Mac Johnson

Use of hyperpolarized helium-3 MRI to assess response to ivacaftor treatment in patients with cystic fibrosis

BACKGROUND This pilot study evaluated the effect of short- and long-term ivacaftor treatment on hyperpolarized 3He-magnetic resonance imaging (MRI)-defined ventilation defects in patients with cystic fibrosis aged ≥12years with a G551D-CFTR mutation. METHODS Part A (single-blind) comprised 4weeks of ivacaftor treatment; Part B (open-label) comprised 48weeks of treatment. The primary outcome was change from baseline in total ventilation defect (TVD; total defect volume:total lung volume ratio). RESULTS Mean change in TVD ranged from -8.2% (p=0.0547) to -12.8% (p=0.0078) in Part A (n=8) and -6.3% (p=0.1953) to -9.0% (p=0.0547) in Part B (n=8) as assessed by human reader and computer algorithm, respectively. CONCLUSIONS TVD responded to ivacaftor therapy. 3He-MRI provides an individual quantification of disease burden that may be able to detect aspects of the disease missed by population-based spirometry metrics. Assessments by human reader and computer algorithm exhibit similar trends, but the latter appears more sensitive. www.clinicaltrials.gov identifier: NCT01161537.

Spatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model

Cuprizone administration in mice provides a reproducible model of demyelination and spontaneous remyelination, and has been useful in understanding important aspects of human disease, including multiple sclerosis. In this study, we apply high spatial resolution quantitative MRI techniques to establish the spatio-temporal patterns of acute demyelination in C57BL/6 mice after 6 weeks of cuprizone administration, and subsequent remyelination after 6 weeks of post-cuprizone recovery. MRI measurements were complemented with Black Gold II stain for myelin and immunohistochemical stains for associated tissue changes. Gene expression was evaluated using the Allen Gene Expression Atlas. Twenty-five C57BL/6 male mice were split into control and cuprizone groups; MRI data were obtained at baseline, after 6 weeks of cuprizone, and 6 weeks post-cuprizone. High-resolution (100μm isotropic) whole-brain coverage magnetization transfer ratio (MTR) parametric maps demonstrated concurrent caudal-to-rostral and medial-to-lateral gradients of MTR decrease within corpus callosum (CC) that correlated well with demyelination assessed histologically. Our results show that demyelination was not limited to the midsagittal line of the corpus callosum, and also that opposing gradients of demyelination occur in the lateral and medial CC. T2-weighted MRI gray/white matter contrast was strong at baseline, weak after 6 weeks of cuprizone treatment, and returned to a limited extent after recovery. MTR decreases during demyelination were observed throughout the brain, most clearly in callosal white matter. Myelin damage and repair appear to be influenced by proximity to oligodendrocyte progenitor cell populations and exhibit an inverse correlation with myelin basic protein gene expression. These findings suggest that susceptibility to injury and ability to repair vary across the brain, and whole-brain analysis is necessary to accurately characterize this model. Whole-brain parametric mapping across time is essential for gaining a real understanding of disease processes in-vivo. MTR increases in healthy mice throughout adolescence and adulthood were observed, illustrating the need for appropriate age-matched controls. Elucidating the unique and site-specific demyelination in the cuprizone model may offer new insights into in mechanisms of both damage and repair in human demyelinating diseases.

Hyperpolarized helium-3 magnetic resonance lung imaging of non-sedated infants and young children: a proof-of-concept study

PURPOSE To develop and evaluate a protocol for hyperpolarized helium-3 (HHe) ventilation magnetic resonance imaging (MRI) of the lungs of non-sedated infants and children. MATERIALS AND METHODS HHe ventilation MRI was performed on seven children ≤4years old. Contiguous 2D-spiral helium-3 images were acquired sequentially with a scan time of ≤0.2s/slice. RESULTS Motion-artifact-free, high signal-to-noise ratio (SNR) images of lung ventilation were obtained. Gas was homogeneously distributed in healthy individuals; focal ventilation defects were found in patients with respiratory diseases. CONCLUSION HHe ventilation MRI can aid assessment of pediatric lung disease even at a young age.

WS3.2 The effect of ivacaftor treatment on lung ventilation defects, as measured by hyperpolarized helium-3 MRI, on patients with cystic fibrosis and a G551D-CFTR mutation

WS3.1 The effect of ivacaftor on the rate of lung function decline in CF patients with a G551D-CFTR mutation G.S. Sawicki1, E. McKone2, D.J. Pasta3, J. Wagener4, C. Johnson4, M.W. Konstan5. 1Boston Children’s Hospital, Boston, United States; 2St. Vincent’s University Hospital, Dublin, Ireland; 3ICON Late Phase and Outcomes Research, San Francisco, United States; 4Vertex Pharmaceuticals Incorporated, Boston, United States; 5Case Western Reserve University School of Medicine Rainbow Babies and Children’s Hospital, Cleveland, United States

