β-thalassemia is a monogenic disease that results in varying degrees of anemia. In the most severe form, known as transfusion-dependent β-thalassemia (TDT), the clinical hallmarks are ineffective erythropoiesis and a requirement of regular, life-long red blood cell transfusions, with the development of secondary clinical complications such as iron overload, end-organ damage, and a risk of early mortality. With the exception of allogeneic hematopoietic cell transplantation, current treatments for TDT address disease symptoms and not the underlying cause of disease. Recently, a growing number of gene addition and gene editing-based treatments for patients with TDT with the potential to provide a one-time functional cure have entered clinical trials. A key challenge in the design and evaluation of these trials is selecting endpoints to evaluate if these novel genetic therapies have a curative versus an ameliorative effect. Here, we present an overview of the pathophysiology of TDT, review emerging gene addition or gene editing therapeutic approaches for TDT currently in clinical trials, and identify a series of endpoints that can quantify therapeutic effects, including a curative outcome.

Software to more rapidly and accurately predict protein--ligand binding affinities is of high interest for early-stage drug discovery, and physics-based methods are among the most widely used technologies for this purpose. The accuracy of these methods depends critically on the accuracy of the potential functions they use. Potential functions are typically trained against a combination of quantum chemical and experimental data. However, although binding affinities are among the most important quantities to predict, experimental binding affinities have not to date been integrated into the experimental dataset used to train potential functions. In recent years, the use of host--guest complexes as simple and tractable models of binding thermodynamics has gained popularity due to their small size and simplicity, relative to protein--ligand systems. Host--guest complexes can also avoid ambiguities that arise in protein--ligand systems, such as uncertain protonation states. Thus, experimental host--guest binding data are an appealing additional data type to integrate into the experimental dataset used to optimize potential functions. Here, we report the extension of the Open Force Field Evaluator framework to enable the systematic calculation of host--guest binding free energies and their gradients with respect to force field parameters, coupled with the curation of 126 host--guest complexes with available experimental binding free energies. As an initial application of this novel infrastructure, we optimized generalized Born (GB) cavity radii for the OBC2 GB implicit solvent model against experimental data for 36 host--guest systems. This refitting led to a dramatic improvement in accuracy for both the training set and a separate test set with 90 additional host--guest systems. The optimized radii also showed encouraging transferability from host--guest systems to 59 protein-ligand systems. However, the new radii are significantly smaller than the baseline radii and lead to excessively favorable hydration free energies (HFE). Thus, users of the OBC2 GB model currently may choose between GB cavity radii that yield more accurate binding affinities or GB cavity radii that yield more accurate HFEs. We suspect that achieving good accuracy on both will require more far-reaching adjustments to the GB model. We note that binding free energy calculations using the OBC2 model in OpenMM gain about a 10x speedup relative to corresponding explicit solvent calculations, suggesting a future role for implicit solvent absolute binding free energy (ABFE) calculations in virtual compound screening. This study proves the principle of using host--guest systems to train potential functions that are transferrable to protein--ligand systems, and provides an infrastructure that enables a range of applications.

Background: Frequent episodes of vaso-occlusion are the hallmark of sickle cell disease (SCD), but the definition of what constitutes a vaso-occlusive episode is not consistently applied across clinical trials, creating challenges in evaluating and comparing efficacy results among different therapies. Here, we compare vaso-occlusion endpoint definitions from clinical trials for various therapies, including genetic therapies, and use clinical trial data to demonstrate the potential for outcomes differences based on differing definitions of vaso-occlusive episodes. Methods: We reviewed completed and ongoing clinical trials and published articles using endpoints assessing the reduction or elimination of vaso-occlusive crisis/events, including trials of (i) exagamglogene autotemcel (exa-cel, CRISPR/Cas-9 based genome editing treatment), (ii) lovotibeglogene autotemcel (lovo-cel, gene addition therapy), (iii) L-glutamine, (iv) voxelotor, (v) hydroxyurea (HU) and (vi) crizanlizumab. Outcomes related to vaso-occlusion were compared across variables including care setting, care duration, treatments, and complications. Data from the CLIMB SCD-121 trial of exa-cel in patients aged 12 to 35 years with severe SCD (data cut as of 10 Feb 2023) were evaluated using different published definitions of vaso-occlusion. Results: The most substantial differences in vaso-occlusion endpoint definitions were associated with frequency and duration of visits to medical facilities for acute pain and inclusion of specific SCD specific complications. Definitions of vaso-occlusions for acute pain related events differed across studies. The definitions of severe vaso-occlusive crises for exa-cel (severe VOC; exa-cel), sickle cell pain-related crises (SCPC; crizanlizumab and L-glutamine), and VOC (VOC; voxelotor) include events with medical facility visits of any duration (severe VOC and SCPC) or medical records of a patient being seen or contacting a physician within 1 business day of an event (VOC), whereas the definition of severe vaso-occlusive events (severe VOE; lovo-cel) requires a ≥ 24-hour hospital or emergency room (ER) observation unit visit or ≥2 visits to a day unit or ER over 72 hours. Vaso-occlusion definition for HU (painful crisis) required a facility visit of ≥4 hours duration. All endpoints include acute chest syndrome and priapism; however, the definition of severe VOE requires ≥4 visits to a medical facility for priapism to meet criterion, while others require only a single visit. The exa-cel phase 3 trial in SCD employs a broad and inclusive definition for severe VOC which counts each individual medical facility visit, regardless of frequency or duration of hospitalization. Based on this, 19 out of 20 patients (95%) met the primary endpoint of freedom from severe VOCs for at least 12 consecutive months (95% CI, 75.1%, 99.9%; P<0.0001). However, when the primary endpoint was analyzed using the severe VOE definition, all patients (20/20; 100.0%) were free from severe VOEs for at least 12 consecutive months (95% CI: 83.2%, 100.0%; P<0.0001). Conclusions: Requirements for health care facility visits in the definitions of severe VOC (exa-cel), VOC, and SCPC were more broadly inclusive and include events that would not be counted in the definitions of severe VOE (lovo-cel) or painful crisis. Clinically, support for this observation comes from our analysis of exa-cel SCD pivotal clinical trial data using these different definitions, which showed the number of patients free from vaso-occlusive episodes changed depending on the definition of vaso-occlusion employed. These results show differences in vaso-occlusion definitions have the potential to impact assessments of treatment efficacy across different SCD therapies.

