes in the total peripheral inflammation index (83 joints and 33 entheses) were calculated using the OMERACT MRI-WIPE scoring system, as were changes in separate enthesitis and joint inflammation WB-MRI indices (WIPE-enthesitis and WIPE-joint inflammation). Changes in the heel enthesitis inflammation index (HEMRIS),

the hip joint inflammation MRI index (HIMRISS), and the knee joint inflammation MRI index (KIMRISS) were explored.

Results:

Overall, 122 patients were enrolled and treated with APR; 55% were women, mean age was 47 years, and patients had a mean duration of PsA of 1.9 years. The least squares mean (95% CI) change from baseline in total WIPE score based on total peripheral inflammation index (including both joint and enthesitis inflammation) as assessed by WB-MRI was -3.49 (- 5.46, -1.52) at Week 24 and -4.06 (-6.39, -1.72) at Week 48, indicating significant improvement in peripheral inflammation (Figure). Significant improvements were also observed in the WIPE-joint inflammation scores at both Week 24 and 48, and in the WIPE- enthesitis scores at Week 48 (Figure). Both the heel enthesitis inflammation index (HEMRIS) and the hip joint inflammation MRI index (HIMRISS) showed little change, while the knee joint inflammation MRI index (KIMRISS) showed numerical, but not significant, improvement (Figure). No new safety signals were identified.

Conclusion:

Patients with PsA treated with APR experienced a significant reduction in total peripheral inflammation, including significant improvement in peripheral joint inflammation and enthesitis, as assessed by WB-MRI. Results highlight the efficacy of APR on inflammatory manifestations of PsA as well as the benefit of using WB-MRI as a measure of inflammatory disease activity.

Apremilast Reduces Inflammation in Patients With Psoriatic Arthritis.

Apremilast Reduces Inflammation as Measured by MRI of the Hand in Patients With Psoriatic Arthritis: Primary Results from the Phase 4 MOSAIC Study

Background:

Psoriatic arthritis (PsA) is characterized by inflammatory arthritis, enthesitis, dactylitis, and spondylitis. Apremilast is an oral immunomodulating phosphodiesterase-4 inhibitor approved for the treatment of PsA. The impact of apremilast on objective measures of inflammation and structural progression of PsA has not yet been characterized. Here, we evaluate the efficacy of apremilast 30 mg BID (APR) on inflammation measured by dedicated MRI of the hand.

Objectives:

To evaluate the efficacy of APR on inflammation and imaging outcomes and the safety profile of APR in this setting.

Methods:

MOSAIC (NCT03783026) was a phase 4, multicenter, single-arm, open-label study in patients (pts) with active PsA (≥3 months but ≤5 years since diagnosis, meeting CASPAR criteria for PsA) evaluating APR as monotherapy or in combination with stable methotrexate. Pts were treated with APR for 48 weeks and had MRI of the hand (contrast-enhanced) performed at baseline (BL), Week 24, and Week 48. All images were read and adjudicated by 2 experienced readers blinded to clinical information and time of acquisition. The primary endpoint was change from BL in the composite score of hand bone marrow edema (BME), synovitis, and tenosynovitis in fingers 2–5, as assessed by the PsA MRI Score (PsAMRIS) at Week 24. Total inflammation score, comprised of BME, synovitis, tenosynovitis, and periarticular inflammation in fingers, was also assessed. Structural progression was assessed by the total hand damage score (determined by bone erosion and bone proliferation in fingers 2–5). Subgroup analyses based on BL disease activity as measured

by Clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) were performed for key endpoints.

Results:

A total of 122 pts enrolled and received APR. Mean age was 47 years, 55% were women, and mean duration of PsA was 1.9 years. The Full Analysis Set (FAS) included 98 pts evaluable for the primary endpoint (having BL and Week 24 data); 4 had major protocol deviations and 94 were evaluable as part of the per protocol (PP) population. The least- squares (LS) mean (95% CI) change from BL in the composite inflammation score of BME, synovitis, and tenosynovitis as assessed by PsAMRIS (FAS) was -2.32 (-4.73, 0.09) at Week 24 and -2.91 (-5.45, -0.37) at Week 48 (Figure). In the PP population, the LS mean (95% CI) change from BL in the composite score at Weeks 24 and 48 indicated a significant reduction of disease activity (Figure). Significant improvements from BL were seen in total inflammation scores (BME + synovitis + tenosynovitis + periarticular inflammation) in the FAS (Figure). The structural outcome indicated by the total hand damage score, including bone erosion, showed no significant change from BL to Week 48 (Figure). Pts also experienced significant improvements from BL in cDAPSA at Weeks 24 and 48 (Figure).

Subgroup analyses based on disease activity at BL showed significant improvements from BL in inflammation in pts with moderate disease activity (ModDA; cDAPSA score >13 to ≤27) and no significant change from BL in total damage (Figure). Though it was insignificant, pts with high disease activity (HDA; cDAPSA score >27) did have improvement from BL in inflammation indices (Figure).

Common treatment-emergent adverse events were diarrhea (33.6%), nausea (12.3%), headache (10.7%), nasopharyngitis (7.4%), and dyspepsia (6.6%). No new safety signals were identified.

Conclusion:

Pts with PsA treated with APR had improvements in both clinical indices and objective MRI indices of inflammation assessed by PsAMRIS in the target hand at Week 24 and Week 48, confirming an effect of APR on clinical and inflammatory manifestations of PsA. Pts with ModDA seemed to have greater improvement from BL in MRI inflammation scores than pts with HDA. No significant structural progression was observed. These results offer important insights on the effect of apremilast in PsA and highlight the value of using MRI and PsAMRIS as measures of inflammatory disease activity and change following treatment.

