Clinical Pharmacology & Therapeutics

Weaver, James L.; Wu, Wendy; Hyland, Paula L.; Lim, Robert; Smpokou, Patroula; Pacanowski, Michael

doi: 10.1002/cpt.2414pmid: 34496049

In vitro cell‐based data can be used to support the extension of pharmaceutical approval to patient subsets with unique genetic variants. A set of conditions should be satisfied to support the extension of approval. The disease mechanism should be well described, and the impact of variants on protein function should be reasonably understood. The incidence data should show that clinical trials for the variants in question are not practical. The overall safety and efficacy of the drug should be clear in adequate and well‐controlled clinical trials. The clinical trial should include patients found to be responders and nonresponders so that both positive and negative predictive power of the in vitro assay may be measured. The mechanism of action of the drug should be clearly defined and should be consistent with the disease mechanism. The assay system should be qualified, including the following points: (i) each variant construct should be confirmed by bidirectional sequencing; (ii) the in vitro assay should directly measure the variant protein function in comparison with the reference protein; (iii) the assay should be formally validated to the extent possible, clearly demonstrating precision, reproducibility, and sensitivity used to support the efficacy claim; and (iv) the primary data should be available for inspection and analytical validation. The overall goal is a robust and validated cell‐based system that can be shown to predict the outcome of targeted therapy.

With, Mirjam; Knikman, Jonathan; Man, Femke M.; Lunenburg, Carin A. T. C.; Henricks, Linda M.; Kuilenburg, André B. P.; Maring, Jan G.; Staveren, Maurice C.; Vries, Niels; Rosing, Hilde; Beijnen, Jos H.; Pluim, Dick; Modak, Anil; Imholz, Alex L. T.; Schaik, Ron H. N.; Schellens, Jan H. M.; Gelderblom, Hans; Cats, Annemieke; Guchelaar, Henk‐Jan;

Bakker, Elisabeth; Hendrikse, Natalie M.; Ehmann, Falk; Meer, Daniëlla S.; Llinares Garcia, Jordi; Vetter, Thorsten; Starokozhko, Viktoriia; Mol, Peter G.M.

doi: 10.1002/cpt.2554pmid: 35137949

Regulatory qualification of biomarkers facilitates their harmonized use across drug developers, enabling more personalized medicine. This study reviews various aspects of the European Medicines Agency’s (EMA’s) biomarker qualification procedure, including frequency and outcome, common challenges, and biomarker characteristics. Our findings provide insights into the EMA’s biomarker qualification process and will thereby support future applications. All biomarker‐related “Qualification of Novel Methodologies for Medicine Development” procedures that started from 2008 to 2020 were included. Procedural data were extracted from relevant documents and analyzed descriptively. In total, 86 biomarker qualification procedures were identified, of which 13 resulted in qualified biomarkers. Whereas initially many biomarker qualification procedures were linked to a single company and specific drug development program, a shift was observed to qualification efforts by consortia. Most biomarkers were proposed (n = 45) and qualified (n = 9) for use in patient selection, stratification, and/or enrichment, followed by efficacy biomarkers (37 proposed, 4 qualified). Overall, many issues were raised during qualification procedures, mostly related to biomarker properties and assay validation (in 79% and 77% of all procedures, respectively). Issues related to the proposed context of use and rationale were least common yet were still raised in 54% of all procedures. While few qualified biomarkers are currently available, procedures focus increasingly on biomarkers for general use instead of those linked to specific drug compounds. The issues raised during qualification procedures illustrate the thorough discussions taking place between applicants and regulators—highlighting aspects that need careful consideration and underlining the importance of an appropriate validation strategy.

Ogasawara, Ken; Lymp, James; Mack, Timothy; Dell’Aringa, Justine; Huang, Chang‐pin; Smith, Jeff; Peiser, Leanne; Kostic, Ana

