# A nonpsychoactive cannabinoid receptor-2 agonist to treat itch and inflammation in dermatomyositis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $401,824

## Abstract

Abstract
Dermatomyositis (DM) is a multiorgan autoimmune disease that causes significant skin activity
and severe pruritus, both of which worsen the patients’ quality of life (QoL). Despite its clinical
importance, however, the pathogenesis of skin activity and itch in DM remains poorly
understood. Accordingly, no new therapies for DM have been approved in the last 70 years.
Currently available off-label therapies are frequently ineffective or have significant risks. We
recently completed a successful NIH-funded phase 2 randomized controlled trial of lenabasum,
a novel nonpsychoactive CB2 inverse agonist, to treat skin-predominant DM. Lenabasum
produced significant improvements in skin disease activity, itch, and key QoL measures.
Mechanistic studies performed in our lab using the limited number of biopsies of lesional skin
from the trial demonstrated that lenabasum decreased the numbers of dermal CD4+ T-cells and
dermal staining areas for interferon (IFN)ß, IFNγ, and interleukin (IL)31. None of these four
parameters changed in the placebo group. The first three of these changes significantly
correlated with improvement in skin disease activity. The decreases in dermal staining for IFNγ
and IL31 each significantly correlated with improvement in itch. Our recent work demonstrates
prominent myeloid dendritic cells (mDCs) in the skin of patients with DM, in contrast to the
predominance of plasmacytoid DCs (pDCs) and the IFNα signature in the skin of many lupus
patients. Given the prominent IFNß signal in skin previously reported in DM and the decrease in
IFNß and skin disease activity in response to lenabasum, we now propose to evaluate the role
of mDCs in the production of IFNß in DM. We have an opportunity to expand the scientific
advances we made in the phase 2 trial in an upcoming phase 3 international trial of lenabasum
for DM. We hypothesize that lenabasum, acting through the CB2 receptor on mDCs, decreases
mDC expression of IFNß through effects on IRF-3, -5, and -7. We also hypothesize that
lenabasum, either through the downregulation of IFNß from mDCs or by direct effects on T
cells, decreases production of IFNγ and IL31 in skin. In DM patients treated with lenabasum in
the phase 3 trial, we will identify cellular and molecular changes in pathways relevant to skin
disease activity and itch that predict or correlate with clinical improvements. We will also
perform mechanistic studies of pathways promoting activity and itch in DM and the improvement
with lenabasum. Our proposed studies utilizing samples from the upcoming phase 3 trial will
enhance our understanding of how lenabasum works, thereby shedding light on key disease
mechanisms and possibly providing a basis for additional novel therapeutic approaches.

## Key facts

- **NIH application ID:** 10437840
- **Project number:** 5R01AR076766-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** VICTORIA P WERTH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $401,824
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437840

## Citation

> US National Institutes of Health, RePORTER application 10437840, A nonpsychoactive cannabinoid receptor-2 agonist to treat itch and inflammation in dermatomyositis (5R01AR076766-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10437840. Licensed CC0.

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