Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials.

BACKGROUND: There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. METHODS: This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16-75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5-9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH). FINDINGS: Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 [26%] of 319 patients in UC1 and 114 [34%] of 341 patients in UC2) than in the placebo group (seven [5%] of 154 patients in UC1 and seven [4%] of 174 patients; p<0·0001; adjusted treatment difference 21·6% [95% CI 15·8-27·4] for UC1 and 29·0% [23·2-34·7] for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg 63 [42%] of 148; 30 mg 80 [52%] of 154) than those receiving placebo (18 [12%] of 149; p<0·0001; adjusted treatment difference 30·7% [21·7-39·8] for upadacitinib 15 mg vs placebo and 39·0% [29·7-48·2] for upadacitinib 30 mg vs placebo). The most commonly reported adverse events in UC1 were nasopharyngitis (15 [5%] of 319 in the upadacitinib 45 mg group vs six [4%] of 155 in the placebo group), creatine phosphokinase elevation (15 [4%] vs three [2%]), and acne (15 [5%] vs one [1%]). In UC2, the most frequently reported adverse event was acne (24 [7%] of 344 in the upadacitinib 45 mg group vs three [2%] of 177 in the placebo group). In both induction studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the upadacitinib 45 mg group than in the placebo group (serious adverse events eight [3%] vs nine (6%) in UC1 and 11 [3%] vs eight [5%] in UC2; adverse events leading to discontinuation six [2%] vs 14 [9%] in UC1 and six [2%] vs nine [5%] in UC2). In UC3, the most frequently reported adverse events (≥5%) were worsening of ulcerative colitis (19 [13%] of 148 in the upadacitinib 15 mg group vs 11 [7%] of 154 in the upadacitinib 30 mg group vs 45 [30%] of 149 in the placebo group), nasopharyngitis (18 [12%] vs 22 [14%] vs 15 [10%]), creatine phosphokinase elevation (nine [6%] vs 13 [8%] vs three [2%]), arthralgia (nine [6%] vs five [3%] vs 15 [10%]), and upper respiratory tract infection (seven [5%] vs nine [6%] vs six [4%]). The proportion of serious adverse events (ten [7%] vs nine [6%] vs 19 [13%]) and adverse events leading to discontinuation (six [4%] vs ten [6%] vs 17 [11%]) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths. INTERPRETATION: Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis. FUNDING: AbbVie.

T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells.

Several gene-deficiency models promote the development of innate CD8(+) T cells that have diverse T cell antigen receptors (TCRs) but have a memory phenotype and rapidly produce cytokines. We demonstrate here that similar cells developed in mice deficient in the transcription factor KLF2. However, this was not due to intrinsic deficiency in KLF2 but instead was due to interleukin 4 (IL-4) produced by an expanded population of T cells expressing the transcription factor PLZF. The development of innate CD8(+) T cells in mice deficient in the tyrosine kinase Itk and coactivator CBP was also attributable to this IL-4-dependent mechanism. Finally, we show that the same mechanism drove the differentiation of innate CD8(+) T cells in BALB/c mice. Our findings identify a previously unknown mechanism of regulation of CD8(+) T cells via the production of IL-4 by PLZF(+) T cells.

Krüppel-like factor 2 regulates trafficking and homeostasis of gammadelta T cells.

gammadelta T cells are generated in the thymus and traffic to secondary lymphoid organs and epithelial surfaces, where they regulate immune responses. alphabeta T cells require sphingosine 1-phosphate receptor type 1 (S1P(1)) and CD62L for thymic emigration and circulation through secondary lymphoid organs. Both of these genes are regulated by the transcription factor Krüppel-like factor 2 (KLF2) in conventional alphabeta T cells. It is unclear if gammadelta T cells use similar mechanisms. In this study, we show that thymic gammadelta T cells express S1P(1) and that it is regulated by KLF2. Furthermore, KLF2 and S1P(1)-deficient gammadelta T cells accumulate in the thymus and fail to populate the secondary lymphoid organs or gut, in contrast to the expectation from published work. Interestingly, KLF2 but not S1P(1) deficiency led to the expansion of a usually rare population of CD4(+) promyelocytic leukemia zinc finger(+) "gammadelta NKT" cells. Thus, KLF2 is critically important for the homeostasis and trafficking of gammadelta T cells.

Growth factor receptors as regulators of hematopoiesis.

Nearly 15 years have elapsed since the US Food and Drug Administration last approved a major new hematopoietic cytokine. Promiscuous binding to multiple receptors, or to receptors expressed by multiple tissues, reduces growth factor specificity and promotes side effects. Here we show that hematopoiesis can be differentially regulated using receptors rather than ligands. Conditional derivatives of both fibroblast growth factor receptor-1 (F36VFGFR1) and the thrombopoietin receptor (F36VMpl) induced a sustained expansion of mouse marrow cells ex vivo, and erythroid cells in vivo. Only F36VFGFR1 could support the ex vivo expansion of short-term repopulating hematopoietic stem cells (HSCs), the ex vivo survival of long-term repopulating HSCs, and the prolonged in vivo expansion of granulocytes, monocytes, and platelets. Only F36VMpl induced a response sufficiently rapid to accelerate recovery from radiation-induced anemia. These results establish receptors as a new class of hematopoietic regulators possessing activities unobtainable with growth factors.

Kruppel-like factor 2 regulates thymocyte and T-cell migration.

Mammalian Kruppel-like transcription factors are implicated in regulating terminal differentiation of several tissue types. Deficiency in Kruppel-like factor (KLF) 2 (also known as LKLF) leads to a massive loss of the peripheral T-cell pool, suggesting KLF2 regulates T-cell quiescence and survival. Here we show, however, that KLF2 is essential for T-cell trafficking. KLF2-deficient (Klf2-/-) thymocytes show impaired expression of several receptors required for thymocyte emigration and peripheral trafficking, including the sphingosine-1-phosphate (S1P) receptor S1P1, CD62L and beta7 integrin. Furthermore, KLF2 both binds and transactivates the promoter for S1P1--a receptor that is critical for thymocyte egress and recirculation through peripheral lymphoid organs. Our findings suggest that KLF2 serves to license mature T cells for trafficking from the thymus and recirculation through secondary lymphoid tissues.

In vivo selection of genetically modified erythroid cells using a jak2-based cell growth switch.

Cell-based therapies have potential widespread applications in clinical medicine, and methods for controlling the fate of transplanted cells are needed. We have previously described a means for directing the growth of genetically modified cells in vivo using a derivative of the thrombopoietin receptor, mpl, that is reversibly activated by a drug called a chemical inducer of dimerization (CID). Since Jak2 participates in signaling from a number of different cytokine receptors (including mpl), we tested whether direct activation of the JH1 domain of Jak2 would broaden the repertoire of hematopoietic lineages responsive to the CID. While the engineered Jak2 induced a significant rise in genetically modified red cells, as we have observed previously with mpl, it lacked mpl's ability to expand genetically modified platelets and failed to expand genetically modified granulocytes, B cells, or T cells. These findings identify a signaling molecule other than mpl that can function as a cell growth switch in vivo and demonstrate that signaling molecules used for in vivo selection need not be confined to receptors. The erythroid-restricted growth response suggests that CID-activated Jak2 may be well suited to gene therapy applications in sickle cell anemia or beta-thalassemia.