Effect of Calcipotriene/Betamethasone Dipropionate 0.005%/0.064% Foam on Target Lesions in Plaque Psoriasis: A Post-Hoc Analysis

Objective: Investigate the effect of fixed-combination calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) foam on target lesion severity in plaque psoriasis. Design: Post-hoc analysis was conducted on data from a Phase 3, randomized, double-blind, multicenter clinical study of Cal/BD foam in the treatment of psoriasis vulgaris for 4 weeks (PSO-FAST; NCT01866163). Participants: In PSO-FAST, 426 patients (≥18 years) with psoriasis vulgaris (≥mild severity) were randomized 3:1 to Cal/BD foam (n=323) or vehicle foam (n=103), applied once daily. Measurements: Assessments included (1) target lesion severity (redness, scaliness, and thickness) at baseline and weeks 1, 2, and 4; and (2) the proportion of patients with ≥50% reduction in total sign score (TSS-50) from baseline at weeks 1, 2, and 4. Results: A greater proportion of patients achieved considerable improvement (a score of 0 or 1) in the severity of target lesions after 4 weeks of treatment with Cal/BD foam vs vehicle foam at week 4 (redness: 76.2% vs 21.4%; P<.001; scaliness: 91.3% vs 61.2%; P<.001; and thickness: 83.3% vs 35.0%; P<.001, respectively). Rapid onset of efficacy was observed as early as week 1. Significantly more patients also achieved TSS-50 at week 4 with Cal/BD foam vs vehicle foam for their target lesions regardless of treatment area, including the elbows and knees (P<.05 for all). Conclusions: Significant improvements in target lesion severity were achieved with up to 4 weeks of treatment with once-daily Cal/BD foam for adults with plaque psoriasis versus vehicle foam, with rapid onset of efficacy observed at week 1. J Drugs Dermatol. 2020;19(2)121-126. doi:10.36849/JDD.2020.4750

53BP1 ablation rescues genomic instability in mice expressing 'RING-less' BRCA1.

BRCA1 mutations strongly predispose affected individuals to breast and ovarian cancer, but the mechanism by which BRCA1 acts as a tumor suppressor is not fully understood. Homozygous deletion of exon 2 of the mouse Brca1 gene normally causes embryonic lethality, but we show that exon 2-deleted alleles of Brca1 are expressed as a mutant isoform that lacks the N-terminal RING domain. This "RING-less" BRCA1 protein is stable and efficiently recruited to the sites of DNA damage. Surprisingly, robust RAD51 foci form in cells expressing RING-less BRCA1 in response to DNA damage, but the cells nonetheless display the substantial genomic instability. Genomic instability can be rescued by the deletion of Trp53bp1, which encodes the DNA damage response factor 53BP1, and mice expressing RING-less BRCA1 do not show an increased susceptibility to tumors in the absence of 53BP1. Genomic instability in cells expressing RING-less BRCA1 correlates with the loss of BARD1 and a defect in restart of replication forks after hydroxyurea treatment, suggesting a role of BRCA1-BARD1 in genomic integrity that is independent of RAD51 loading.

Male fertility defect associated with disrupted BRCA1-PALB2 interaction in mice.

PALB2 links BRCA1 and BRCA2 in homologous recombinational repair of DNA double strand breaks (DSBs). Mono-allelic mutations in PALB2 increase the risk of breast, pancreatic, and other cancers, and biallelic mutations cause Fanconi anemia (FA). Like Brca1 and Brca2, systemic knock-out of Palb2 in mice results in embryonic lethality. In this study, we generated a hypomorphic Palb2 allele expressing a mutant PALB2 protein unable to bind BRCA1. Consistent with an FA-like phenotype, cells from the mutant mice showed hypersensitivity and chromosomal breakage when treated with mitomycin C, a DNA interstrand crosslinker. Moreover, mutant males showed reduced fertility due to impaired meiosis and increased apoptosis in germ cells. Interestingly, mutant meiocytes showed a significant defect in sex chromosome synapsis, which likely contributed to the germ cell loss and fertility defect. Our results underscore the in vivo importance of the PALB2-BRCA1 complex formation in DSB repair and male meiosis.

Qualitative concept elicitation and cognitive debriefing interviews of symptoms, impacts and selected customized PROMIS® Short Forms: a study in patients with axial spondyloarthritis.