Background: Sickle cell disease (SCD) is characterized by recurrent acute vaso-occlusive crises (VOCs), which diminish patient quality-of-life, contribute to end-organ damage and failure, and increase mortality. Currently, approved therapies for SCD are only partially effective and do not fully eliminate VOCs. Allogeneic hematopoietic stem cell transplant (HSCT) is the only known curative option for patients with SCD, however, HSCT is available to <20% of patients who have a matched sibling donor and is associated with significant risks, such as graft-versus-host disease. Autologous gene therapies that have the potential to provide a one-time functional cure to patients with SCD are currently in pivotal trials. The primary endpoint for these pivotal studies is the proportion of patients who become VOC-free for ≥12 months after treatment. Absence of VOCs for ≥12 months is expected to predict long-term efficacy. Given this, we evaluated patients with SCD in the national US Medicaid database who underwent allogeneic-HSCT to determine whether VOC-free status at 12 months was predictive of VOC-free status at 18 and 24 months after HSCT. Methods: A cohort of patients with SCD who had a record of allogeneic HSCT with at least 12 months of continuous Medicaid enrollment during 2000-2014 was identified. The date of HSCT was defined as the cohort entry date and the covariate assessment window was the 12 months continuous enrollment period preceding the cohort entry date. A VOC event was identified using ICD-9 diagnosis codes in hospitalization and ER visit claims for Hb-SS disease with crisis, other acute pain crisis, acute chest syndrome, priapism, and splenic sequestration. The cohort was further restricted to patients who had ≥24 months of follow-up after cohort entry to accurately assess VOC outcomes. Diagnosis codes associated with the delivery of healthcare and pharmacy claims were used to identify patient characteristics and outcomes of interest. Primary study outcome was the proportion of patients with no VOCs at 6 months, 12 months, 18 months, and 24 months after allogeneic HSCT. Results: During the study period, 44,685 patients with SCD were identified, out of whom 103 patients had undergone allogeneic HSCT, were enrolled for ≥12 months in the Medicaid program and had ≥24 months of follow-up after HSCT. Mean (SD) age was 10.3 (7.2) years, with 55.3% being male and majority (67%) Black. Patients had an average of 2.7 (SD, 7.9) VOC events during the 12-month period prior to HSCT. The most common (>10%) baseline comorbidities were chronic cardiac disease (42.7%), infections (36.9%), chronic pulmonary disease (31.1%), and acute chest syndrome (12.6%). Among the cohort of 103 patients who had undergone HSCT, 79% (n=81) were VOC-free by 12 months. Furthermore, among patients who were VOC-free at 12 months, 91% (n=74) were VOC-free at 18 months and 90% (n=73) were VOC-free at 24 months. Conclusions: This population-based study provides valuable information regarding long-term VOC-free status among patients with SCD who have undergone allogeneic HSCT in routine clinical care. Our findings suggest that patients with SCD who are VOC-free by 12 months post-HSCT are highly likely to stay VOC-free for longer durations (i.e. 18 and 24 months) after HSCT.

A growing number of gene therapy- and gene editing-based treatments for patients with sickle cell disease (SCD) are entering clinical trials. These treatments, designed to target the underlying cause of SCD, have the potential to provide functional cures, which until now were possible only through allogeneic hematopoietic stem cell transplant. However, as these novel approaches advance from early- to late-stage clinical trials, it is essential to identify physiologically and clinically relevant endpoints that can demonstrate the achievement of a functional cure for SCD. Here, we present an overview of the pathophysiology of SCD and current treatment options, review ongoing SCD clinical trials using gene therapy or gene editing approaches, and identify the most relevant endpoints for demonstrating the attainment of a functional cure for SCD.

