Clinical Development Plan Research Articles

Bayesian Predictive Probability Based on a Bivariate Index Vector for Single-Arm Phase II Study With Binary Efficacy and Safety Endpoints.

In oncology, Phase II studies are crucial for clinical development plans as such studies identify potent agents with sufficient activity to continue development in the subsequent Phase III trials. Traditionally, Phase II studies are single-arm studies, with the primary endpoint being short-term treatment efficacy. However, drug safety is also an important consideration. In the context of such multiple-outcome designs, predictive probability-based Bayesian monitoring strategies have been developed to assess whether a clinical trial will provide enough evidence to continue with a Phase III study at the scheduled end of the trial. Therefore, we propose a new simple index vector to summarize the results that cannot be captured by existing strategies. Specifically, we define the worst and most promising situations for the potential effect of a treatment, then use the proposed index vector to measure the deviation between the two situations. Finally, simulation studies are performed to evaluate the operating characteristics of the design. The obtained results demonstrate that the proposed method makes appropriate interim go/no-go decisions.

Characteristics of individuals with cystic fibrosis in the United States ineligible for ivacaftor and elexacaftor/tezacaftor/ivacaftor

BackgroundWe characterized people with cystic fibrosis (CF) ineligible by genotype (not age) for currently approved CFTR modulator therapy using data from the US CF Foundation Patient Registry (CFFPR). MethodsWe summarized clinical characteristics using CFFPR data from 2017 to 2022. Annual rate of change in percent predicted of forced expiratory volume in one second (ppFEV1) was estimated using generalized estimating equations. ResultsA total of 2,790 individuals with CF met inclusion criteria. In 2022, 12 % were less than 6 years old, 16 % were age 6–12 years, 18 % age 12–18 years and 54 % were ≥18 years. The proportion identified as White was 74 %, 17 % Black, and 26 % as Hispanic. The median (IQR) age at diagnosis was 1.2 (0.5, 9.1) months for children and 3.1 (0.3, 17.4) years for adults. Median (IQR) ppFEV1 among children was 91.9 (80.3; 102.4) and among adults, 74.3 (52.4; 90.4). Pancreatic enzymes were prescribed for 77.8 %. Population-level average (95 % CI) rates of decline in ppFEV1 among the pancreatic insufficient population was -1.5 per year (-1.8; -1.2) for ages 6 to <11 years, -2.2 per year (-2.6; -1.8) for ages 12 to <18 years, and -1.5 per year (-1.7; -1.3) for adults. ConclusionsWe describe the CFTR modulator ineligible population in the US in 2017–2022. With a growing pipeline of therapies aimed at improving CFTR function for those who cannot benefit from modulators due to ineligibility, characterization of both the size and outcomes of these populations are critical to inform optimal clinical development plans and future clinical trials.

Safety, efficacy, and biomarker results from an open-label, multicenter, phase 1 study of RP2 alone or combined with nivolumab in a cohort of patients with uveal melanoma.