BACKGROUND: Sleep disturbance, pain, and fatigue are key symptoms/impacts of axial spondyloarthritis (axSpA). Three customized Patient-Reported Outcomes Measurement Information System (PROMIS®) Short Forms (Sleep Disturbance, Pain Interference, and Fatigue) have been proposed for use in axSpA to assess these key disease concepts. This study was designed to further understand the patient experience of axSpA and evaluate the content validity of the three customized PROMIS® Short Forms to support their use in axSpA clinical trials. METHODS: Non-interventional, cross-sectional, qualitative (concept elicitation [CE] and cognitive debriefing [CD]) study. Participants took part in 90-min telephone interviews. The CE section used open-ended questions to elicit information about axSpA symptoms and impacts. The CD section involved a 'think-aloud' exercise where participants read out each instruction, item, and response option for the customized PROMIS® Short Forms and shared their feedback. Participants also discussed the relevance of the items, response options and recall period. Verbatim interview transcripts were subject to thematic and content analysis. RESULTS: In total, there were 28 participants (non-radiographic axSpA, n = 12; ankylosing spondylitis, n = 16), from the US (n = 20) and Germany (n = 8). Mean age was 52.8 years, and 57% were male; mean time since diagnosis was 9.5 years. The CE section identified 12 distinct symptoms that characterized axSpA: pain, sleep problems, fatigue/tiredness, stiffness, swelling, vision/eye issues, restricted body movements, headache/migraine, spasms, change in posture/stature, balance/coordination problems, and numbness. Pain, sleep problems, and fatigue/tiredness were experienced by ≥ 90% of participants, occurring simultaneously and exacerbating one another. Participants reported axSpA impacted their lives across six domains of health-related quality of life (HRQoL): physical functioning (100%), emotional wellbeing (89%), work/volunteering (79%), social functioning (75%), activities of daily living (61%) and cognitive functioning (54%). Impacts were most frequently associated with pain, stiffness, and fatigue. CD showed the PROMIS® instruments were conceptually comprehensive and well understood, with all items relevant to ≥ 50% of participants. CONCLUSIONS: Pain, sleep problems and fatigue are pivotal symptoms of axSpA and associated with HRQoL impacts. These results were used to update a conceptual model of axSpA which was originally developed based on a targeted literature review. Interpretability and content validity of the customized PROMIS® Short Forms were confirmed, with each deemed to adequately assess key impacts associated with axSpA, making them suitable for use in axSpA clinical trials.

Efficacy of Fixed-combination Calcipotriene 0.005% and Betamethasone Dipropionate 0.064% Foam for Scalp Plaque Psoriasis: Additional Analysis of a Phase II, Randomized Clinical Study.

BACKGROUND: There are a variety of treatment options currently available for plaque psoriasis affecting the scalp, yet scalp psoriasis remains one of the most frustrating and difficult-to-manage forms of the disease. OBJECTIVE: We investigated the efficacy of fixed-combination calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) foam for the treatment of scalp psoriasis. METHODS: Additional (including post-hoc) analysis was conducted on data from a Phase II, randomized, double-blind, multicenter study of Cal/BD foam for the treatment of psoriasis vulgaris (NCT01536938). A total of 302 patients, ages 18 years or older, with psoriasis vulgaris of at least mild severity (scalp involvement of at least 10%) were included; 100, 101, and 101 patients were randomized to once-daily Cal/BD foam, Cal foam, or BD foam, respectively. Assessments included a severity score for lesion redness, scaliness, and plaque thickness, modified Psoriasis Area and Severity Index (mPASI) score, proportion of patients with reduction of 50 percent or greater in total sign score (TSS-50), and proportion of patients with at least a 75-percent reduction in mPASI score (mPASI-75). RESULTS: Patients achieved greater improvements in their scalp psoriasis with Cal/BD foam versus BD or Cal foam alone at Week 4 considering mPASI, mPASI-75, and TSS-50 outcomes. After four weeks of treatment, more patients receiving Cal/BD foam had a severity score for redness, scaliness, and thickness indicating "none" or "mild" versus BD foam or Cal foam alone. Improvements on the scalp appear to be consistent with those on the trunk and limbs. CONCLUSION: Scalp lesion severity improved considerably and rapidly with a four-week regimen of Cal/BD foam, suggesting that Cal/BD foam is an effective topical treatment option for scalp psoriasis.