Abstract We propose an adaptive hybrid control causal (AHCC) design to leverage historical control data to reduce the sample size demanded by standard randomised controlled trials (RCT). Under the causal inference framework, we define the causal estimand of the average treatment effect and derive the corresponding estimator based on the trial data and historical control data. The AHCC design takes a multistage or group sequential approach. The number of patients randomised to the concurrent control is adaptively adjusted based on the amount of information borrowed from the historical control data. At each stage, based on the interim data, the contribution of the historical control data, quantified by the effective sample size, is updated and used to determine the randomisation ratio between the treatment and control arms for the next stage, with the goal to resemble a standard RCT upon the completion of the trial. Simulation studies show that the AHCC design has desirable operating characteristics. For example, it saves on sample size when substantial information can be borrowed from the historical control, and it maintains power when little information can be borrowed from the historical control.

A Real-World Evidence (RWE) Scientific Working Group (SWG) of the American Statistical Association Biopharmaceutical Section (ASA BIOP) has been reviewing statistical considerations for the generation of RWE to support regulatory decision-making. As part of the effort, the working group is addressing estimands in RWE studies. Constructing the right estimand—the target of estimation—which reflects the research question and the study objective, is one of the key components in formulating a clinical study. ICH E9(R1) describes statistical principles for constructing estimands in clinical trials with a focus on five attributes—population, treatment, endpoints, intercurrent events, and population-level summary. However, defining estimands for clinical studies using real-world data (RWD), that is, RWE studies, requires additional considerations due to, for example, heterogeneity of study population, complexity of treatment regimes, different types and patterns of intercurrent events, and complexities in choosing study endpoints. This article reviews the essential components of estimands and causal inference framework, discusses considerations in constructing estimands for RWE studies, highlights similarities and differences in traditional clinical trial and RWE study estimands, and provides a roadmap for choosing appropriate estimands for RWE studies.

In two pivotal phase 3 trials, up to 24 weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis (CF) ≥12 years of age who have at least one F508del allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients. In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function (from a 24-week parent study; n=399) or F508del-F508del (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h). The primary end-point is safety and tolerability. A prespecified interim analysis was conducted when the last participant reached the Week 144 visit. At the Week 144 interim analysis, mean duration of exposure to ELX/TEZ/IVA in the extension study was 151.1 weeks. Exposure-adjusted rates of adverse events (AEs) (586.6 events per 100 participant-years) and serious AEs (22.4 events per 100 participant-years) were lower than in the ELX/TEZ/IVA treatment group in the 24-week parent study (1096.0 and 36.9 events per 100 participant-years, respectively); most participants had AEs classified as mild (16.4% of participants) or moderate (60.3% of participants) in severity. 14 participants (2.8%) had AEs that led to treatment discontinuation. Following initiation of ELX/TEZ/IVA, participants had increases in forced expiratory volume in 1 s (FEV1) percentage predicted, Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbation rates that were maintained over the interim analysis period. The mean annualised rate of change in FEV1 % pred was +0.07 (95% CI -0.12-0.26) percentage points among the participants. ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study. Participants had sustained improvements in lung function, respiratory symptoms, CF transmembrane conductance regulator function, pulmonary exacerbation rates and nutritional status. These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.

Existing phase II clinical trial designs focus on a single scalar endpoint, such as a binary, continuous, or survival endpoint. In some clinical trials, such as pain management studies, the efficacy endpoint of interest is measured longitudinally. We propose a Bayesian phase II design for such clinical trials. We model the longitudinal measurement process using Bayesian hierarchical model, where subject-specific trajectory shrinks toward the population trajectory to borrow information across subjects. The Bayesian penalized spline is used to model subject-specific and population trajectories without making strong parametric assumption on their shapes. We use the area under the curve of the trajectory as the summary of the treatment effect over time. The design takes a group sequential approach and takes into account both statistical significance and clinical relevance. Bayesian criteria is proposed to make interim and final decisions based on the evidence of statistical significance and clinical relevance. The proposed design is highly flexible and can accommodate trials with one or multiple longitudinal endpoints, as well as a longitudinal primary endpoint with a secondary endpoint. Simulation study shows that the proposed design is robust with desirable operating characteristics.

The in-person workshop “Drug Dissolution in Oral Drug Absorption” was held on May 23–24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. Topics that repeatedly surfaced across breakout sessions were the following: (1) meaning and assessment of “dissolved drug,” particularly of poorly water soluble drug in colloidal environments (e.g., fed conditions, ASDs); (2) potential limitations of a test that employs sink conditions for a poorly water soluble drug; (3) non-compendial methods (e.g., two-stage or multi-stage method, dissolution/permeation methods); (4) non-compendial conditions (e.g., apex vessels, non-sink conditions); and (5) potential benefit of having both a quality control method for batch release and a biopredictive/biorelevant method for biowaiver or bridging scenarios. An identified obstacle to non-compendial methods is the uncertainty of global regulatory acceptance of such methods.