9511 Background: Uveal melanoma is the most common primary intraocular tumor in adults and has a high risk of liver metastasis. Effective treatments for metastatic uveal melanoma (MUM) are limited, as MUM responds poorly to immune checkpoint inhibition. RP2 is an enhanced-potency oncolytic HSV-1–expressing human GM-CSF, a fusogenic glycoprotein (GALV-GP-R−), and an anti–CTLA-4 antibody-like molecule. We present safety, efficacy, and biomarker data for RP2 monotherapy and RP2 +nivolumab (nivo; anti–PD-1) in patients (pts) with MUM (NCT04336241). Methods: Pts ≥18 years old with advanced or metastatic non-neurologic solid tumors (including MUM) who progressed on, or could not tolerate, standard therapy were included in the clinical trial; pts had ≥1 measurable and injectable tumor (≥1 cm). After determination of the recommended phase 2 dose of intratumoral RP2 (1×106 PFU/mL once, then ≤7 doses at 1×107 PFU/mL; ≤10 mL total/treatment day), pts received RP2 Q2W as monotherapy or in addition to nivo (240 mg Q2W/480 mg Q4W). Responses were assessed per modified RECIST v1.1.Tumor biopsies and peripheral blood mononuclear cells were collected pre-treatment and at day 43 and were analyzed by immunohistochemistry (IHC) and/or sequencing of the CDR3β region of the T-cell receptor (TCR) by immunoSEQ. Results: A total of 17 pts with MUM were enrolled (RP2 monotherapy, n = 3; RP2 + nivo, n = 14). Most pts had received both anti–PD-1 and anti–CTLA-4 therapy (12/17 [70.6%]), and 3/17 (17.6%) had received ≥3 prior lines of therapy. The ORR was 29.4% (5/17; all PRs; RP2 monotherapy, 1/3; RP2 + nivo, 4/14). The DCR (CR + PR + SD) was 58.8% (10/17). The median (range) duration of response at the data cutoff was 11.5 (2.8–21.2) months, with some responses and disease stabilizations ongoing. The most common overall grade 1–2 treatment-related AEs (TRAEs; ≥20% overall) were pyrexia, chills, fatigue, hypotension, and pruritus. The only grade 3 TRAE in &gt; 1 pt was hypotension (2 pts receiving RP2 + nivo); no grade 4/5 TRAEs occurred. Evaluable baseline and post-treatment biopsies were used for IHC (n = 8) and TCR sequencing analyses. Paired biopsies from pts with clinical benefit (n = 5; 2 PR, 3 SD) showed an increase in tumor PD-L1 expression by IHC analysis, and 4 of these pts (2 PR, 2 SD) exhibited an increase in CD8+ T-cell infiltration into tumors. TCR sequencing following treatment with RP2 + nivo revealed expansion of pre-existing TCRs and generation of new T-cell clones. Conclusions: RP2 alone or combined with nivo demonstrated a favorable safety profile and meaningful antitumor activity in pts with previously treated MUM. Biomarker data indicated immune cell infiltration and increased PD-L1 expression in tumors and changes in the peripheral T-cell repertoire following RP2 ± nivo therapy. Based on these results, a randomized, controlled clinical development plan is being planned. Clinical trial information: NCT04336241 .

Human Pharmacokinetic and CYP3A Drug-Drug Interaction Prediction of GDC-2394 Using Physiologically Based Pharmacokinetic Modeling and Biomarker Assessment.

Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and drug-drug interaction (DDI) of GDC-2394. PBPK models were developed using in vitro and in vivo data to reflect the oral and intravenous PK profiles of mouse, rat, dog, and monkey. The learnings from preclinical PBPK models were applied to a human PBPK model for prospective human PK predictions. The prospective human PK predictions were within 3-fold of the clinical data from the first-in-human study, which was used to optimize and validate the PBPK model and subsequently used for DDI prediction. Based on the majority of PBPK modeling scenarios using the in vitro CYP3A induction data (mRNA and activity), GDC-2394 was predicted to have no-to-weak induction potential at 900 mg twice daily (BID). Calibration of the induction mRNA and activity data allowed for the convergence of DDI predictions to a narrower range. The plasma concentrations of the 4β-hydroxycholesterol (4β-HC) were measured in the multiple ascending dose study to assess the hepatic CYP3A induction risk. There was no change in plasma 4β-HC concentrations after 7 days of GDC-2394 at 900 mg BID. A dedicated DDI study found that GDC-2394 has no induction effect on midazolam in humans, which was reflected by the totality of predicted DDI scenarios. This work demonstrates the prospective utilization of PBPK for human PK and DDI prediction in early drug development of GDC-2394. PBPK modeling accompanied with CYP3A biomarkers can serve as a strategy to support clinical pharmacology development plans. SIGNIFICANCE STATEMENT: This work presents the application of physiologically based pharmacokinetic modeling for prospective human pharmacokinetic (PK) and drug-drug interaction (DDI) prediction in early drug development. The strategy taken in this report represents a framework to incorporate various approaches including calibration of in vitro induction data and consideration of CYP3A biomarkers to inform on the overall CYP3A-related DDI risk of GDC-2394.

Abstract 3296: IK-595, a best-in-class MEK-RAF molecular glue, drives broad and potent anti-tumor activity across RAS-MAPK pathway-altered cancers as a monotherapy and in combination

