Aim:Although regulatory guidances require human metabolism information of drug candidates early in the development process, the human mass balance study (or hADME study), is performed relatively late. hADME studies typically involve the administration of a 14 C-radiolabelled drug where biological samples are measured by conventional scintillation counting analysis. Another approach is the administration of therapeutic doses containing a 14 C-microtracer followed by accelerator mass spectrometry (AMS) analysis, enabling hADME studies completion much earlier. Consequently, there is an opportunity to change the current drug development paradigm. Materials & methods: To evaluate the applicability of the MICADAScAMS method, we successfully performed: the validation of MICADAS-cAMS for radioactivity quantification in biomatrices and, a rat ADME study, where the conventional methodology was assessed against a microtracer MICADAS-cAMS approach. Results & discussion: Combustion AMS (cAMS) technology is applicable to microtracer studies. A favorable opinion from EMA to complete the hADME in a Phase I setting was received, opening the possibilities to change drug development. Keywords:In the scope of drug development, regulatory guidances encourage the early identification of relevant human metabolites [1][2][3]. A human ADME study that used radiolabeled drugs allows the identification of metabolites and the elucidation of key biotransformation pathways and clearance mechanisms in humans. However, due to the high study cost, the needs for a dosimetry assessment (which include a rat distribution investigation) and for a GMP manufacturing as well as the high attrition rates encountered in drug development, the conventional hADME is generally performed late in drug development (Phase II, see Supplementary Figure 1). The administered dose in a conventional hADME study can contain up to 3.7 mBq of radioactivity which is analysed by scintillation counting. To address the regulatory demands earlier, a first investigation of pharmacokinetics (PK) and excretion routes is typically performed with a radiolabeled drug in rodents. Subsequently, exploratory analysis of potentially relevant metabolites is investigated in early clinical samples (Phase I) without the use of radiolabel [4,5] (Supplementary Figure 1). However, the applied LC-MS methods can fail to identify unknown metabolites. If human-specific metabolites are generated in early clinical samples, these metabolites will not be detected in preclinical species using radiolabeled drug, and will not be discovered in humans until the radiolabeled human mass balance ADME study is completed. To address this gap, we propose to dose a normal, therapeutically relevant dose spiked with very low amounts of a radiotracer to healthy volunteers or patients in a Phase I setting. Thereafter, the mass balance, the excretion routes and levels of circulating metabolites in humans are determined by accelerator mass spectrometry (AMS) as suggested by Lappin and Garner [6,7].AMS is a highly sensit...
Polycomb Repressive Complex 2 (PRC2) plays an important role in transcriptional regulation during animal development and in cell differentiation, and alteration of PRC2 activity has been associated with cancer. On a molecular level, PRC2 catalyzes methylation of histone H3 lysine 27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27, of which the trimethylated form H3K27me3 leads to transcriptional repression of polycomb target genes. Previously, we have shown that binding of the lowmolecular-weight compound EED226 to the H3K27me3 binding pocket of the regulatory subunit EED can effectively inhibit PRC2 activity in cells and reduce tumor growth in mouse xenograft models. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound 22) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development.
Fevipiprant is a novel oral prostaglandin D receptor 2 (DP; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multidrug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.
Neonatal dopamine (DA) depletion produces learning impairments both during development and throughout adulthood in the rat. The present experiment further investigated the memory capabilities of the dopamine-depleted rat by assessing performance in the radial arm maze. Results showed that, following neonatal injection of 6-hydroxydopamine and desmethylimipramine, lesioned rats per-performed more accurately than controls. In this paradigm, DA-depleted rats tended to enter each arm to obtain a food pellet and not enter unbaited, incorrect arms. The difference in performance of control and treated rats could not be accounted for by differences in locomotor activity, body weights, or motivational factors. A computer analysis of the data revealed that DA-depleted animals adopted a strategy of choosing adjacent arms consecutively, which probably accounted for their superior performance. Results are discussed in terms using algorithms versus extra-maze cues to complete the maze following early brain injury.
List of AbbreviationsADME, absorption, distribution, metabolism, and excretion; Ae, amount of drug excreted into urine; AUC, area under the concentration-time curve; AUClast, area under the concentration-time curve from time zero to the time of the last quantifiable concentration; AUCtau,ss, area under the concentration-time curve from time zero to the end of the dosing interval tau at steady state; AUC0-t, area under the concentration-time curve from time zero to time "t" where t is a defined time-point
Tisagenlecleucel demonstrated high response rates and a manageable safety profile in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. However, lack of response and CAR-T cell exhaustion were observed in patients with PD-1 overexpression. Hence, pembrolizumab, a PD-1 inhibitor, was hypothesized to improve efficacy and cellular expansion of CAR-T cells in vivo. Here, we report the final analysis of the PORTIA trial in adult patients with r/r DLBCL who had ≥2 prior lines of therapy and had an Eastern Cooperative Oncology Group performance status of ≤1. Patients received one tisagenlecleucel infusion on Day 1. Pembrolizumab 200 mg was given every 21 days, for up to 6 doses. Three cohorts initiated pembrolizumab on Days 15 (n=4), 8 (n=4), or -1 (n=4). Safety, efficacy, cellular kinetics, and biomarker analyses were included. Tisagenlecleucel and pembrolizumab was feasible and showed a manageable safety profile, without dose-limiting toxicities. Emerging efficacy with tisagenlecleucel was observed when pembrolizumab was given the day before tisagenlecleucel; however, the limited patient sample and short follow-up do not allow for definitive conclusions. Adding pembrolizumab to tisagenlecleucel did not augment the cellular expansion of tisagenlecleucel but delayed peak expansion if given the day before tisagenlecleucel (NCT03630159).
