Evaluating Safety & Efficacy of Apremilast in the Treatment of Cutaneous Disease in Patients With Recalcitrant Dermatomyositis
Evaluating Safety & Efficacy of Apremilast in the Treatment of Cutaneous Disease in Patients With Recalcitrant Dermatomyositis
With limited treatment options available for dermatomyositis, the investigators hypothesize
 that apremilast, a phosphodiesterase-4 (PDE-4) inhibitor, is a safe and efficacious add-on
 treatment in patients with refractory cutaneous dermatomyositis.

 The study will investigate the efficacy, safety and toxicity of apremilast given at 30 mg
 twice daily to patients with refractory 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, creatine kinase, aldolase). Treatment will be discontinued at disease
 progression or unacceptable adverse events. Disease progression is defined as 4 points
 increase in the cutaneous dermatomyositis disease area and severity index (CDASI) score,
 worsening of muscle disease by manual muscle testing (MMT-8) score and 5 points increase in
 dermatomyositis life quality index (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.
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.