Abstract Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. Although MEK is a clinically validated cancer target and several MEK inhibitors have been approved by the FDA, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas. We developed the molecular glue, IK-595, a potent inhibitor of the MEK-RAF complex, to overcome the limitations of available MEK inhibitors. IK-595 traps MEK in an inactive complex with all RAF isoforms, as well as mutant forms of BRAF (Class I, II, and III), and blocks RAF-dependent MEK phosphorylation, thereby alleviating CRAF-mediated MEK reactivation that limits the efficacy of approved MEK inhibitors in RAS/RAF-driven tumors. We demonstrate that IK-595 leads to potent and prolonged inhibition of MEK and ERK1/2 phosphorylation in RAS-mutant cancer models. Importantly, IK-595 has a much slower off-rate binding to MEK and retains CRAF longer in an inactive complex with MEK than other MEK/RAF inhibitors, allowing for prolonged target engagement and durable pathway inhibition in RAS/RAF mutant cancer cells. IK-595 exhibits potent single agent activity across a wide range of cancer model indications harboring various RAS/MAPK pathway alterations, including KRAS, NRAS, BRAF and NF1 mutations, and BRAF and CRAF fusions. The benefits of combining IK-595 with inhibitors targeting key resistance mechanisms both within the RAS/MAPK pathway and across parallel survival pathways has also been observed in multiple models. Additionally, IK-595 improved the response of KRAS-driven tumor models to standard of care chemotherapeutic agents, expanding the potential clinical opportunity for IK-595. Key to the design of IK-595 is its PK profile that enables transient high plasma drug exposure and flexible dosing schedules. Intermittent dosing of IK-595 every other day (QOD) or every three days (Q3D) in KRAS-mutant mouse tumor models shows similar efficacy and improved tolerability compared to daily dosing (QD), affording a larger therapeutic window. Preclinical pharmacology studies provide clear guidance to the clinical development plan of IK-595, where flexible dosing schedules, multiple expansion cohorts in RAS/RAF altered patient populations, and combination therapies with mediators of resistance will be explored. IK-595 is a novel MEK-RAF molecular glue that prolongs pathway inhibition, minimizing the potential for resistance, while providing an optimal therapeutic window for patients with RAS/RAF-driven cancer. Citation Format: Eric Haines, Rachel Catterall, Victor De Jesus, Daniel Hidalgo, Jill Cavanaugh, Marta Sanchez-Martin, Joseph D. Manna, Michael Burke, Bin Li, Sarah R. Wessel, Ao Yang, Sergio Santillana, Jeffrey Ecsedy, X. Michelle Zhang, Sabine K. Ruppel. IK-595, a best-in-class MEK-RAF molecular glue, drives broad and potent anti-tumor activity across RAS-MAPK pathway-altered cancers as a monotherapy and in combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3296.

Abstract 5707: Preclinical evaluation of KRLS-017, a potent, highly selective and reversible CDK7 inhibitor with broad antitumor effect in preclinical models, in preparation for a Phase 1 clinical trial in advanced solid tumor malignancies

Abstract KRLS-017 is a potent, selective, and reversible inhibitor of Cyclin Dependent Kinase 7 (CDK7). Its molecular formula is C24H35N5O2Si and its molecular weight is 453.65 Daltons. KRLS-017 is being developed for the treatment of patients with advanced solid tumor malignancies. To differentiate KRLS-017 from other CDK7 inhibitors, we created a reversible inhibitor to allow for treatment schedule optimization and maximization of therapeutic index in clinic. High selectivity of KRLS-017 for CDK7 was confirmed using a panel of 313 recombinant human kinases. The IC50 of KRLS-017 against recombinant human CDK7 was determined to be 16 nM, and no other kinases in the panel showed IC50 values less than 300 nM. Antiproliferative activity of KRLS-017 was investigated in vitro using a broad panel of human tumor cell lines. KRLS-017 showed potent antiproliferative effect across a wide variety of both solid and hematologic tumor types, producing GI50 values &amp;lt;200 nM in 258/302 human tumorcell lines tested. Antitumor activity of KRLS-017 was investigated in vivo using multiple mouse xenograft tumormodels at dose levels ranging from 25 mg/kg to 200 mg/kg using both continuous (daily) andintermittent dosing schedules. Statistically significant tumor growth inhibition was seen at doselevels of 50 mg/kg and higher, with tumor regression observed at 100 mg/kg and 200 mg/kg. Better in vivo tolerability at efficacious doses was observed using intermittent dosing schedules in mouse xenograft models, which led to adoption of an intermittent schedule in the proposed first-in-human phase 1 trial. KRLS-017 is orally bioavailable in mice, rats, and dogs and plasma drug exposure increased in a proportional manner with dose. Comparing first dose and 28th dose in the dog, minimal plasma accumulation was observed, suggesting once daily dosing in humans would be initially tested. Repeat dose 28 day GLP toxicology studies in rat and dog showed adverse effects in highly proliferative bone marrow and gastrointestinal tissues which is consistent with the known mechanism of action for CDK7 and is considered to be monitorable and manageable in the setting of oncology. The clinical development plan for KRLS-017 includes an initial Phase 1 dose escalation study (KRLS-017-101) in patients with refractory solid tumor malignancies to assess pharmacokinetics/pharmacodynamics and to determine an optimal dose level and treatment schedule to test in expansion cohorts. Given the potential of CDK7 inhibitors in the treatment of hormone receptor positive breast cancer, combination work with other agents (such as selective estrogen receptor degraders) is on-going. Citation Format: Alison L. Hannah, Steve Ritland, Thomas Steele, Steven Smith, Ashwin Ram, BT Slingsby, Kapil Dhingra, James Chrisman, Rajesh Dua, Yasunori Tokunaga, Shigeyuki Kono, Yasuhiro Aga. Preclinical evaluation of KRLS-017, a potent, highly selective and reversible CDK7 inhibitor with broad antitumor effect in preclinical models, in preparation for a Phase 1 clinical trial in advanced solid tumor malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5707.

