"Stick or Twist?" Negotiating Price and Data in an Era of Conditional Approval.

BACKGROUND: Changes in the regulatory context enable faster approval of transformative medicines. They also lead to health technology assessment (HTA) agencies having to make decisions with less evidence. In response, HTA agencies have also initiated forms of conditional approval. When the evidence base for a new oncology treatment leaves substantial uncertainty, the new Cancer Drugs Fund allows the National Institute for Heath and Care Excellence to give the manufacturer two options: (1) offer a low price based on conservative assumptions and obtain immediate approval ("stick") or (2) wait until the evidence base has further matured before finalizing a potentially higher agreed price ("twist"). OBJECTIVES: The purpose of this article is to explain how, using the theoretical framework of the expected value of sample information, simulation methods can help inform a manufacturer's decisions when faced with the option to stick or twist. METHODS: We first summarize a general model to help frame the manufacturer's negotiating strategy. We then use a motivating case study, based on a hypothetical immunotherapy, to illustrate how manufacturers can use simulation methods to robustly characterize the uncertainty inherent to further data collection and incorporate this uncertainty within their decision making. RESULTS: Our approach allows us to estimate the commercial value of generating additional data (the difference between the estimated net present value of stick and twist). We test the sensitivity of the results to different assumptions via scenario analyses. CONCLUSIONS: This article shows that simulation methods can be used to help pharmaceutical managers make informed strategic decisions in contexts of uncertainty.

Human CDK18 promotes replication stress signaling and genome stability.

Cyclin-dependent kinases (CDKs) coordinate cell cycle checkpoints with DNA repair mechanisms that together maintain genome stability. However, the myriad mechanisms that can give rise to genome instability are still to be fully elucidated. Here, we identify CDK18 (PCTAIRE 3) as a novel regulator of genome stability, and show that depletion of CDK18 causes an increase in endogenous DNA damage and chromosomal abnormalities. CDK18-depleted cells accumulate in early S-phase, exhibiting retarded replication fork kinetics and reduced ATR kinase signaling in response to replication stress. Mechanistically, CDK18 interacts with RAD9, RAD17 and TOPBP1, and CDK18-deficiency results in a decrease in both RAD17 and RAD9 chromatin retention in response to replication stress. Importantly, we demonstrate that these phenotypes are rescued by exogenous CDK18 in a kinase-dependent manner. Collectively, these data reveal a rate-limiting role for CDK18 in replication stress signalling and establish it as a novel regulator of genome integrity.

Clinicopathological and prognostic significance of RECQL5 helicase expression in breast cancers.

RECQL5 is a member of the RecQ family of DNA helicases and has key roles in homologous recombination, base excision repair, replication and transcription. The clinicopathological significance of RECQL5 expression in breast cancer is unknown. In this study, we have evaluated RECQL5 mRNA expression in 1977 breast cancers, and RECQL5 protein level in 1902 breast cancers [Nottingham Tenovus series (n = 1650) and ER- cohort (n = 252)]. Expression levels were correlated to aggressive phenotypes and survival outcomes. High RECQL5 mRNA expression was significantly associated with high histological grade (P = 0.007), HER2 overexpression (P = 0.032), ER+/HER2-/high proliferation genefu subtype (P < 0.0001), integrative molecular clusters (intClust 1and 9) (P < 0.0001) and poor survival (P < 0.0001). In subgroup analysis, high RECQL5 mRNA level remains significantly associated with poor BCSS in ER+ cohort (P < 0.0001) but not in ER- cohort (P = 0.116). At the protein level, in tumours with low RAD51, high RECQL5 level was significantly associated with high histological grade (P < 0.0001), higher mitotic index (P = 0.008), dedifferentiation (P = 0.025), pleomorphism (P = 0.027) and poor survival (P = 0.003). In subgroup analysis, high RECQL5/low RAD51 remains significantly associated with poor BCSS in ER+ cohort (P = 0.010), but not in ER- cohort (P = 0.628). In multivariate analysis, high RECQL5 mRNA and high RECQL5/low RAD51 nuclear protein coexpression independently influenced survival (P = 0.022) in whole cohort and in the ER+ subgroup. Preclinically, we show that exogenous expression of RECQL5 in MCF10A cells can drive proliferation supporting an oncogenic function for RECQL5 in breast cancer. We conclude that RECQL5 is a promising biomarker in breast cancer.

Modelling Treatment Sequences in Immunology: Optimizing Patient Outcomes.

