Evaluating Safety & Efficacy of Apremilast in the Treatment of Cutaneous Disease in Patients With Recalcitrant Dermatomyositis
Condition: Dermatomyositis, Adult Type
MeSH terms: Dermatomyositis
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Apremilast 30mg
Intervention type(s): Drug
Intervention description(s): Patients with refractory cutaneous dermatomyositis will be started on apremilast 30 mg twice a day in addition to a stable dose of their treatment regimen (including steroids and steroid sparing agents).
Intervention MeSH terms: Apremilast
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: dermatomyositis; apremilast; recalcitrant cutaneous disease