Abstract 6356: Novel antibody targeting tumor NKG2D ligand MIC: Preclinical studies and clinical development plan for mCRPC

Abstract In response to genomic insults and DNA double-strand breaks, the stressed epithelial cells express the MHC I-chain related molecule (MIC) on the surface as a byproduct of activating the ATM pathway. The MIC molecule itself has no known impact on tumor survival or growth. In the context of immune microenvironment, tumor cell surface MIC can activate NK cells and co-stimulate CD8 T cells by engaging in the activating receptor NKG2D to hinder the early tumorigenesis. However, in established malignancies, in particular metastatic diseases, tumor cells shed surface MIC to release the soluble form MIC (sMIC). It has been well demonstrated that, in contrary to cell surface MIC, sMIC is highly immune suppressive by disturbing NK cell homeostasis and repolarizing NK cells function, impairing antigen-specific CD8 T cell function by downmodulating NKG2D expression and CD3z expression, and facilitating immune suppression of MDSCs and TAMs in tumor microenvironment. We have demonstrated that MIC is prevalently expressed by prostate tumor cells and significantly upregulated in mCRPC tumors. We have shown significantly elevated levels of serum sMIC in prostate cancer patients with metastatic diseases. We have developed a novel class of clinical candidate monoclonal antibody huB10G5 that can target both sMIC and surface MIC to re-invigorate both NK and CD8 T cell function and inhibit MDSCs and TAMs in preclinical models. The huB10G5 has an acceptable safety profile and is currently completing CMC for IND enabling. We hypothesize that huB10G5 is a novel immune therapeutic reagent for mCRPC patients. To test our hypothesis, we first conducted serial studies of the clinical candidate huB10G5 in pre-clinical models of prostate cancers. We found that huB10G5 can effectively induce 100% long-term tumor complete regression (CR) as low as 1.0 mg/KG. These animals are fully protected from tumor re-challenge. The anti-tumor effect is mediated by the combined action of NK and CD8 T cells. With the support of our pre-clinical efficacy and safety data, we have planned to initiate Phase I clinical trial with huB10G5 for mCRPC patients in 2024. Citation Format: Jennifer Donglan Wu, Jeff Sosman, Masha Kocherginsky, Anthony Serritella, Maha Hussian, David J. Vanderweele. Novel antibody targeting tumor NKG2D ligand MIC: Preclinical studies and clinical development plan for mCRPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6356.

Abstract B155: IK-595, a best-in-class MEK-RAF complex inhibitor, drives broad and potent anti-tumor activity in RAS/RAF-driven tumors

