Evaluating Safety & Efficacy of Apremilast in the Treatment of Cutaneous Disease in Patients With Recalcitrant Dermatomyositis

1. Sponsor Name (PI): Carole Bitar, MD

2. Sub-PI: Erin Boh, MD, PhD; Brittany Stumpf, MD; Collaborator: Nakhle Saba, MD

3. # of Participants Sites: 1, Tulane University 4: Participant Countries: United States

II. PRODUCT INFORMATION

1. Study Title: A phase 2, open label single arm study for evaluating safety & efficacy of
apremilast in the treatment of cutaneous disease in patients with recalcitrant
dermatomyositis.

2. Clinical Phase: Phase II clinical trial

3. Primary Celgene Product: Apremilast

III. CONCEPT DESIGN AND RATIONAL

1. Therapeutic Area: Immunology

2. Specialty: Connective tissue disease

3. Disease State: Dermatomyositis

4-If other specify: None

5. Study Rationale: Dermatomyositis is an inflammatory disease that predominantly involves
the skin with or without proximal muscle weakness. First line treatment for dermatomyositis
is systemic steroids however due to long-term side effects, patients are usually treated with
a steroid sparing agent. There is no known consensus on treatment guidelines for
dermatomyositis and many anti- inflammatory medications have been successfully used. Tulane
University is a referral center for recalcitrant dermatomyositis cases.The investigators
present the case of a 57 y.o female patient with multidrug recalcitrant dermatomyositis
showing complete remission of her skin disease with apremilast and improvement of her muscle
disease. This patient was diagnosed with dermatomyositis. Over a 6-year period, she was
treated with adequate trials of multiple immunosuppressive agents, including
hydroxychloroquine, mycophenolate mofetil, azathioprine, methotrexate, soriatane, Intravenous
immunoglobulin (IVIG), tacrolimus, chlorambucil, infliximab and rituximab. For the last four
years, physicians were unable to lower corticosteroids below 40 mg per day. Her disease
continued to flare despite these therapies. Chronic steroid use resulted in insulin dependent
diabetes mellitus as well as other steroids associated side effects. While on stable doses of
mycophenolate mofetil, prednisone and rituximab, the patient developed arthritis and was
started on apremilast 30 mg twice a day. Two months into her treatment she noticed
significant improvement of her skin disease and then nearly complete clearance of the skin.
Her muscle weakness lagged behind and she noticed improvement after 9 months of being on
apremilast with normalization of her aldolase and CK. The patient was able to wean off all
immunosuppressive agents and prednisone. She was in remission for over 2 years and off all
medications. She experienced a mild flare of skin disease recently and she resumed apremilast
only and cleared immediately and continues on apremilast as a monotherapy. Patient
experienced mild nausea and diarrhea with apremilast that improved four weeks into the
treatment. She was able to discontinue insulin, lose weight and she has continued to be clear
of both skin and muscle symptoms for over 1.5 years.

This case was accepted as a poster presentation at the 2018 Annual Meeting of the American
Academy of Dermatology "Poster #: 6672 - Apremilast: a Potential Treatment for
Dermatomyositis." Following this successful outcome, the investigators initiated apremilast
in 3 other patients with recalcitrant dermatomyositis. Two patients had recalcitrant
cutaneous disease and responded to add on therapy of apremilast in 2 months with significant
improvement of their skin disease. The third patient had refractory dermatomyositis to
several steroid-sparing agents and with severe muscle disease was started on apremilast for
arthritis. She experienced significant improvement of her muscle weakness together with
decrease in her muscle enzyme creatine kinase.

These very exciting findings triggered the idea of studying apremilast as an adjunct
treatment for recalcitrant cutaneous disease in dermatomyositis patients. This is a novel
idea; apremilast was never studied for dermatomyositis. Apremilast may have more advantages
in dermatomyositis compared to other immunosuppressive treatments. Dermatomyositis patients
may have lung involvement, and apremilast is an agent that doesn't have lung side effects in
contrast to methotrexate for example which is one of the main steroid sparing agents used for
dermatomyositis.

The pathogenesis of dermatomyositis is multifactorial with environmental, genetic and immune
factors contribution.T helper-1 (Th1) and T helper-2 (Th2) immune pathways play a fundamental
role in dermatomyositis.There is increase in proinflammatory cytokines including tumor
necrosis factor alpha (TNF-α), interleukin (IL) 1, IL 6, and interferon (INF) α,γ shifting
the immune balance to a Th1 response.Th1 immune response was also involved in the
pathogenesis of interstitial pneumonia in the setting of dermatomyositis.IL4 released by
lymphocytes infiltrating skin and muscles in dermatomyositis patients contributes to increase
in Th2 response in conjunction with Th1 response.