Effectiveness comparison and incremental cost-per-responder analysis of calcipotriene 0.005%/betamethasone dipropionate 0.064% foam vs. halobetasol 0.01%/tazarotene 0.045% lotion for plaque psoriasis: a matching-adjusted indirect comparative analysis.

Background: The fixed-dose combination foam formulation of calcipotriene 0.005% plus betamethasone dipropionate 0.064% (Cal/BD) has demonstrated efficacy and a favorable safety profile for the treatment of plaque psoriasis. Recently, a topical lotion of the combination of halobetasol 0.01% plus tazarotene 0.045% (HP/TAZ) was approved for treating adult plaque psoriasis. Currently, no head-to-head studies have compared Cal/BD foam with HP/TAZ lotion.Objective: Compare the effectiveness and drug incremental cost per responder (ICPR) of Cal/BD foam vs. HP/TAZ lotion in moderate-to-severe plaque psoriasis.Methods: An anchor-based, matching-adjusted indirect comparison was conducted for PGA treatment success (Physician's Global Assessment of "clear" or "almost clear," [PGA 0/1] with at least a 2-point improvement) using individual patient data from 3 randomized clinical studies of Cal/BD foam and published data from 2 randomized, Phase 3 clinical studies of HP/TAZ lotion. The number needed to treat and ICPR were also calculated.Results: After reweighting of patients in the Cal/BD foam studies to match summary baseline characteristics of the HP/TAZ lotion study patients and anchoring to vehicle effect, 4 weeks of Cal/BD foam produced a significantly greater rate of treatment success than 8 weeks of HP/TAZ lotion treatment (51.4 vs. 30.7%; treatment difference = 20.7%, p < .001). The number needed to treat with Cal/BD foam was also less than HP/TAZ lotion (1.9 vs. 3.3). Using US wholesale acquisition costs and equal weekly consumption rates, the incremental cost per PGA 0/1 responder relative to vehicle for Cal/BD foam was $3,988 and was 37% lower compared with HP/TAZ lotion ($6,294).Conclusions: The indirect comparison analyses showed that Cal/BD foam was associated with a greater rate of treatment success, lower ICPR, and quicker treatment response than HP/TAZ lotion in adult patients with moderate-to-severe plaque psoriasis.

DNA repair and cell cycle checkpoint defects in a mouse model of 'BRCAness' are partially rescued by 53BP1 deletion.

'BRCAness' is a term used to describe cancer cells that behave similarly to tumors with BRCA1 or BRCA2 mutations. The BRCAness phenotype is associated with hypersensitivity to chemotherapy agents including PARP inhibitors, which are a promising class of recently-licensed anti-cancer treatments. This hypersensitivity arises because of a deficiency in the homologous recombination (HR) pathway for DNA double-strand break repair. To gain further insight into how genetic modifiers of HR contribute to the BRCAness phenotype, we created a new mouse model of BRCAness by generating mice that are deficient in BLM helicase and the Exo1 exonuclease, which are involved in the early stages of HR. We find that cells lacking BLM and Exo1 exhibit a BRCAness phenotype, with diminished HR, and hypersensitivity to PARP inhibitors. We further tested how 53BP1, an important regulator of HR, affects repair efficiency in our BRCAness model. We find that deletion of 53BP1 can relieve several of the repair deficiencies observed in cells lacking BLM and Exo1, just as it does in cells lacking BRCA1. These results substantiate the importance of BRCAness as a concept for classification of cancer cases, and further clarify the role of 53BP1 in regulation of DNA repair pathway choice in mammalian cells.

BLM helicase regulates DNA repair by counteracting RAD51 loading at DNA double-strand break sites.

The BLM gene product, BLM, is a RECQ helicase that is involved in DNA replication and repair of DNA double-strand breaks by the homologous recombination (HR) pathway. During HR, BLM has both pro- and anti-recombinogenic activities, either of which may contribute to maintenance of genomic integrity. We find that in cells expressing a mutant version of BRCA1, an essential HR factor, ablation of BLM rescues genomic integrity and cell survival in the presence of DNA double-strand breaks. Improved genomic integrity in these cells is linked to a substantial increase in the stability of RAD51 at DNA double-strand break sites and in the overall efficiency of HR. Ablation of BLM also rescues RAD51 foci and HR in cells lacking BRCA2 or XRCC2. These results indicate that the anti-recombinase activity of BLM is of general importance for normal retention of RAD51 at DNA break sites and regulation of HR.