Abstract Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. Although MEK is a clinically validated cancer target and several MEK inhibitors have been approved by the FDA, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas. We developed IK-595, a potent inhibitor of the MEK-RAF complex, to overcome the limitations of available MEK inhibitors. IK-595 traps MEK in an inactive complex with all RAF isoforms and blocks RAF-dependent MEK phosphorylation, thereby alleviating CRAF-mediated MEK reactivation that hinders the efficacy of approved MEK inhibitors in RAS/RAF-driven tumors. We demonstrate that IK-595 leads to potent and prolonged inhibition of MEK and ERK1/2 phosphorylation, in KRAS-mutant cancer and NRAS-mutant melanoma models. In addition to trapping all three RAF isoforms, IK-595 stabilizes the interaction of MEK with BRAF Class I, II, and III mutant proteins. This delays the onset of known resistance mechanisms to other MAPK pathway targeting agents, such as CRAF-mediated pathway reactivation and receptor tyrosine kinase upregulation and/or activation. Importantly, IK-595 has a much slower off-rate binding to MEK and retains CRAF longer in an inactive complex with MEK than other MEK/RAF inhibitors allowing for more prolonged target engagement and durable pathway inhibition in RAS/RAF mutant cancer cells. Moreover, CRAF-ARAF heterodimerization, which is detected in type II pan-RAF inhibitor-treated KRAS mutant cells as an established resistance mechanism, is not observed upon IK-595 treatment. IK-595 exhibits potent signal agent activity across a wide range of cancer models harboring various RAS/RAF alterations, including lung, pancreatic, colorectal cancer (CRC), melanoma, AML, and others. Strong synergy with inhibitors targeting multiple key mechanisms, both within the RAS/MAPK pathway and across parallel survival pathways, has also been observed in multiple models. Key to the design of IK-595 is its PK profile that enables transient high plasma drug exposure and flexible dosing schedules. Intermittent dosing of IK-595 every other day (QOD) or every three days (Q3D) in KRAS mutant mouse tumor models shows similar efficacy and improved tolerability compared to daily dosing (QD), affording a larger therapeutic window. Preclinical pharmacology studies provide clear guidance to the clinical development plan of IK-595, where flexible dosing schedules and multiple expansion cohorts in RAS/RAF altered patient populations will be explored. IK-595 is a novel MEK-RAF complex inhibitor that prolongs pathway inhibition, minimizing the potential for resistance, while providing an optimal therapeutic window for patients with RAS/RAF-driven cancer. Citation Format: Eric Haines, Rachel Catterall, Victor De Jesus, Bin Li, Sarah R Wessel, Jill Cavanaugh, Michael Burke, Joseph D Manna, Okzana Zavidij, Ao Yang, Lan Xu, Sergio Santillana, Jeffrey Ecsedy, X. Michelle Zhang, Sabine K Ruppel. IK-595, a best-in-class MEK-RAF complex inhibitor, drives broad and potent anti-tumor activity in RAS/RAF-driven tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B155.

Abstract B054: TNG348, a selective USP1 inhibitor, shows strong preclinical combination activity with PARP inhibitors and other agents targeting DNA repair

Abstract Tumors that are deficient in homologous recombination repair are generally sensitive to agents that target pathways involved in DNA repair, including PARP inhibitors (PARPi) and platinum-based drugs. Despite the clinical benefit of PARP1/2 inhibitors, which are FDA-approved for the treatment of certain BRCA-mutant cancers, many patients achieve incomplete disease control and develop resistance. PARP inhibitors have been shown to synergize with chemotherapy and platinum-based drugs, but such combinations are limited clinically due to overlapping toxicities, highlighting the need for novel combination strategies. We previously reported on the identification of USP1 as a target that selectively kills BRCA1/2-mutant cancer cells. TNG348 is an oral, allosteric and potent inhibitor of USP1 (USP1i). Here we present the mechanism of action and preclinical efficacy of TNG348 across multiple BRCA1/2 mutant and other homologous recombination deficient (HRD) tumor models, demonstrating its therapeutic potential. In preclinical models, TNG348 activity is further enhanced when combined with agents targeting DNA repair pathways, including PARP inhibitors. In a PDX model of acquired PARPi resistance, TNG348 demonstrates strong combination activity with PARPi demonstrating the ability of USP1i + PARPi to restore sensitivity to PARPi in the setting of acquired resistance. CRISPR-based drug anchor screens with and without PARPi or USP1i reveal that this synergy is driven by non-overlapping mechanisms of action. While sensitivity to either USP1i or PARPi is associated with HRD status, resistance to PARPi, but not USP1i, occurred with knock out of shieldin components, 53BP1, PARG and other previously reported mechanisms. In contrast, resistance to USP1i was uniquely gained by knocking out genes involved in PCNA ubiquitination and translesion synthesis. In summary, these data support the clinical development plan to evaluate TNG348 in patients with BRCA1/2 mutant and other HRD tumors as single agent and in combination with PARPi. Citation Format: Antoine Simoneau, Charlotte Pratt, Grace Comer, Hsin-Jung Wu, Ashley Choi, Tenzing Khendu, Samuel Meier, Yi Yu, Shangtao Liu, Wenhai Zhang, Douglas Whittington, William Mallender, Sirimas Sudsakorn, Yingnan Chen, Brian Haines, Scott Throner, Adam Crystal, Alan Huang, John Maxwell, Jannik Andersen. TNG348, a selective USP1 inhibitor, shows strong preclinical combination activity with PARP inhibitors and other agents targeting DNA repair [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B054.