INTRODUCTION: For some immune-mediated disorders, despite the range of therapies available there is limited evidence on which treatment sequences are best for patients and healthcare systems. We investigated how their selection can impact outcomes in an Italian setting. METHODS: A 3-year state-transition treatment-sequencing model calculated potential effectiveness improvements and budget reallocation considerations associated with implementing optimal sequences in ankylosing spondylitis (AS), Crohn's disease (CD), non-radiographic axial spondyloarthritis (NR-AxSpA), plaque psoriasis (PsO), psoriatic arthritis (PsA), rheumatoid arthritis (RA), and ulcerative colitis (UC). Sequences included three biological or disease-modifying treatments, followed by best supportive care. Disease-specific response measures were selected on the basis of clinical relevance, data availability, and data quality. Efficacy was differentiated between biologic-naïve and experienced populations, where possible, using published network meta-analyses and real-world data. All possible treatment sequences, based on reimbursement as of December 2022 in Italy (analyses' base country), were simulated. RESULTS: Sequences with the best outcomes consistently employed the most efficacious therapies earlier in the treatment pathway. Improvements to prescribing practice are possible in all diseases; however, most notable was UC, where the per-patient 3-year average treatment failure was 37.3% higher than optimal. The results focused on the three most crowded and prevalent immunological sub-condition diseases in dermatology, rheumatology, and gastroenterology: PsO, RA, and UC, respectively. By prescribing from within the top 20% of the most efficacious sequences, the model found a 15.1% reduction in treatment failures, with a 1.59% increase in drug costs. CONCLUSIONS: Prescribing more efficacious treatments earlier provides a greater opportunity to improve patient outcomes and minimizes treatment failures.

Targeted literature review exploring the predictive value of estimated glomerular filtration rate and left ventricular mass index as indicators of clinical events in Fabry disease.

BACKGROUND: Fabry disease is a rare, progressive X-linked lysosomal storage disorder. It is caused by mutations in the GLA gene resulting in deficiency of α-galactosidase A (α-Gal A), leading to peripheral neuropathy, cardiovascular disease, stroke, end-stage renal disease, gastrointestinal disorders and premature death. Given the long-term nature of disease progression, trials in Fabry disease are often not powered to capture these clinical events. Clinical measures such as estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) are often captured instead. eGFR and LVMI are believed to be associated with long-term Fabry disease clinical events of interest, but the precise relationships are unclear. OBJECTIVE: We aimed to identify published literature exploring the link between eGFR/LVMI and long-term clinical events in Fabry disease. METHODS: A comprehensive literature search was conducted in Embase® and MEDLINE® (using Embase.com), and a targeted literature review was conducted. Studies reporting a quantitative relationship between eGFR and/or LVMI and clinical events in Fabry disease were extracted, and narrative synthesis was conducted to understand these predictive relationships. RESULTS: Eight studies, consisting of seven patient-level retrospective analyses plus one prospective cohort study, met the inclusion criteria. Seven of these studies reported eGFR and six reported LVMI, with five reporting both. All studies presented results for either a composite measure including a range of key Fabry disease clinical events, or a composite outcome that included at least one key Fabry disease clinical event. All studies employed Cox proportional hazards survival modelling. The studies consistently reported that eGFR and LVMI are predictors of key clinical events in Fabry disease, with the findings remaining consistent regardless of the therapy received by patients in the studies. CONCLUSIONS: The evidence identified suggests that eGFR and LVMI outcomes may be appropriate indicators for long-term clinical events in Fabry disease, and all identified papers implied the same directional relationship. However, additional research is needed to further understand the specific details of these relationships and to quantify them.

Cost-effectiveness of Pembrolizumab versus Carboplatin-based Chemotherapy as First-line Treatment of PD-L1-positive Locally Advanced or Metastatic Urothelial Carcinoma Ineligible for Cisplatin-based Therapy in the United States.