doi: 10.1002/cpt.2561pmid: 35156195

Lisocabtagene maraleucel (liso‐cel) is an autologous, CD19‐directed, chimeric antigen receptor T‐cell product for the treatment of adult patients with relapsed or refractory large B‐cell lymphoma (LBCL) after 2 or more lines of systemic therapy. In vivo cellular expansion after single‐dose administration of liso‐cel has been characterized. In this article, in vivo liso‐cel expansion in the pivotal study TRANSCEND NHL 001 (ClinicalTrials.gov identifier, NCT02631044) was further characterized to assess the relationship between in vivo cellular expansion after single‐dose administration of liso‐cel and efficacy or safety after adjusting for key baseline characteristics. Two bioanalytical methods, quantitative polymerase chain reaction and flow cytometry, were used for the assessment of cellular kinetics of liso‐cel, which showed high concordance for in vivo cellular expansion. Multivariable logistic regression analyses demonstrated that higher in vivo cellular expansion of liso‐cel was associated with a higher overall response and complete response rate, and a higher incidence of cytokine release syndrome and neurological events in patients with relapsed or refractory LBCL. Age and tumor burden (by sum of the product of perpendicular diameters) were likely to confound the relationship between in vivo cellular expansion and efficacy, where the association became stronger after controlling for these factors. Repeat dosing of liso‐cel was tested in the study; however, in vivo cellular expansion of liso‐cel was lower after repeat dosing than after the initial dose. These findings should enable a comprehensive understanding of the in vivo cellular kinetics of liso‐cel and the association with outcomes in relapsed/refractory LBCL.

Mukherjee, Arnab; Tsuchiwata, Shinichi; Nicholas, Timothy; Cook, Jack A.; Modesto, Irene; Su, Chinyu; D’Haens, Geert R.; Sandborn, William J.

doi: 10.1002/cpt.2601pmid: 35380740

Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis. Relationships between plasma tofacitinib concentration and efficacy were characterized using exposure‐response (E‐R) models, with demographic and disease covariates evaluated as potential predictors of efficacy. Data were from phase II and III (OCTAVE Induction 1 and 2) induction studies, and a phase III maintenance study (OCTAVE Sustain). Induction studies included 1,355 patients (tofacitinib 0.5, 3, 10, or 15 mg b.i.d. or placebo). The maintenance study included 592 patients (tofacitinib 5 or 10 mg b.i.d. or placebo). E‐R models, including induction patients predicted placebo‐adjusted remission rates of 6.4% and 12.7% at week 8 for tofacitinib 5 and 10 mg b.i.d., respectively; corresponding rates in patients without prior tumor necrosis factor inhibitor (TNFi) failure were 12.8% and 20.4%. Estimates to achieve/maintain remission at week 52 of maintenance were 29% and 18% (tofacitinib 5 mg b.i.d.), and 41% and 26% (tofacitinib 10 mg b.i.d.), for patients in remission or not following induction, respectively. During maintenance, patients with prior TNFi failure had lower probability of remission on 5 mg b.i.d. (24.9%) than 10 mg b.i.d. (35.0%). Results indicated tofacitinib 10 mg b.i.d. was an appropriate induction dose but suggested efficacy with 5 mg b.i.d. in patients without prior TNFi failure. Tofacitinib 5 mg b.i.d. was efficacious for maintenance, although patients with prior TNFi failure might see additional benefit on 10 mg b.i.d. Per product labeling, recommended tofacitinib induction dose is 10 mg b.i.d., then maintenance at 5 mg b.i.d. For patients who lose response during maintenance, 10 mg b.i.d. may be considered, limited to the shortest duration.

Singh, Ravi Shankar P.; Toussi, Sima S.; Hackman, Frances; Chan, Phylinda L.; Rao, Rohit; Allen, Richard; Van Eyck, Lien; Pawlak, Sylvester; Kadar, Eugene P.; Clark, Frances; Shi, Haihong; Anderson, Annaliesa S.; Binks, Michael; Menon, Sandeep; Nucci, Gianluca; Bergman, Arthur

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Leohr, Jennifer; Kjellsson, Maria C.

doi: 10.1002/cpt.2604pmid: 35388464

The integrated glucose‐insulin model is a semimechanistic model describing glucose and insulin after a glucose challenge. Similarly, a semiphysiologic model of the postprandial triglyceride (TG) response in chylomicrons and VLDL‐V6 was recently published. We have developed the triglyceride‐insulin‐glucose‐GLP‐1 (TIGG) model by integrating these models and active GLP‐1. The aim was to characterize, using the TIGG model, the postprandial response over 13 hours following a high‐fat meal in 3 study populations based on body mass index categories: lean, obese, and very obese. Differential glucose and lipid regulation were observed between the lean population and obese or very obese populations. A population comparison revealed further that fasting glucose and insulin were elevated in obese and very obese when compared with lean; and euglycemia was achieved at different times postmeal between the obese and very obese populations. Postprandial insulin was incrementally elevated in the obese and very obese populations compared with lean. Postprandial chylomicrons TGs were similar across populations, whereas the postprandial TGs in VLDL‐V6 were increased in the obese and very obese populations compared with lean. Postprandial active GLP‐1 was diminished in the very obese population compared with lean or obese. The TIGG model described the response following a high‐fat meal in individuals who are lean, obese, and very obese and provided insight into the possible regulation of glucose homeostasis in the extended period after the meal by utilizing lipids. The TIGG‐model is the first model to integrate glucose and insulin regulation, incretin effect, and postprandial TGs response in chylomicrons and VLDL‐V6.