Think Globally, Act Globally: The Key Role Global Hubs Play in Oncological Drug Development

When global health crises such as the COVID-19 pandemic and HIV/AIDS epidemic occur, drug developers and researchers have an opportunity to highlight the benefits of implementing international clinical development plans to make treatments available as quickly as possible for patients around the world. However, when these public crises are not a factor, organizations typically wait until a product is nearing its approval stage before planning for and developing an international strategy.

A Comparison of Treatment Effect Sizes in Matched Phase 2 and Phase 3 Trials of Advanced Therapeutics in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.

Phase 2 trials are fundamental to the rational and efficient design of phase 3 trials. We aimed to determine the relationship of treatment effect size estimates from phase 2 and phase 3 clinical trials on advanced therapeutics in inflammatory bowel disease. MEDLINE, EMBASE, CENTRAL, and the Cochrane library were searched from inception to December 19, 2022, to identify paired phase 2 and 3 placebo-controlled induction studies of advanced therapeutics for Crohn's disease (CD) and ulcerative colitis (UC). Treatment effect sizes were expressed as a risk ratio (RR) between the active arm and placebo arm. For the same therapeutics, RRs from phase 2 trials were divided by the RR from phase 3 trial to quantify the relationship of effect sizes between phases. Twenty-two studies (9 phase 2 trials, 13 phase 3 trials) were included for CD and 30 studies (12 phase 2 trials, 18 phase 3 trials) for UC. In UC (pooled RR 0.72; 95% confidence interval: 0.58-0.86; RR <1 indicates smaller treatment effect sizes in phase 2 trials), but not CD (pooled RR 1.01; 95% confidence interval: 0.84-1.18), phase 2 trials systematically underestimated treatment effect sizes for the primary endpoint compared with phase 3 trials. The underestimation was observed for clinical, but not endoscopic, endpoints in UC. Treatment effect sizes for the primary and clinical endpoints were similar across clinical trial phases in CD, but not UC, where only endoscopic endpoints were comparable. This will help inform clinical development plans and future trial design.

Oncology drug lag in Japan: has it improved over the last decade?

Existing studies and statistics on the drug lag between Japan and the United States (US) for anti-cancer drugs indicate that it has decreased, whereas more drugs are left unapproved in Japan. This study aimed to quantify the impact of unapproved drugs on the drug lag. Information on 136 anti-cancer drugs approved in the US between 2011 and 2022 was collected. The approval lag, defined as the number of days from the date of approval in the US to the date of approval in Japan, was calculated for all selected drugs, and the median was calculated using the Kaplan-Meier method. The approval lag for drugs not approved in Japan was treated as censored data. Factors potentially associated with the approval lag were explored using Cox regression analysis. The median approval lags for the first half-period (2011-2016) and the last half-period (2017-2022) were 961 days (2.6 years) and 1547 days (4.2 years), respectively (Log-rank test: p = 0.0687). The participation of Japan in the global pivotal trial was associated with a shorter approval lag, and new drug applications by non-Japanese companies that did not rank in the global sales top 20 were associated with a longer approval lag. Drug lag has not decreased over the last decade. The percentage of pivotal trials for US approval that included Japan has increased but should be further increased in the future. Japan may require a scheme to encourage smaller non-Japanese companies to include Japan in their global clinical development plan.