Apremilast is a PD4-E inhibitor currently used for psoriasis and psoriatic arthritis.However,
its usage on patients with dermatomyositis has not been investigated.

By inhibiting PDE-4 apremilast increases the level of cyclic adenosine monophosphate (c-AMP),
leading to decreased expression of proinflammatory cytokines including TNF-α and INF-γ thus
inhibiting Th1 response. Apremilast can also block Th2 response by interfering with the level
of IL6 secreted by type2 macrophages.While the mechanism of action of apremilast in
dermatomyositis is unknown, we suggest that apremilast can be a potential treatment option
for dermatomyositis through interfering with Th1 and Th2 response.

Apremilast is a well-tolerated oral medicine with transient gastrointestinal side effects.
Apremilast offers an additional treatment option for those patients with recalcitrant
dermatomyositis, unresponsive to more conventional therapy.

6. Treatment and Dosing: Investigators will enroll patients seen at our facilities with a
known diagnosis of dermatomyositis who are still experiencing cutaneous disease after a trial
of systemic steroids and one steroid-sparing agent. Investigators will add apremilast to
their treatment regimen according to the approved dosage for psoriasis and psoriatic
arthritis: 10 mg orally one time on day 1, 10 mg orally twice daily on day 2, 10 mg orally in
AM and 20 mg orally in PM on day 3, 20 mg orally twice daily on day 4, 20 mg orally in AM and
30 mg orally in PM on day 5, then 30 mg orally twice daily thereafter.

7. Brief Study Synopsis: With limited treatment options available for dermatomyositis,
investigators hypothesize that apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, is a safe
and efficacious add-on treatment in patients with recalcitrant cutaneous dermatomyositis.

The study will investigate the efficacy, safety and toxicity of apremilast given at 30 mg
twice daily to patients with recalcitrant cutaneous dermatomyositis. Clinical response will
be assessed at 1 and 3 months. Patients will also be evaluated for durability of their
response for up to 6 months.

Treatment will be monitored with frequent clinical visits (0, 1, 3 and 6 months) and blood
tests (CBC, CMP, CK, aldolase). Treatment will be discontinued at disease progression or
unacceptable adverse events. Disease progression is defined as a 4 points increase in CDASI
score, worsening of muscle disease by MMT-8 score and 5 points increase in DLQI.

5 mm skin biopsies from lesional skin will be performed before treatment with apremilast and
after 3 months of treatment for gene expression profiling and confirmatory
immunohistochemical stains.

8. Sampling and correlative analysis

Although, the proposed mechanism of action of apremilast is though PDE-4 inhibition resulting
in c-AMP upregulation, the exact biological process that leads to dermatological response in
dermatomyositis remains ill-defined.Investigators propose to perform gene expression
profiling (GEP) using RNA sequencing on skin biopsies collected before and after treatment
with apremilast. In addition, we plan to confirm our GEP findings at the protein level using
immunohistochemical (IHC) stains.

A. Tissue sampling and preparation

1. Tissue collection 5 mm punch biopsy from dermatomyositis skin lesions will be performed
at baseline and another 5 mm punch biopsy will be performed at the 3-month time point.
Each biopsy will be vertically split in two pieces and snap frozen on dry ice then it
will be stored at -80C for further analysis with RNA sequencing and IHC stains.

2. RNA extraction At the end of all timeline collections, each skin biopsy will be
mechanically broken down followed by mRNA extraction using the RNeasy extraction Kit
from QIAGENzz. mRNA will then be stored at -80°C for subsequent RNA sequencing as
detailed below.

B. Correlative Analysis

Determining the mechanism of action of apremilast in dermatomyositis.

1. Gene expression profiling RNA extracted form skin biopsies collected before and after in
vivo treatment with apremilast (as detailed above) will be subjected to RNA sequencing.
Illumina strand-specific TruSeq libraries will be prepared from the polyA selected RNA
and subjected to 1x100 base sequencing on an Illumina HiSeq2500 machine. The number of
samples proposed here (10 samples before treatment and 10 samples after treatment) is
expected to yield sufficient statistical power for this approach; smaller numbers have
been used in similar approaches to investigate drugs' mechanism of action (usually three
samples).

