Kristine Rose

Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

A human antibody to interleukin-17A is well tolerated and may be effective in the treatment of psoriasis, rheumatoid arthritis, and noninfectious uveitis. Stopping Inflammation in Its Tracks Inflammation—characterized by redness, swelling, and pain and derived from the Latin word inflammare (to set on fire)—is the body’s principal defense against infection and injury. Once the infection has been squelched by the immune system, the inflammatory response is usually switched off. Sometimes, however, immune cells activated during inflammation elude the “off switch,” resulting in tissue destruction and various diseases—including cancer, rheumatoid arthritis, and skin disorders such as psoriasis. Cytokines that activate immune cells are key drivers of inflammation. To address whether blocking one of these cytokines, interleukin-17A (IL-17A), might be a useful therapeutic strategy for treating inflammatory diseases, Hueber and colleagues used a human monoclonal antibody (AIN457) against IL-17A to treat patients in three small proof-of-concept trials for psoriasis, rheumatoid arthritis, and uveitis (eye inflammation). Their results demonstrate that IL-17A participates in these diseases and that the antibody against this cytokine may be an effective therapeutic agent. The proinflammatory cytokine IL-17A is produced by T helper 17 (TH17) cells and affects many different cell types including macrophages and dendritic cells of the immune system, as well as epithelial, endothelial, and skin cells. IL-17A has been implicated in psoriasis, rheumatoid arthritis, and uveitis, but its exact role is unclear. The etiologies and symptoms of these three diseases are very different. TH17 and TH1 cells have been implicated in both psoriasis (characterized by excessive turnover of skin cells resulting in scaly skin patches) and uveitis (intraocular inflammation that can lead to vision loss). In contrast, in the autoimmune disease rheumatoid arthritis, autoreactive T and B cells together with autoantibodies promote prolonged inflammation, ultimately resulting in the destruction of cartilage and bone. In their three proof-of-concept trials, Hueber and co-workers treated a total of 60 patients with the human monoclonal antibody AIN457 at different doses and observed no major adverse effects. Although the trials were small and the results were preliminary, improvements were seen in all three disease groups. Psoriasis patients receiving AIN457 showed reduced scaly skin patches, decreased production of inflammatory cytokines, and a reduction in T cells infiltrating the skin lesions compared with placebo-treated patients. After receiving infusions of AIN457, rheumatoid arthritis patients exhibited reduced inflammation of the synovial joints as shown by improvements in three different clinical scores compared with placebo-treated patients. Meanwhile, patients with uveitis treated with AIN457 showed improved visual acuity, reduced ocular inflammation, or a reduced need for steroid drugs after 8 weeks. These encouraging results warrant larger clinical trials to assess further the safety and efficacy of AIN457 for treating psoriasis, rheumatoid arthritis, and uveitis and perhaps other inflammatory diseases in which IL-17A has been implicated. Interleukin-17A (IL-17A) is elaborated by the T helper 17 (TH17) subset of TH cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A–producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.

A Phase I, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Smoothened Inhibitor Sonidegib (LDE225) in Patients with Advanced Solid Tumors

Purpose: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors. Experimental Design: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. Dose escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor biopsies were assessed. Results: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ≥ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear pharmacokinetics at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with medulloblastoma and BCC were associated with evidence of hedgehog pathway activation. Conclusions: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed medulloblastoma, both of which are strongly associated with activated hedgehog pathway, as determined by gene expression. Clin Cancer Res; 20(7); 1900–9. ©2014 AACR.

Topical Treatment of Basal Cell Carcinomas in Nevoid Basal Cell Carcinoma Syndrome with a Smoothened Inhibitor

Basal cell carcinoma (BCC) is a distinctive manifestation in nevoid basal cell carcinoma syndrome (NBCCS) patients. Both inherited and acquired mutations of patched 1 (PTCH1), a tumor-suppressor gene controlling the activity of Smoothened (SMO), are the primary cause of the constitutive activation of the Hedgehog (HH) pathway, leading to the emergence of BCCs in NBCCS. LDE225, a distinct, selective antagonist of SMO, showed potent inhibition of basaloid tumor nest formation and mediated regression of preformed basaloid tumors in organ cultures of skin derived from Ptch1 heterozygous knockout mice. In a double-blind, randomized, vehicle-controlled, intraindividual study, a total of 8 NBCCS patients presenting 27 BCCs were treated twice daily with 0.75% LDE225 cream or vehicle for 4 weeks. Application of 0.75% LDE225 cream was well tolerated and showed no skin irritation. Of 13 LDE225-treated BCCs, 3 showed a complete, 9 a partial, and only 1 no clinical response. Except for one partial response, the vehicle produced no clinical response in any of the 14 treated BCCs. Treatment with 0.75% LDE225 cream in NBCCS patients was very well tolerated and caused BCC regression, thus potentially offering an attractive therapeutic alternative to currently available therapies for this indication.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub.