Background: Chimeric antigen receptor (CAR)-T cells are highly effective in patients (pts) with multiple myeloma (MM), but duration of response can be limited, and pts with rapidly progressing disease require a fast and reliable CAR-T cell manufacturing process. Here, we report initial clinical data from a Phase I trial assessing PHE885 manufactured using the T-Charge TM process and characterization of in vivo expansion, suggesting a preserved T-cell stemness (T scm) phenotype in pts with relapsed/refractory (r/r) MM (NCT04318327). Methods: PHE885 is a unique and fully human BCMA CAR-T cell product manufactured using the novel T-Charge TM platform, which reduces ex vivo culture time to about 24 hours and takes <2 days to manufacture the final product, thereby relying entirely on in vivo expansion after CAR-T cell infusion. Pts with MM r/r to ≥2 prior lines of treatment (tx), including an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody, were eligible. Pts received fludarabine and cyclophosphamide for lymphodepletion prior to a single PHE885 intravenous injection. Primary objectives were safety, including dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary objectives were clinical responses, evaluation of the T-Charge TM process, and pharmacokinetic properties. Results: As of data cut (April 1, 2021), 7 pts were enrolled in the dose escalation portion; 1 pt failed screening (prolonged QTc), and 6 pts were successfully infused with PHE885. All pts were heavily pretreated, penta-refractory, and refractory to the last line of tx. Fixed doses received were 5×10 6 (n=5) and 14.3×10 6 CAR+ T cells (n=1). All 6 pts were eligible for safety and efficacy. Two DLTs were reported: asymptomatic grade 3 transaminitis in the pt infused with 14.3×10 6 CAR+ T cells, and asymptomatic grade 4 lipase increased in 1 pt infused with 5×10 6 CAR+ T cells. Treatment-related grade ≥3 AEs included anemia and neutropenia in all pts; thrombocytopenia (n=4, 67%); and leukopenia, cytokine release syndrome (CRS), ALT and AST increase, and decreased blood fibrinogen (each n=2, 33%). All pts experienced grade ≤3 CRS per Lee 2014 criteria; median times to CRS onset and resolution were 7 d (range, 4-9 d) and 22 d (range, 10-27 d), respectively. All pts received at least 1 dose each of steroids and tocilizumab; 3 pts received anakinra to manage CRS. Two pts experienced grade 2 neurotoxicity related to PHE885. Both events were nonserious and temporally associated with grade 3 CRS. No deaths occurred on study. At 1 mo after tx, all pts had achieved at least a partial response (PR), with complete response (CR) in 1 pt (17%) and very good PR in 2 pts (33%). Of 4 pts evaluable at 3 mo after tx, 2 had stringent CR, 1 had PR, and 1 pt in PR experienced progressive disease, presumed to be due to loss of BCMA. Of 3 pts evaluable for minimal residual disease (MRD) at 1 mo after tx, all were MRD negative: 2 at sensitivity of 10 -6 and 1 at 10 -5. Robust cellular expansion was observed in all pts via qPCR and flow cytometry; maximum expansion (geometric mean C max) was 283000 copies/μg by qPCR and 69.3% of circulating T cells by flow cytometry. Maximum expansion was reached by 30 d, with median T max of 21.1 d by qPCR (16.4 d by flow cytometry). PHE885 was detectable in peripheral blood up to the latest measured sample for each pt (6 mo for the longest followed pt; range of follow-up, 1-6 mo). A naïve-like T-cell phenotype (T naïve+T scm) was preserved during manufacturing of all PHE885 products. Conclusions: Initial data from this Phase I study demonstrate that low doses of BCMA CAR-T cells manufactured by T-Charge TM in <2 days have encouraging clinical activity and a manageable safety profile in pts with r/r MM. PHE885 CAR-T cells expand rapidly in vivo, persist at relatively high levels for prolonged periods, and demonstrate a relatively immature T-cell phenotype. The trial is ongoing and updated data will be presented at the annual meeting. Clinical trial information: NCT04318327 Figure 1 Figure 1. Disclosures Sperling: Adaptive: Consultancy. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Nadeem: Bristol Myer Squibb: Consultancy; GSK: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy. Mo: Eli Lilly: Consultancy; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AbbVIE: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ikegawa: Bristol Myers Squibb: Honoraria. Shaw: Orchard Therapeutics, Ltd: Current equity holder in publicly-traded company. Ansari: Novartis: Current Employment. Quinn: Novartis: Current Employment, Current equity holder in publicly-traded company. Pearson: Novartis: Current Employment, Current equity holder in publicly-traded company. Hack: Novartis: Current Employment. Treanor: Novartis: Current Employment, Current holder of individual stocks in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties: no royalties as company-held patents. Bu: Novartis: Current Employment, Patents & Royalties: Co-inventor on patent applications. Mataraza: Novartis: Current Employment, Current holder of stock options in a privately-held company. Rispoli: Novartis: Current Employment. Credi: Novartis: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Ritz: Amgen: Research Funding; Equillium: Research Funding; Kite/Gilead: Research Funding; Avrobio: Membership on an entity's Board of Directors or advisory committees; Akron: Consultancy; Biotech: Consultancy; Blackstone Life Sciences Advisor: Consultancy; Clade Therapeutics, Garuda Therapeutics: Consultancy; Immunitas Therapeutic: Consultancy; LifeVault Bio: Consultancy; Novartis: Consultancy; Rheos Medicines: Consultancy; Talaris Therapeutics: Consultancy; TScan Therapeutics: Consultancy. De Vita: Novartis: Current Employment. Munshi: Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Adaptive Biotechnology: Consultancy; Abbvie: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Janssen: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Legend: Consultancy; Bristol-Myers Squibb: Consultancy.
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