Accelerating the development of genetically engineered cellular therapies: a framework for extrapolating data across related products.

BACKGROUND: Significant advancements have been made in the field of cellular therapy as anti-cancer treatments, with the approval of chimeric antigen receptor (CAR)-T cell therapies and the development of other genetically engineered cellular therapies. CAR-T cell therapies have demonstrated remarkable clinical outcomes in various hematological malignancies, establishing their potential to change the current cancer treatment paradigm. Due to the increasing importance of genetically engineered cellular therapies in the oncology treatment landscape, implementing strategies to expedite development and evidence generation for the next generation of cellular therapy products can have a positive impact on patients. METHODS: We outline a risk-based methodology and assessment aid for the data extrapolation approach across related genetically engineered cellular therapy products. This systematic data extrapolation approach has applicability beyond CAR-T cells and can influence clinical development strategies for a variety of immune therapies such as T cell receptor (TCR) or genetically engineered and other cell-based therapies (e.g., tumor infiltrating lymphocytes, natural killer cells and macrophages). RESULTS: By analyzing commonalities in manufacturing processes, clinical trial designs, and regulatory considerations, key learnings were identified. These insights support optimization of the development and regulatory approval of novel cellular therapies. CONCLUSIONS: The field of cellular therapy holds immense promise in safely and effectively treating cancer. The ability to extrapolate data across related products presents opportunities to streamline the development process and accelerate the delivery of novel therapies to patients.

Detection of chromosomal alteration after infusion of gene-edited allogeneic CAR T cells.

A chromosome 14 inversion was found in a patient who developed bone marrow aplasia following treatment with allogeneic chimeric antigen receptor (CAR) Tcells containing gene edits made with transcription activator-like effector nucleases (TALEN). TALEN editing sites were not involved at either breakpoint. Recombination signal sequences (RSSs) were found suggesting recombination-activating gene (RAG)-mediated activity. The inversion represented a dominant clone detected in the context of decreasing absolute CAR Tcell and overall lymphocyte counts. The inversion was not associated with clinical consequences and wasnot detected in the drug product administered to this patient or in any drug product used in this or other trials using the same manufacturing processes. Neither was the inversion detected in this patient at earlier time points or in any other patient enrolled in this or other trials treated with this or other product lots. This case illustrates that spontaneous, possibly RAG-mediated, recombination events unrelated to gene editing can occur in adoptive cell therapy studies, emphasizes the need for ruling out off-target gene editing sites, and illustrates that other processes, such as spontaneous V(D)J recombination, can lead to chromosomal alterations in infused cells independent of gene editing.

Pharmacokinetics of dapoxetine, a new treatment for premature ejaculation: Impact of age and effects of a high-fat meal.

Dapoxetine is being developed as a treatment for premature ejaculation and has demonstrated rapid absorption and elimination in previous pharmacokinetic studies. Two open-label studies were conducted in healthy men: a parallel-group pharmacokinetic and safety study in young and elderly men and a randomized crossover food-effect study. Maximal plasma dapoxetine concentrations (C(max)) were similar in young and elderly men (338 and 310 ng/mL, respectively), as were the corresponding area under the plasma concentration versus time curve (AUC) values (2040 and 2280 ng x h/mL, respectively). When coadministered with food, C(max) was reduced by 11% (398 vs 443 ng/mL in the fed and fasted states, respectively), and the peak was delayed by approximately 30 minutes, indicating that food slowed the rate of absorption; however, systemic exposure to dapoxetine (ie, AUC) was not affected by food consumption. Thus, age or consumption of a high-fat meal has only a modest impact on dapoxetine pharmacokinetics in healthy men.

Evaluation of the bioequivalence of two transdermal fentanyl systems following single and repeat applications.

