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Adeno‐associated virus (AAV) vector‐based gene therapy is an innovative modality being increasingly investigated to treat diseases by modifying or replacing defective genes or expressing therapeutic entities. With its unique anatomic and physiological characteristics, the eye constitutes a very attractive target for gene therapy. Specifically, the ocular space is easily accessible and is generally considered "immune‐privileged" with a low risk of systemic side effects following local drug administration. As retina cells have limited cellular turnover, a one‐time gene delivery has the potential to provide long‐term transgene expression. Despite the initial success with voretigene neparvovec (Luxturna), the first approved retina gene therapy, there are still challenges to be overcome for successful clinical development of these products and scientific questions to be answered. The current review paper aims to integrate published experience learned thus far for AAV‐based retina gene therapy related to preclinical to clinical translation; first‐in‐human dose selection; relevant bioanalytical assays and strategies; clinical development considerations including trial design, biodistribution and vector shedding, immunogenicity, transgene expression, and pediatric populations; opportunities for model‐informed drug development; and regulatory perspectives. The information presented herein is intended to serve as a guide to inform the clinical development strategy for retina gene therapy with a focus on clinical pharmacology. [ABSTRACT FROM AUTHOR]

CAR‐T therapies have shown remarkable efficacy against hematological malignancies in the clinic over the last decade and new studies indicate that progress is being made to use these novel therapies to target solid tumors as well as treat autoimmune disease. Innovation in the field, including TCR‐T, allogeneic or "off the shelf" CAR‐T, and autoantigen/armored CAR‐Ts are likely to increase the efficacy and applications of these therapies. The unique aspects of these cell‐based therapeutics; patient‐derived cells, intracellular expression, in vivo expansion, and phenotypic changes provide unique bioanalytical challenges to develop pharmacokinetic and immunogenicity assessments. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Translational and ADME Sciences Leadership Group (TALG) has brought together a group of industry experts to discuss and consider these challenges. In this white paper, we present the IQ consortium perspective on the best practices and considerations for bioanalytical and immunogenicity aspects toward the optimal development of CAR‐T and TCR‐T cell therapies. [ABSTRACT FROM AUTHOR]

With the promise of a potentially "single dose curative" paradigm, CAR‐T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies. Both CAR‐T and TCR‐T cell therapies have also made great progress toward the successful treatment of solid tumor indications. The field is rapidly evolving with recent advancements including the clinical development of "off‐the‐shelf" allogeneic CAR‐T therapies that can overcome the long and difficult "vein‐to‐vein" wait time seen with autologous CAR‐T therapies. There are unique clinical pharmacology, pharmacometric, bioanalytical, and immunogenicity considerations and challenges in the development of these CAR‐T and TCR‐T cell therapies. Hence, to help accelerate the development of these life‐saving therapies for the patients with cancer, experts in this field came together under the umbrella of International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) to form a joint working group between the Clinical Pharmacology Leadership Group (CPLG) and the Translational and ADME Sciences Leadership Group (TALG). In this white paper, we present the IQ consortium perspective on the best practices and considerations for clinical pharmacology and pharmacometric aspects toward the optimal development of CAR‐T and TCR‐T cell therapies. [ABSTRACT FROM AUTHOR]

JNJ‐64264681 is an irreversible covalent inhibitor of Bruton's tyrosine kinase. This phase 1, first‐in‐human, 2‐part (single‐ascending dose [SAD]; multiple‐ascending dose [MAD]) study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD; Bruton's tyrosine kinase occupancy [BTKO]) of JNJ‐64264681 oral solution in healthy participants. For SAD (N = 78), 6 increasing doses of JNJ‐64264681 (4–400 mg) or placebo were evaluated in fasted males. The effects of sex, food, and a capsule formulation were evaluated in separate cohorts. For MAD (N = 27), sequential cohorts of male and female participants received 36/100/200 mg JNJ‐64264681 once daily for 10 days. JNJ‐64264681 exposure (peak concentration; area under the concentration‐time curve) was less than dose proportional from 4 mg to 36 mg. Dose‐normalized area under the concentration‐time curves following the 36 mg and 100 mg doses were generally similar. The mean terminal half‐life was 1.6–13.2 hours. With multiple doses, steady state was achieved by day 2. A semimechanistic PK/PD model was developed using the first 5 SAD cohorts' data to predict %BTKO in MAD cohorts. PK/PD model guided dose‐escalation, and all participants in the 200/400 mg single‐dose cohorts achieved ≥90% BTKO at 4 hours after dosing (peak) with prolonged occupancy. As BTKO data became available from MAD cohorts, it was found that observed BTKO data were consistent with model predictions. JNJ‐64264681 showed no safety signals of concern. Overall, safety, tolerability, PK, BTKO, and PK/PD modeling guided the rationale for dose selection for the subsequent first‐in‐patient lymphoma studies. [ABSTRACT FROM AUTHOR]

Aims: To assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of CNTO 7160, an anti‐interleukin‐33 receptor (IL‐33R) monoclonal antibody, in healthy subjects and patients with asthma or atopic dermatitis (AD). Methods: In Part 1 of this Phase I, randomized, double‐blind, placebo‐controlled study, healthy subjects (n = 68) received single ascending intravenous (IV) CNTO 7160 dose (0.001 to 10 mg/kg) or placebo. In Part 2, patients with mild asthma (n = 24) or mild AD (n = 15) received 3 biweekly IV CNTO 7160 doses (3 or 10 mg/kg) or placebo. Results: CNTO 7160 was generally well tolerated, with 1 serious adverse event of severe cellulitis reported (AD, CNTO 7160, 3 mg/kg). CNTO 7160 exhibited nonlinear PK (0.01–10 mg/kg). Mean clearance decreased with increasing dose (2.43 to 18.03 mL/d/kg). CNTO 7160 PK was similar between healthy subjects and patients with asthma or AD (3 or 10 mg/kg). Free sIL‐33R suppression was rapid and dose dependent. Ex vivo inhibition of p38 phosphorylation of basophils was dose‐dependent (1–10 mg/kg) and sustained inhibition (≥75%) was observed at higher doses (3 or 10 mg/kg). PK/PD modelling and simulation suggests that 1 mg/kg IV every 2 weeks provides adequate systemic drug exposure for sustained inhibition of p38 phosphorylation of basophils. Despite confirmation of target engagement, no apparent CNTO 7160 clinical activity was observed in patients (asthma or AD). Conclusion: This first‐in‐human study provides PK, PD and safety data, supporting further clinical investigation of CNTO 7160 in patients with asthma and AD. [ABSTRACT FROM AUTHOR]