RNA-seq analysis will be performed in conjunction with the Tulane Cancer Crusaders Next
Generation Sequence Analysis Core (Tulane Cancer Center -
https://tulane.edu/som/cancer/research/core-facilities/cancer-crusaders/). Gene and
isoform expression will be determined using RSEM and differential expression will be
analyzed using EB-seq. Genes that are identified as differentially expressed between the
two groups with a False Discovery Rate (FDR) of < 0.05 will be subjected to analysis by
Ingenuity (IPA, Redwood City, CA). This analysis will group the identified genes into
specific pathways, cell types, or disease process. A similar approach will be conducted
using Gene Set Enrichment Analysis (GSEA). These experiments and GEP analysis will be
performed in conjunction with our collaborator's (Dr. Nakhle Saba) lab, given his
extensive experience in this field.

2. Protein analysis Information identified by Ingenuity or GSEA (signaling pathways,
regulatory molecules, etc…) will be verified using IHC staining on select samples.

Inclusion Criteria:

- Must understand the risks and the benefits/purpose of the study and provide signed and
dated informed consent.

- Must be 18 years at time of signing the informed consent form.

- Willing to participate in all required evaluations and procedures in the study
including the ability to swallow pills without difficulty.

- Patients must have a diagnosis of DM based upon the characteristic cutaneous findings
proposed by Sontheimer[6] and/or a skin biopsy consistent with DM.

- Patients must be candidate for systemic therapy for their DM skin disease defined by
inadequate response to aggressive sun protection along with the use of potent topical
corticosteroids and/or immunomodulators.

- Patients with a diagnosis of dermatomyositis on steroid-sparing agent and/or systemic
steroids (maximum dose of prednisone 1mg/Kg) and still having cutaneous disease
activity of at least 5 on the CDASI scale.

- If on immunosuppressive treatments and/or steroids, patients must be on stable doses
for at least 4 weeks (28 days).

- Patients must undergo age appropriate cancer screening.

- Females of childbearing potential (FCBP) must have a negative pregnancy test at
screening (day 0 of the study and every month throughout the study). While on
investigational product and for at least 28 days after taking the last dose of
investigational product.

Exclusion Criteria:

- Increasing or changing dose of topical therapy within 14 days of study day 0
(including but not limited to topical corticosteroids, tacrolimus, pimecrolimus).

- Increasing or changing systemic steroids dosing within 28 days of study day 0.

- Increasing or changing dosing for concurrent therapy agents within 28 days or 5
half-lives of the biologic agent, whichever is longer, before study day 0:
methotrexate, azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone,
leflunomide, cyclosporine, biologic agents (anti-TNFs), IVIG, rituximab.

- History of any clinically significant (as determined by the investigators) cardiac,
endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic,
immunologic, or other major uncontrolled disease.

- Any condition, including the presence of laboratory abnormalities, which places the
patient at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study.

- Pregnant or breastfeeding.

- Untreated Latent Mycobacterium tuberculosis infection or active tuberculosis infection
as indicated by a positive Purified Protein Derivative (PPD) skin test or T-spot.

- Any condition, including the presence of laboratory abnormalities that places the
patient at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study.

- Patients with acute dermatomyositis onset and rapid progression of muscle disease or
significant systemic involvement including pulmonary diseases associated with DM.

- Prior major surgery or major life-threatening medical illness within 2 weeks.

- Inflammatory bowel disease, malabsorption or any other gastrointestinal motility
disorders that limit the absorption of the study drug.

- Active hepatitis B or C infection with detectible viral nucleic acid in the blood or
known Human Immunodeficiency Virus (HIV) positivity.

- Prior history of suicide attempt at any time in the patient's lifetime prior to
screening or randomization, or major psychiatric illness requiring hospitalization
within the last 3 years.

- Active substance abuse or a history of substance abuse within 6 months prior to
screening.

- Use of any investigational drug within 4 weeks prior to randomization, or 5
pharmacokinetic/pharmacodynamic half-lives, if known (whichever is longer).

- Prior treatment with apremilast.

- Any severe systemic illness requiring IV antibiotics within the two weeks prior to
initiation of the study drug.

- Malignancy or history of malignancy within the past four years, except for:

- treated [ie, cured] basal cell or squamous cell in situ skin carcinomas;

- treated [ie, cured] cervical intraepithelial neoplasia (CIN) or carcinoma in situ
of cervix with no evidence of recurrence within the previous 4 years.