Walford, Geoffrey A.; Duncan, Kelly E.; Hernandez, Moises; Vaddady, Pavan; Hompesch, Marcus; Morrow, Linda; Stoch, S. Aubrey

doi: 10.1002/cpt.2607pmid: 35390172

Insulin molecules of size much greater than natural insulin have been synthesized and studied with the intention of widening the therapeutic window between adequate glycemic control and hypoglycemia as compared with conventional insulins. MK‐1092 is a synthetic insulin dimer with favorable properties demonstrated in preclinical studies. Here, we report the results of the first‐in‐human, randomized, double‐blind, active‐control, single ascending dose trial of MK‐1092, conducted in healthy adults, adults with type 1 diabetes (T1D), and adults with type 2 diabetes (T2D). MK‐1092 was well tolerated in all study populations, and no dose‐related adverse events were identified across the evaluated dose range (4–64 nmol/kg). Circulating concentrations of MK‐1092 were approximately dose‐proportional. Maximum glucose infusion rate (GIR) and 24‐hour time‐weighted average GIR were evaluated under euglycemic clamp conditions. These pharmacodynamic measurements were approximately dose‐proportional in all study populations; at similar doses, the GIR parameters were lower in adults with T2D than in healthy adults or adults with T1D, likely due to the influence of insulin resistance. At doses ≥ 16 nmol/kg, MK‐1092 had similar or greater effects than glargine 3 nmol/kg (0.5 units/kg) on increasing GIR in each study population and on suppressing free fatty acids and ketone generation in adults with T1D. MK‐1092 did not prevent a subsequent high dose of lispro from increasing the GIR in healthy adults. Additional studies in adults with T1D and T2D are needed to further evaluate the safety, tolerability, and efficacy profile of MK‐1092 and its potential for differentiation from more conventional insulins. (ClinicalTrials.gov: NCT03170544)

Kang, Hye‐Rim; Lo‐Ciganic, Wei‐Hsuan; DeRemer, Christina E.; Dietrich, Eric A.; Huang, Pei‐Lin; Park, Haesuk

doi: 10.1002/cpt.2611pmid: 35420702

Limited real‐world evidence exists for effectiveness and safety of extended oral anticoagulation beyond 6 months of initial treatment in prevention of recurrent venous thromboembolism (VTE) and adverse major bleeding events among patients with VTE. Using MarketScan Commercial and Medicare Supplemental databases (2013–2019), we conducted a retrospective cohort study to compare the risk of recurrent VTE and major bleeding events during extended treatment among patients with VTE who completed the 6‐month initial treatment and received extended oral anticoagulant treatment with apixaban, warfarin, or no extended treatment. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards modeling with inverse probability treatment weighting. We identified 14,818 patients with extended treatment of apixaban (n = 4,338), warfarin (n = 5,298), or no extended treatment (n = 5,182). Compared with no extended treatment, apixaban use was associated with decreased risk of recurrent VTE (HR: 0.10, 95% CI: 0.04–0.26) without increased risk of major bleeding events (HR: 1.06, 95% CI: 0.52–2.17); warfarin use was associated with decreased risk of recurrent VTE (HR: 0.23, 95% CI: 0.12–0.44) but with increased risk of major bleeding events (HR: 2.64, 95% CI: 1.51–4.59). Compared with warfarin, apixaban use was associated with decreased risk of major bleeding events (HR: 0.42, 95% CI: 0.22–0.80) but no difference in risk of recurrent VTE (HR: 0.46, 95% CI: 0.15–1.36). In a real‐world clinical setting, extended anticoagulation with apixaban or warfarin was associated with decreased risk of recurrent VTE compared with no extended treatment, and apixaban had a better safety profile with fewer major bleeding events compared with warfarin among commercially insured patients with VTE.

Thomas, Cameron D.; Franchi, Francesco; Keeley, Ellen C.; Rossi, Joseph S.; Winget, Marshall; David Anderson, R.; Dempsey, Alyssa L.; Gong, Yan; Gower, Megan N.; Kerensky, Richard A.; Kulick, Natasha; Malave, Jean G.; McDonough, Caitrin W.; Mulrenin, Ian R.; Starostik, Petr;