Idiopathic Aneurysms of the Ascending Aorta in the Mouse and Rat

Aneurysms of the ascending aorta, unrelated to xenobiotic administration, are described in 5 rats and 2 mice in nonclinical safety studies conducted at Charles River Laboratories (CRL) sites over the past 10 years. The most prominent microscopic finding was focal dilation with disruption of the wall of the ascending aorta with chronic adventitial inflammation or fibroplasia. The pathogenesis of this finding is unknown. There were no associated macroscopic findings, clinical abnormalities, or vascular lesions elsewhere. The results of a search of historical control data from toxicology studies of 1 day to 72 weeks’ duration performed at CRL for aortic findings from 5900 mice and 23,662 rats are also reported. Aortic lesions are uncommon in mice and rats used in nonclinical safety studies, but toxicologic pathologists should be aware that aneurysms of the ascending aorta with fibroplasia and inflammation in the aortic wall and adventitia may occur spontaneously or iatrogenically, as they have the potential to impact interpretation in toxicology studies.

Innovative Adaptive Study Design in Transfusion-Dependent Beta-Thalassemia: Bayesian Design with Concurrent Randomization and Borrowing from Historical Data

Background Clinical development of new therapies in transfusion-dependent beta-thalassemia has several challenges. Patient enrollment in rare diseases requires multi-center multi-country studies, and the lack of reliable surrogate endpoint for dose selection requires powering for clinical endpoints usually used in Phase 3 trials. An acceptable endpoint from a regulatory perspective which is based on responders analysis, such as proportion of patients experiencing ≥50% reduction in Red Blood Cell (RBC) transfusion burden and a reduction of ≥2 units, requires 12 weeks screening period to establish baseline transfusion burden for reliable comparison. Importantly, higher randomization ratio of treatment:placebo can improve patients' motivation to enroll into a trial, but it is less statistically efficient and requires higher sample size. We designed a Phase-2b, double-blind, randomized, placebo controlled, multi-center study with Vamifeport (NCT04938635) to assess the efficacy and safety of multiple doses of a new therapy in adults with transfusion-dependent beta-thalassemia. The proposed design follows the Bayesian framework with borrowing from published historical control data. The historical control data is used to construct an informative prior for the control arm to reduce the burden of patients randomized to a control arm and improve the trial's efficiency in performing dose selection. Study Design and Methods Adults (18 to 65 y.o.) with documented diagnosis of β-thalassemia or hemoglobin E / β-thalassemia will be randomized to three doses of the investigational drug or placebo plus best supportive care. RBC transfusion dependence is defined as at least 6 RBC Units in the 24 weeks prior to randomization and no transfusion-free period for ≥35 days during that period. The primary endpoint is the proportion of patients experiencing ≥33% reduction of RBC units from baseline and a reduction of ≥2 units assessed from week 13 to week 24. The key secondary endpoints include proportion of patients experiencing ≥33% reduction from week 37 to week 48; proportion of patients experiencing ≥50% reduction over any consecutive 12-week interval from week 1 to week 48 and the mean change from baseline in RBC transfusions (units) from week 13 to week 24. The primary and key-secondary analysis will be conducted in a hierarchical fashion to account for multiplicity. We proposed a Bayesian design with the use of noninformative, or weakly informative, priors for the active dose arms while using a robustified informative prior for the control arm. Historical control data will be "borrowed" in an informative prior for the control arm rate from the Phase 3 trial - BELIEVE. The robustification is required in order to control the level of borrowing depending on the level of prior-data conflict. Prior-data conflict can arise from multiple sources like population heterogeneity between the historical and current study. Therefore, the selection of historical data (BELIEVE trial) addresses similarity in inclusion / exclusion criteria, standard of care etc. The robustification of the informative prior does not take into account prior-data conflict in terms of population or study characteristics but directly focuses on the informative prior of the parameter of interest and the corresponding likelihood of the current data. For example, in the BELIEVE study, out of 112 patients randomized to the control arm, 5 patients (4.5%) had a ≥33% reduction in transfusion burden over 24 weeks. A prior-data conflict may arise if the Phase-2b trial of interest here, suggests that the proportion is substantially different that 4.5% and this can inflate the frequentist Type-I or Type-II error rates examined via simulations. We evaluated Type-I error rates of the proposed design with 5000 Monte-Carlo runs for each scenario of the response rates. Using informative prior with no prior-data conflict the type-I error with no robustification is ≈ 2.4%. As the prior-data conflict increases, without robustification, the type-I error cannot be controlled. However, with a robustification weight of 0.5 the type-I errors can be controlled in line with regulatory requirements. Discussion A proposed Bayesian design with robustified informative prior for the control arm helps reduce patients' burden of randomization to control arm and reduce overall sample size for a rare disease trial when recruitment and trial duration are challenging. Disclosures Muehlemann: Vifor Pharma AG: Consultancy. Mukherjee: Vifor Pharma AG: Consultancy. Taher: Bristol Myers Squibb: Consultancy, Research Funding; Vifor Pharma: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Gudmundsdottir: Vifor Pharma AG: Current Employment. Morin: Vifor Pharma AG: Current Employment. Richard: Vifor Pharma AG: Current Employment.

Spontaneous Ocular Abnormalities in Sprague–Dawley Rats

We collected historical control data derived from pretreatment ophthalmologic examinations of young (4 to 7 wk of age) Sprague–Dawley (Crl:CD[SD]) male, (2033, 42 lots) and female (1322, 32 lots) rats used in toxicity studies at our facility from 2004 through 2015. Ophthalmologic examination of male and female rats by using a binocular indirect ophthalmoscope and slit lamp revealed high incidences of corneal opacity (61% and 60%, respectively), lenticular opacity (43% and 47%), persistent hyaloid artery (21% and 17%), and retinal folds (27% and 27%). All other ocular abnormalities of the globe, conjunctiva, cornea, anterior chamber, lens, iris, vitreous, and choroid or retina occurred at incidences of less than 5%. Corneal opacities were localized mainly in the corneal nasal (38% and 37%) and paracentral (32% and 33%) areas, and lenticular opacities predominantly occurred in the nuclear area (31% and 34%). We then compared the incidences of spontaneous ocular abnormalities between the first (2004 through 2009) and second (2010 through 2015) 6-y periods. Corneal opacity and persistent hyaloid artery in male and female rats occurred more frequently during the second 6-y than during the first (corneal opacity, second period: male, 68%; female, 66%; corneal opacity, first period: 49% and 51%; persistent artery, second period, 26% and 23%; persistent artery, first period; 12% and 10%). These results support the importance of updating historical control data regularly and providing useful information for toxicologists and ophthalmologists to differentiate treatment-related changes from spontaneous lesions.