An Open-Label, Proof of Consent Study of Vorinostat for the Treatment of Mdoerate-to-Severe Crohn s Disease and Maintenance Therapy With Ustekinumab

Inflammatory bowel disease (IBD), comprised of Crohn s disease and Ulcerative colitis, are chronic, life-long conditions characterized by relapsing inflammation of the gastrointestinal (GI) tract. Despite recent advances in IBD therapeutics, a significant number of patients with IBD continue to have significant symptoms.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency, due to a mutation in one of the 5 genes encoding the phagocyte NADPH oxidase, and inability to generate reactive oxygen species (ROS) and in turn leads to dysregulated inflammation as ROS production is required for normal innate immune function but also plays a role in regulating inflammation Almost 50% of individuals with CGD develop intestinal inflammation, ranging from mild dysmotility to severe IBD.

In prior studies, it has been demonstrated that epigenetic modifications of the genome are associated with and may contribute to the pathogenesis of various disease entities. One type of epigenetic modification involves acetylation and deacetylation of histones, mediated by histone acetyl transferases (HATs) and histone deacetylases (HDACs). Acetylation and deacetylation of histones regulate the affinity of histones for DNA, thus modulating the accessibility of transcription factors to gene promoters and enhancer sites. Of interest in this context is evidence that epigenetic modifications brought about by HDAC inhibitors (HDACi), i.e., agents that cause hyperacetylation of histones, can limit the course of gastrointestinal inflammation. One naturally occurring HDAC inhibitor, the bacterial product butyrate, has been shown to have effects on gene transcription that regulate potentially deleterious pro-inflammatory responses to microbiota in the gut environment. It has been shown that treatment of dendritic cells and macrophages with butyrate leads to down-regulation of lipopolysaccharide induced proinflammatory mediators such as nitric oxide, IL-6 and IL-12. In addition, butyrate has been shown to enhance the differentiation of intestinal Foxp3-positive T cells (T regulatory T cell (Treg) development that then modulates GI inflammation and contributes to mucosal homeostasis.

Along the same lines, another HDAC inhibitor, vorinostat, has been shown to ameliorate graftvs-host disease (GVHD) affecting the GI tract in patients undergoing allogeneic bone marrow transplantation. This anti-inflammatory effect was also attributable to increased Treg activity, suggesting that vorinostat, like butyrate, decreases inflammation by enhancing the activity of cells with the capacity to down-regulate immune responses. The effect of vorinostat on Treg cell expansion in this study was particularly notable because it suggested that Treg cell numbers can be increased by agents that have an intrinsic effect on the transcription of key Treg cell transcription factors. On this basis, treatment of patients with inflammatory and autoimmune diseases by influencing Treg cell numbers may be a more effective than alternative existing methods of inducing Treg cell expansion such as administration of purified Tregs.

In this protocol we propose a proof-of-concept clinical trial to study the safety and efficacy of vorinostat (100 mg PO BID for 36 weeks) in treating 20 individuals with moderate-to-severe CD, UC, or CGD colitis who have not been controlled by standard maintenance therapy. This will be accomplished in Phase II (12 weeks of treatment) and Phase III (36 weeks of treatment). We will assess the effectiveness of vorinostat by evaluating changes in symptom scores, endoscopic/histologic findings, and immunologic/laboratory parameters. The participant will return to the NIH Clinical Center (CC) after starting treatment on week 4, week 8, and week 24 for assessment of safety labs and testing of clinical response. On Week 12 and week 36 participants will return to the NIH CC for assessment of safety labs and testing of clinical and immunologic response.

In IBD, 10-15 % of patients require surgery within 10 years of diagnosis with about 20-30% of patients ultimately requiring surgery due to failure of medical management . Therefore, the approach to treatment must also evolve from induction control of symptoms to preventing progression of the disease with maintenance therapy. Thus, the current paradigm has moved beyond treatment of just clinical symptoms to address inflammatory activity early on in the disease process and effectively down-modulate these pathways before irreversible intestinal damage and disability occur. The treatment goal is for patients to achieve a clinical response of symptoms but also subsequent development of clinical remission with the long term goal of optimizing treatment to have patients achieve a sustained clinical remission with endoscopic mucosal healing (STRIDE Committee).

Thus, treatments that safely maintain long-term remission are essential. Treatment guidelines for CD and UC recommend maintenance therapy after remission is achieved, particularly for moderate-to-high risk patients. Potential benefits include reduction in hospitalization and surgery and improved quality of life. Long-term efficacy has been studied with azathioprine/mercaptopurine, methotrexate tumor necrosis factor (TNF) antagonists, vedolizumab. Although TNF antagonists have significantly advanced the care of CD and UC, their efficacy is limited and the development of anti-drug antibodies is associated with loss of response in maintenance therapy. In addition, potential significant side effects of maintenance treatments include bone marrow suppression, malignancy, and serious infections. Therefore, a need exists for safer agents that have demonstrated improved long-term maintenance efficacy.

The gut inflammation complicating Crohn s disease has been characterized as a T helper type 1 (Th1)/T helper type 17 (Th17) inflammatory response, with excess IL-12, IL-23 cytokine production leading to the generation of excessive IFNgamma and IL-17. In comparison, the intestinal inflammation observed in UC can be characterized as a mixed T helper 2/Th17/Th1 response with predominately excess IL-13 and IL-17 excess but IFN-gamma can also be observed albeit decreased in levels opposite to CD patients.

Intestinal inflammation observed in CGD colitis is typically chronic, relapsing, and difficult to manage. CGD colitis has some degree of association with CD and UC, as it is characterized by an increased secretion of inflammatory cytokines such as IFNgamma, IL-17 and IL-6. Glucocorticoids can be effective but often require addition of steroid-sparing agents such as purine antimetabolites, 5-aminosalicylates or other immunomodulators such as methotrexate cyclosporine, (Rosh et al. 1995), anakinra (Hahn et al. 2015), vedolizumab, and anti TNF alpha agents all with limited success. Most important, although decreased inflammatory responses can be observed with anti-TNF alpha therapy it is not without risk in these patients as TNFblockade therapy has led to life threatening infections.

Ustekinumab, a monoclonal antibody to the p40 subunit of IL-12 and IL-23, is currently FDA approved for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, moderately to severely active CD and ulcerative colitis.

Prior clinical trials have demonstrated long-term efficacy and safety profile of ustekinumab in psoriasis. Similarly, the long-term efficacy and safety of ustekinumab in CD dosing had been established in the UNITI trial studies (up to 44 week treatment) in patients who have failed TNF antagonists or other conventional therapy. These studies demonstrated significant response rates and induction of remission rates with a positive safety profile. In a phase 3 trial of IL-12 p40 monoclonal antibody in patients with moderate-to-severe UC, ustekinumab was found to be effective than placebo in achieving induction of clinical remission at 8 weeks. This effect was also observed in patients with or without previous treatment failure with other biologic agents. Studies addressing long term maintenance efficacy of ustekinumab in patients that are in remission are limited.

In a prior retrospective review of CGD patients that received ustekinumab for CGD colitis at the NIH, nine patients were summarized. Six patients were reported with a clinical response and four patients achieved clinical remission. No long-term maintenance efficacy studies have been performed.

In the present protocol (Phase IV), CD, UC, or CGD colitis patients that have achieved either a defined clinical response or are in remission with vorinostat will then be enrolled to receive long term maintenance treatment with ustekinumab. Participants will receive a weight-based IV loading dose of ustekinumab (see section 5.5) followed by administration of maintenance doses of 90 mg subcutaneously (SC) every 8 weeks with participants followed over a 2-year period.