Impact of an online pharmacy precepting-focused continuing professional development program

IntroductionThis study aimed to determine the preceptor-reported impact of an online continuing professional development (CPD) program on pharmacy preceptors' abilities and techniques for teaching students in clinical settings. MethodsIn 2017, an online program to educate and support pharmacy preceptors' use of CPD to create individualized clinical teaching development plans was launched. After allowing time for preceptors to implement their CPD plan, a follow-up program was launched in 2019 where preceptors completed a seven-question survey to assess their impact on clinical teaching from the initial program. Two questions described completion of the CPD plan with response options including “Yes,” “No,” or “Partially”. Five open-ended questions allowed for descriptions of changes implemented and overall teaching impact. Impact of implemented changes were categorized as positive, negative, or no change. Changes implemented by preceptors were categorized as goal setting, feedback, communication/education skills, student-teacher connection, or educational resources development. ResultsOf the 119 preceptors who responded to at least one question, 52% fully implemented and 39% partially implemented their pre-identified CPD plan. A total of 75 preceptors provided responses regarding impact of implemented activities; 69 (92%) were coded as a positive impact on their clinical teaching. Preceptor skill development was most commonly in communication/educational skills (45%), student/teacher connection (33%), and educational resources development (33%). ConclusionsThis online precepting CPD program had a positive preceptor-reported impact on clinical teaching delivered by preceptors to students. Further investigation is warranted to disseminate this program.

Model-Informed Approaches and Innovative Clinical Trial Design for Adeno-Associated Viral Vector-Based Gene Therapy Product Development: A White Paper.

The promise of viral vector-based gene therapy (GT) as a transformative paradigm for treating severely debilitating and life-threatening diseases is slowly coming to fruition with the recent approval of several drug products. However, they have a unique mechanism of action often necessitating a tortuous clinical development plan. Expertise in such complex therapeutic modality is still fairly limited in this emerging class of adeno-associated virus (AAV) vector-based gene therapies. Because of the irreversible mode of action and incomplete understanding of genotype-phenotype relationship and disease progression in rare diseases careful considerations should be given to GT product's benefit-risk profile. In particular, special attention needs to be paid to safe dose selection, reliable dose exposure response (including clinically relevant endpoints), or creative approaches in study design targeting small patient populations during clinical development. We believe that quantitative tools encompassed within model-informed drug development (MIDD) framework fits quite well in the development of such novel therapies, as they enable us to benefit from the totality of data approach in order to support dose selection as well as optimize clinical trial designs, end point selection, and patient enrichment. In this thought leadership paper, we provide our collective experiences, identify challenges, and suggest areas of improvement in applications of modeling and innovative trial design in development of AAV-based GT products and reflect on the challenges and opportunities for incorporating MIDD tools and more in rational development of these products.

Driving Diversity and Inclusion in Cancer Drug Development - Industry and Regulatory Perspectives, Current Practices, Opportunities, and Challenges.

In April 2022, the FDA issued draft guidance to help industry develop strategies to improve diversity in clinical trials. Historically, clinical trial sponsors have not systematically incorporated efforts to promote diversity, equity, and inclusion (DEI), particularly during the early design stages of clinical development plans and operational strategies. Unfortunately, a retrospective approach to DEI often results in clinical trial participants not being reflective of the diversity of patients intended to be treated with new therapies. A shift to prospective, intentional DEI strategies for clinical trials, including long-term engagement with diverse patients and communities throughout the development life cycle, is necessary to maximize the benefits and minimize the risks of new drugs and devices for all patients. Sponsors' current practices and opportunities for improving DEI address four major topics: institutional commitment, culture change, and governance; clinical development strategy; setting enrollment goals to ensure trial participant diversity; and development and implementation of the operational strategy. As DEI practices gain wider adoption in clinical trials, shared learning and collaboration among stakeholders on an ongoing and noncompetitive basis will lead to sustainable change. Prioritization of enrollment of diverse populations as an integral part of study start-up planning, clinical trial design, and recruitment capabilities will enhance the clinical development process for oncology therapies. Importantly, these efforts will help provide equitable access to clinical trials and innovative cancer therapies.

Investigational Use of Mesenchymal Stem/Stromal Cells and Their Secretome as Add-On Therapy in Severe Respiratory Virus Infections: Challenges and Perspectives.