Abstract 3717: Defining optimal dose schedules for ATR inhibitors in combination with DNA damaging drugs: Informing clinical studies of VX-970, the first-in-class ATR inhibitor

Proficient repair of DNA damage is a cause of the poor response many patients experience when treated with commonly used DNA-damaging drugs such as cisplatin, carboplatin and gemcitabine. The protein kinase ataxia telangiectasia mutated and Rad3 related (ATR) is recruited to DNA damage lesions caused by such drugs during the S and G2 phase of cell cycle, where it coordinates a series of responses including checkpoint activation and DNA repair by homologous recombination. Inhibition of ATR potentiates the cytotoxic activity of DNA damaging drugs in many cancer cells. In stark contrast, non-cancer cells survive inhibition of ATR with just transient growth arrest. Cancer cells carrying common defects in a compensatory repair pathway mediated by the kinase ataxia telangiectasia mutated (ATM) and its principle substrate, p53, are especially sensitive to ATR inhibition. Two ATR inhibitors are in clinical development in combination with DNA damaging drugs, however a comprehensive assessment of dose schedule considerations has not been reported. In pre-clinical models, the efficacy of an ATR inhibitor in combination with multiple DNA damaging drugs was shown to be dependent on dose schedule. In vitro, transient exposure of cancer cells to an ATR inhibitor (2 hours) was highly effective when added after the DNA damaging drug. Maximum activity was observed when addition of the ATR inhibitor was timed to coincide with peak accumulation of cells in S-phase and concomitant activation of ATR (P-Chk1), following treatment with the DNA damaging drug. In mouse xenograft models, strong synergistic activity was achieved from just a single dose of the ATR inhibitor given once per cycle of the DNA damaging drug. Optimal efficacy was achieved by administering the ATR inhibitor 12-24 hours after the DNA damaging drug. Dosing the ATR inhibitor prior to, or greater than 48 hours after, the DNA damaging drug provided limited benefit. On this schedule, addition of the ATR inhibitor had minimal impact on the tolerability profile of the DNA damaging drug. VX-970, the first-in-class ATR inhibitor, is being assessed as monotherapy and in combination with gemcitabine, cisplatin and carboplatin in Ph1/2 clinical studies. Based on pre-clinical data, VX-970 is being dosed approximately 24 hours after the DNA damaging drug. Preliminary tumor biomarker data from three patients showed high P-Chk1 24 hours after treatment with carboplatin, which is inhibited by VX-970. These data suggest the importance of dose scheduling on the efficacy of ATR inhibitors and DNA damaging drug combinations and inform the design of ongoing clinical studies. Citation Format: John Pollard, Phil Reaper, Adele Peek, Stuart Hughes, Scott Gladwell, Julie Jones, Peter Chiu, Mark Wood, Crystal Tolman, Mac Johnson, Peter Littlewood, Marina Penney, Katherine McDermott, Brian Hare, Scott Z. Fields, Mohammed Asmal, Brent O’Carrigan, Timothy A. Yap. Defining optimal dose schedules for ATR inhibitors in combination with DNA damaging drugs: Informing clinical studies of VX-970, the first-in-class ATR inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3717.

Abstract 1644: VX-970, the first-in-class inhibitor of the DNA damage repair enzyme ATR

Proficient repair of DNA damage is important for cancer cell survival and is a leading cause for the poor response many patients experience when treated with DNA-damaging drugs or ionizing radiation. The protein kinase ataxia telangiectasia mutated and Rad3 related (ATR) regulates an important DNA damage response pathway that is most commonly activated by replication stress (RS). RS arises during S-phase when the cell9s DNA replication machinery attempts to copy through an unresolved damage lesion. Such events are common after cells are treated with DNA-damaging agents. Unresolved RS often leads to double strand breaks, which in turn may cause DNA mutations, chromosomal rearrangements or cell death. Pre-clinical data suggests a reliance on ATR for survival is a common feature in cancer cells. This may occur when there are defects in other DNA damage repair pathways or high levels of background RS. VX-970 is the first potent (Ki VX-970 is currently in Phase 1 clinical studies as monotherapy and in combination with gemcitabine, cisplatin and carboplatin. Note: This abstract was not presented at the meeting. Citation Format: John Pollard, Philip Reaper, Julie Jones, Christopher Barnes, Scott Gladwell, Stuart Hughes, Adele Peak, Hakim Djeha, Amy Hall, David Newsome, Yuxin Wang, Diane Boucher, Brenda Eustace, Yong Gu, Brian Hare, Mac Johnson, Sean Milton, Cheryl Murphy, Darin Takemoto, Crystal Tolman, Mark Wood, Brinley Furey, Marina Penney, Howard Li, Christopher Defranco, Mohammed Asmal, Scott Fields. VX-970, the first-in-class inhibitor of the DNA damage repair enzyme ATR. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1644. doi:10.1158/1538-7445.AM2015-1644