OBJECTIVE: Transdermal delivery of fentanyl has potential benefits over slow-release morphine, being largely preferred by patients owing to the combination of effective pain relief, a good safety profile and easy, pain-free dosing. The new drug-in-adhesive Durogesic D-TRANS fentanyl Matrix Delivery System (DDTDF) has improved pharmaceutical characteristics and patient acceptability compared to the original Durogesic transdermal reservoir system (fentanyl transdermal reservoir), whilst still providing reliable and consistent delivery of fentanyl. The bioequivalence of these two systems was evaluated in two studies. RESEARCH DESIGNS AND METHODS: Eighty healthy volunteers received single (72 h) or multiple (288 h) applications of DDTDF and the transdermal reservoir system (100 microg/h) in two separate randomised, crossover bioequivalence studies. Bioequivalence was assessed by calculating the ratio of least squares means based on log-transformed data following single system application and at steady-state during the fourth application. RESULTS: Both transdermal systems were bioequivalent with respect to all tested pharmacokinetic parameters. Inter-subject variability was comparable between the two systems and was greater than intra-subject variability. Transdermal delivery was well tolerated in both groups. CONCLUSIONS: The pharmacokinetic results demonstrate that DDTDF is bioequivalent to the original fentanyl transdermal reservoir system after single and multiple applications.

The effect of dosing frequency on the pharmacokinetics of a fentanyl HCl patient-controlled transdermal system (PCTS).

INTRODUCTION: The fentanyl HCl patient-controlled transdermal system (PCTS) is a noninvasive, needle-free, credit card-sized drug delivery system designed for the on-demand management of acute pain in a medically supervised setting. The objective of these studies was to determine the effect of dosing frequency on the pharmacokinetics of fentanyl delivered by the PCTS. METHODS: All three studies were single-centre, open-label, randomised, crossover studies. The fentanyl HCl PCTS was applied to the upper outer arm of all participants. In the first study, participants (n = 30) received three fentanyl HCl PCTS 25 microg treatments: two sequential doses hourly for 23.33 hours, six sequential doses every 3 hours for 22 hours, and 72 doses continuously over 12 hours. Participants (n = 31) in the second study received three fentanyl HCl PCTS 40 microg treatments: two sequential doses hourly over 23.33 hours, six sequential doses every 3 hours over approximately 10 hours, and 80 doses continuously over 13.33 hours. In the third study, participants (n = 28) received four fentanyl HCl PCTS 40 microg treatments: 6, 18, 36 and 80 doses over 1, 3, 6 and 13.33 hours, respectively. Naltrexone was used to block the opioid effects of fentanyl. Pharmacokinetic parameters, including maximum serum fentanyl concentration (Cmax), time to Cmax (tmax), area under the serum concentration-time curve (AUC) and terminal half-life (t(1/2)) were determined. RESULTS: In the first study, the dose-normalised AUC (AUCn) values for the 2- and 6-dose sequence treatments were not significantly different (p = 0.937), suggesting that the frequency of dosing has little effect on the amount of fentanyl absorbed; however, the AUCn for the 72-dose treatment was significantly lower than that of the other treatments (p = 0.001), which were of longer duration. The results of the second study paralleled those from the first, suggesting that the bioavailability of fentanyl delivered by the PCTS increases as a function of time and is likely to be independent of dosing frequency. Results from the third study suggested that approximately 40% of the nominal 40 microg fentanyl dose is absorbed during the first hour of treatment, with the full nominal dose absorbed after approximately 10 hours. The fentanyl HCl PCTS was well tolerated. CONCLUSION: The amount of fentanyl absorbed from the PCTS increases as a function of time and is independent of both dosing frequency and total number of doses delivered. The fentanyl HCl PCTS is generally safe and well tolerated.

Effect of the proton pump inhibitor omeprazole on the pharmacokinetics of extended-release formulations of oxybutynin and tolterodine.

This study assessed the effect of the proton pump inhibitor omeprazole on the bioavailability of the extended-release formulations of oxybutynin and tolterodine. Forty-four healthy volunteers received each of 4 treatments in a 4-period crossover design. The treatments consisted of osmotically controlled extended-release oxybutynin chloride tablets at 10 mg/d or extended-release tolterodine tartrate capsules at 4 mg/d, with and without preceding treatment with 20 mg omeprazole daily for 4 days. Blood samples collected predose and at scheduled time points for 36 hours postdose were analyzed for oxybutynin and its active metabolite, N-desethyloxybutynin, or tolterodine and its active 5-hydroxymethyl metabolite, as appropriate. The AUCinfinity ratios for oxybutynin and its metabolite with and without prior omeprazole fell within the 80% to 125% range (accepted as the criterion for bioequivalence), as did those for tolterodine and its active moiety. The peak concentration ratios for oxybutynin and metabolite also conformed to this range; those for tolterodine did not. Increasing gastric pH with omeprazole does not substantially alter the pharmacokinetic properties of extended-release oxybutynin but may alter those of extended-release tolterodine.