IAG Collaborates with Peter McCallum Cancer Center on bringing AI into Oncology Drug Development.

IAG Collaborates with Peter McCallum Cancer Center on bringing AI into Oncology Drug Development.

Why Targeted Drugs and Therapies Demand Novel Biomarkers for Assessing Tumour Burden

Cancer treatment is determined by the type of cancer and its stage. If caught at an early stage, treatment options include surgery or radiotherapy. Chemotherapy, drugs that potentially kill cancer cells, is necessary at a later stage when the cancer is more advanced or has spread. Chemotherapy is delivered systemically and acts with limited specificity in the body: cancer cells and healthy cells are affected and therefore, chemotherapy can result in severe side effects.

Today we see the rise of targeted cancer therapies and high-precision imaging

Over the last few decades several novel treatment modalities have become an important part in the fight against cancer.

Targeted cancer drugs work by ‘targeting’ differences of a cancer cell on a molecular level. Popular targets include those important for cancer growth and progression. Targeted drugs for example stop cancer cells from dividing, encourage the immune system to find and kill cancer cells or stop cancers from growing blood vessels. They are delivered systemically and can still have side effects, but, are generally less severe than chemotherapy.

Stereotactic ablative body radiotherapy (SABR) is a novel high-precision treatment modality. Radiotherapy beams originate from different positions around the body and are calibrated by medical imaging. As a result, the tumour receives a high dose and the surrounding tissues a lower dose. Careful treatment planning and the inherent high-precision of the technology allows that the radiotherapy field covers the tumour while avoiding healthy tissue as far as possible. This reduces the risk of side effects.

Effects to the Tumour Morphology

While novel cancer treatments are different in their delivery and mode of action, they share a common motivation and morphological tumour response.

Innovative therapies are specific by focusing on local control of the tumour and thus, lower the risk of side effects. Besides being effective in cancer cell death, they do not necessarily result in tumour morphological change: a residual non-viable tumour architecture can remain for a sustained period post-treatment.

Broadly speaking, novel therapies result in a complex tumour remnant that complicates the assessment of changes in tumour burden.

Cancer Therapy Validation

New drugs and therapies require a thorough validation showing treatment success. The Response Evaluation Criteria in Solid Tumours (RECIST) provides a validated and consistent methodology to evaluate the activity and efficacy of new cancer therapies in solid tumours: RECIST determines the tumour diameter on cross-sectional computed tomography (CT) or magnetic resonance imaging (MRI) scans to assess changes in tumour burden.

In January 2017, the RECIST working group has published on the continued relevance of RECIST guidelines and on the challenge to maintain RECIST as a standard for the assessment of tumour burden in clinical trials. The authors have acknowledged that “…maintaining the validity and relevance of RECIST as a standard evaluation approach is challenging, in particular to maintain a balance between its specificity and generalizability…” Furthermore, the authors noted that the RECIST linked data collection in clinical trials limits the utility of existing databases for the validation of new evaluation approaches to tumour response.

Modifications to Adjust to Novel Therapies

It is critical to note that RECIST version 1.1 remains the only general tool that provides harmonization of tumour response assessment.

However, the working group and a large body of research brings to light the acute need for new imaging modalities, assessment methodologies and updated criteria to support the development of the new classes of treatments. As a response to this need, the immune Response Evaluation Criteria in Solid Tumours for cancer immunotherapy trials (iRECIST) has been developed and validated.

Advanced Imaging and Analysis Methodologies

Recent research has shown that advanced imaging and Artificial Intelligence (AI)-powered analysis provide detailed insight into therapy related tumour microenvironmental changes and are able to predict RECIST outcomes.

MRI poses a promising alternative to evaluate tumour response and is currently rated as equivalent to CT by the American College of Radiology for solid tumours. Multi-parametric MRI (mpMRI) is a sequence of anatomical and functional MRI scans. Several solid tumour trials have successfully implemented mpMRI as an effective explorative endpoint; mpMRI’s ability to predict pathological response is considered as an important advantage over CT.

IAG, Image Analysis Group collaborates with Peter McCallum Cancer Center

IAG’s recent collaborative clinical trial in stereotactic ablative body radiotherapy (SABR) in renal cell cancer (RCC) has implemented a mpMRI protocol.

IAG’s expert team designed and deployed a dynamic contrast enhanced (DCE) MRI and diffusion weighted MRI (DWI) as part of a mpMRI imaging protocol to provide earlier evidence of response (Reynolds et al., 2018).

Resulting quantitative imaging biomarkers have shown to be predictive to RECIST-based assessments.

Together, with our scientific collaborators, IAG’s team brought forward novel imaging biomarkers that have shown significant correlations between the tumour volume change and changes in advanced perfusion imaging biomarkers.

The figure to this article shows colour coded parametric maps before and after therapy. More in the full article.

Full Article: Diffusion weighted and dynamic contrast enhanced MRI as an imaging biomarker for stereotactic ablative body radiotherapy (SABR) of primary renal cell carcinoma

About IAG, Image Analysis Group 

IAG, Image Analysis Group is a unique partner to life sciences companies, leading AI-powered drug development and precision medicine. IAG leverages expertise in medical imaging and the power of Dynamika™ – our proprietary cloud-based platform, to de-risk clinical development and deliver lifesaving therapies into the hands of patients much sooner.  IAG provides early drug efficacy assessments, smart patient recruitment and predictive analysis of advanced treatment manifestations, thus lowering investment risk and accelerating study outcomes. IAG bio-partnering takes a broader view on asset development bringing R&D solutions, operational breadth, radiological expertise via risk-sharing financing and partnering models.

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