Kidney slices of human and rat to characterize cisplatin-induced injury on cellular pathways and morphology

Kidney slices represent an in vitro model that has the cellular complexity of in vivo tissue to provide insights into mechanisms of organ injury, as shown in this study with the model nephrotoxicant cisplatin. Cell pathways altered by cisplatin exposure are assessed by gene expression analysis, cell function, and morphology in human and rat kidney slices in comparison to rat kidney from an in vivo study. The acute nephrosis of the tubular epithelium induced by cisplatin in vivo was reproduced in both human and rat kidney slices, while the glomerulus appeared resistant even at high concentrations. Kidney gene expression changes of in vivo and in vitro samples were indicative of transcription, DNA damage, cell cycle, proliferation, and apoptosis that are in agreement with the mechanism of cisplatin causing DNA damage, growth arrest, and apoptosis; while genes indicative of protein damage, the disruption of transport and calcium homeostasis, cellular metabolism, and oxidative stress are pathways linked with cisplatin binding to various cellular proteins and macromolecules. Both concentration and time-dependent gene expression changes evident in the in vitro model preceded a change in tissue morphology. Functional assays confirming cell dysfunction and increased apoptosis revealed the rat kidney to be more sensitive to the effects of cisplatin than human kidney as demonstrated by significant decreases in slice ATP and GSH levels, significant increases in caspase 9 and 3 activity, p53 protein levels, and increased DNA laddering. The regional markers of proximal and distal tubular injury, alpha- and pi-glutathione S-transferases, were shown for the human kidney slices to be significantly increased by cisplatin. In this study, cisplatin-induced nephrotoxicity was demonstrated morphologically in rat and human kidney slices, and the associated gene expression and functional changes characterized the cellular pathways involved.

A Five-Gene Hedgehog Signature Developed as a Patient Preselection Tool for Hedgehog Inhibitor Therapy in Medulloblastoma

Purpose: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway–activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway–activated medulloblastoma. Experimental Design: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed. Results: Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded. Conclusions: This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment. Clin Cancer Res; 21(3); 585–93. ©2014 AACR.

Abstract 4818: The predictive value of a 5-gene signature as a patient pre-selection tool in medulloblastoma for Hedgehog pathway inhibitor therapy

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Medulloblastoma (MB), an invasive primitive neuroectodermal tumor of the posterior fossa, is the most common brain tumor in children, comprising ∼20% of childhood and <2% of adult brain tumors. Current standard of care treatment, surgery followed by craniospinal radiation and chemotherapy, can lead to significant long term toxicities, especially in very young patients. At the time of relapse, no standard salvage therapy exists. Therefore, targeted therapies are needed. Several studies have used gene expression profiling to identify distinct molecular subgroups of MB, including one characterized by activated Hedgehog (Hh) signaling. Using available gene expression data, a 5-gene Hh signature that can be assayed in formalin-fixed paraffin-embedded (FFPE) samples by standard RT-PCR was identified. Two sets of matched fresh frozen and FFPE MB specimens were used; one for development of the 5-gene signature and one for its independent validation. Hh activation status was determined in fresh frozen samples by gene expression profiling using the GeneChip human genome U133 Plus 2.0 array (Affymetrix, Santa Clara, CA) and in FFPE samples by RT-PCR analysis. The 5-gene Hh signature was selected from a larger panel of 73 genes that were associated with the Hh subgroup classification, as determined by standard Affymetrix gene expression profiling. Eighteen of these genes shown to be differentially expressed in FFPE were chosen for the RT-PCR gene card that formed the basis of the Elastic Net model building exercise. Based on the expression levels of the 5-gene signature, a predictive model was used to compute a propensity score (0-100%) representative of the Hh activation status of each tumor sample. The median propensity scores for the 17 non-Hh-activated tumors was 0.7% (range: 0.1-3.0%) compared to 87.9% (range: 69.1-97.6%) in the eight Hh-activated tumors. Hh activation status of 25 independent MB samples defined by the 5-gene signature and assayed by RT-PCR were in 100% agreement with the Hh activation status determined by gene expression profiling. In order to determine the predictive value of this assay as a tool to identify patients who might benefit from treatment with a Hh pathway inhibitor, MB samples from patients (n=13) enrolled in recent phase I trials of the Smoothened inhibitor LDE225 were analyzed and correlated with the respective tumor responses. Using the 5-gene signature, all patients (n=4) who responded to LDE225 treatment (PR or CR) were found to have Hh-pathway activated tumors, whereas all patients who did not respond (n=9) were found to have Hh non-activated tumors. These results suggest an association between Hh activation status determined by the 5-gene Hh signature and tumor response to LDE225 treatment. Data from an ongoing phase I/II trial in pediatric patients will enable determination of the predictive value of this patient pre-selection assay. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4818. doi:1538-7445.AM2012-4818