INTRODUCTION: Pembrolizumab has been approved in the United States (US) for the first-line treatment of patients with advanced or metastatic urothelial carcinoma, who are ineligible for cisplatin-containing chemotherapy and with tumors expressing programmed death-ligand 1 (PD-L1) (Combined Positive Score ≥ 10), or ineligible for any platinum-containing chemotherapy regardless of PD-L1 status. Long-term KEYNOTE-052 data continue to demonstrate pembrolizumab's meaningful, durable, and well-tolerated antitumor activity. This study evaluates the cost-effectiveness of pembrolizumab versus carboplatin plus gemcitabine as first-line treatment for cisplatin-ineligible patients who have PD-L1-positive tumors from a US third-party healthcare payer's perspective. PATIENTS AND METHODS: A partitioned survival model containing 3 health states (progression-free, progressed, and death) was developed. A simulated treatment comparison and a network meta-analysis were conducted to estimate the comparative efficacy of pembrolizumab versus carboplatin-based chemotherapy. Overall survival, progression-free survival, time on treatment, adverse events, and utilities were modeled using the final analyses of the KEYNOTE-052 trial and 4 studies for carboplatin plus gemcitabine. Cost data were estimated using US standard sources and real-world data. Deterministic, probabilistic, and scenario analyses were conducted to assess the robustness of the results. RESULTS: Over 20 years, pembrolizumab resulted in a mean gain of 2.58 life-years, 2.01 quality-adjusted life-years, and additional costs of $158,561, leading to an incremental cost-effectiveness ratio of $78,925/quality-adjusted life-year compared with carboplatin plus gemcitabine. CONCLUSION: This study suggests that pembrolizumab is cost-effective compared with carboplatin plus gemcitabine as a first-line therapy for patients with advanced or metastatic urothelial carcinoma who are PD-L1-positive.

Cost-effectiveness of Pembrolizumab for Patients with Advanced, Unresectable, or Metastatic Urothelial Cancer Ineligible for Cisplatin-based Therapy.

BACKGROUND: There is an unmet need for effective therapies for patients with advanced or metastatic urothelial cancer who cannot tolerate cisplatin-based chemotherapy. Cisplatin-ineligible patients experience a high frequency of adverse events from the most commonly used standard of care treatment, carboplatin plus gemcitabine, or alternative treatment with gemcitabine monotherapy. Pembrolizumab is a potent, highly selective humanised monoclonal antibody that releases checkpoint inhibition of the immune response system, and provides a new alternative for these patients. OBJECTIVE: To assess the cost-effectiveness of pembrolizumab for first-line treatment of urothelial carcinoma ineligible for cisplatin-based therapy in patients with strongly PD-L1-positive tumours in Sweden. DESIGN, SETTING, AND PARTICIPANTS: Parametric survival curves were fitted to overall survival, progression-free survival, and time on treatment data from KEYNOTE-052 to extrapolate clinical outcomes. A simulated treatment comparison and a network meta-analysis were conducted to estimate the comparative efficacy of pembrolizumab versus carboplatin plus gemcitabine and gemcitabine monotherapy. EQ-5D data from KEYNOTE-052 were used to estimate utility, while resource use and cost inputs were estimated using Swedish regional pricing lists and clinician opinion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The model reported costs, life years, and quality-adjusted life years (QALYs), and results were tested using deterministic and probabilistic sensitivity analysis. RESULTS AND LIMITATIONS: We estimated that pembrolizumab would improve survival by 2.11 and 2.16 years and increase QALYs by 1.71 and 1.75 compared to carboplatin plus gemcitabine and gemcitabine monotherapy, respectively. Pembrolizumab was associated with a cost increase of €90520 versus carboplatin plus gemcitabine and €95055 versus gemcitabine, with corresponding incremental cost-effectiveness ratios of €53055/QALY and €54415/QALY. CONCLUSIONS: At a willingness-to-pay threshold of €100000/QALY, pembrolizumab is a cost-effective treatment versus carboplatin plus gemcitabine and versus gemcitabine. PATIENT SUMMARY: This is the first analysis to show that pembrolizumab is a cost-effective option for first-line treatment of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma in Sweden.

Altered RECQL5 expression in urothelial bladder carcinoma increases cellular proliferation and makes RECQL5 helicase activity a novel target for chemotherapy.

RECQ helicases are a family of enzymes with both over lapping and unique functions. Functional autosomal recessive loss of three members of the family BLM, WRN and RECQL4, results in hereditary human syndromes characterized by cancer predisposition and premature aging, but despite the finding that RECQL5 deficient mice are cancer prone, no such link has been made to human RECQL5. Here we demonstrate that human urothelial carcinoma of the bladder (UCC) has increased expression of RECQL5 compared to normal bladder tissue and that increasing RECQL5 expression can drive proliferation of normal bladder cells and is associated with poor prognosis. Further, by expressing a helicase dead RECQL5 and by depleting bladder cancer cells of RECQL5 we show that inhibition of RECQL5 activity has potential as a new target for treatment of UCC.