Serious manifestations of respiratory virus infections such as influenza and coronavirus disease 2019 (COVID-19) are associated with a dysregulated immune response and systemic inflammation. Treating the immunological/inflammatory dysfunction with glucocorticoids, Janus kinase inhibitors, and monoclonal antibodies against the interleukin-6 receptor has significantly reduced the risk of respiratory failure and death in hospitalized patients with severe COVID-19, but the proportion of those requiring invasive mechanical ventilation (IMV) and dying because of respiratory failure remains elevated. Treatment of severe influenza-associated pneumonia and acute respiratory distress syndrome (ARDS) with available immunomodulators and anti-inflammatory compounds is still not recommended. New therapies are therefore needed to reduce the use of IMV and the risk of death in hospitalized patients with rapidly increasing oxygen demand and systemic inflammation who do not respond to the current standard of care. This paper provides a critical assessment of the published clinical trials that have tested the investigational use of intravenously administered allogeneic mesenchymal stem/stromal cells (MSCs) and MSC-derived secretome with putative immunomodulatory/antiinflammatory/regenerative properties as add-on therapy to improve the outcome of these patients. Increased survival rates are reported in 5 of 12 placebo-controlled or open-label comparative trials involving patients with severe and critical COVID-19 and in the only study concerning patients with influenza-associated ARDS. Results are encouraging but inconclusive for the following reasons: small number of patients tested in each trial; differences in concomitant treatments and respiratory support; imbalances between study arms; differences in MSC source, MSC-derived product, dosing and starting time of the investigational therapy; insufficient/inappropriate reporting of clinical data. Solutions are proposed for improving the clinical development plan, with the aim of facilitating regulatory approval of the MSC-based investigational therapy for life-threatening respiratory virus infections in the future. Major issues are the absence of a biomarker predicting responsiveness to MSCs and MSC-derived secretome and the lack of pharmacoeconomic evaluations.

Abstract 4968: Characterization of the clinical development candidate TNG348 as a potent and selective inhibitor of USP1 for the treatment of BRCA1/2mut cancers

Abstract TNG348 is a selective and potent inhibitor of the deubiquitinating enzyme USP1 specifically designed to target BRCA1/2mut vulnerabilities in breast and ovarian tumors. Here we present the biochemical, mechanistic, and in vitro and in vivo characterization of TNG348, an oral, allosteric and highly potent inhibitor of USP1. Upon treatment, TNG348 causes loss of viability in a panel of breast and ovarian BRCA1/2mut cancer cell lines and displays dose-dependent tumor growth inhibition in BRCA1/2mut xenograft models. Furthermore, TNG348 activity extends beyond BRCA1/2mut models with PARP inhibitor (PARPi) sensitivity and oncogene-induced replication stress being additional features correlating with USP1 inhibitor sensitivity based on cell line panel and CRISPR screening results. We show that TNG348 induces cell death through a pathway that is distinct from PARPi and TNG348 demonstrates robust synergy when combined with first- or second-generation PARPi. The clinical development plan intends to evaluate TNG348 in patients with BRCA1/2 mutations as single agent and in combination with PARP1i in patients naïve to PARPi and with prior PARPi treatment history. Citation Format: Antoine Simoneau, Hsin-Jung Wu, Madhavi Bandi, Katherine Lazarides, Sining Sun, Shangtao Liu, Samuel Meier, Ashley Choi, Hongxiang Zhang, Binzhang Shen, Douglas Whittington, Sirimas Sudsakorn, Wenhai Zhang, Yi Yu, Yong Liu, Colin Liang, Michael Palmieri, Yingnan Chen, Brian Haines, Alice Tsai, Minjie Zhang, Alan Huang, Jannik Andersen, Tianshu Feng, Scott Throner, John Maxwell. Characterization of the clinical development candidate TNG348 as a potent and selective inhibitor of USP1 for the treatment of BRCA1/2mut cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4968.

Strengthening clinical development activities and preparedness for vaccine manufacturers from emerging countries: Results of a survey.

Vaccine development, in most cases, is a long, complex process, often lasting years and involving a combination of public and private stakeholders. Particularly, the vaccine clinical development process is highly regulated by several guidelines, regulatory pathways and science-based recommendations from experts. Designing and executing a successful clinical development plan for any candidate vaccine requires a solid scientific, medical, operational and regulatory knowledge and expertise, to comply with regulations and assure adequate benefit-risk balance for the product to be used in mass vaccination of healthy populations. The purpose of this study was to assess the approaches and practices related to Clinical Development functions, and related activities among vaccine manufacturers based in emerging countries, and to identify industry needs in terms of organizational development and training needs. A structured questionnaire designed specifically for assessing indicators of clinical activities, in the last five years, comprised of four sections aimed to collect information on (1) the organizational structure and the activities conducted by the clinical functions; (2) the clinical trial design ability and the management of clinical trial documents; (3) the clinical trial management and monitoring activities; (4) the quality aspects of clinical activities. The results suggest that the great majority of respondents is engaged in intense clinical development activities, as indicated by the high number of licensed vaccines available and supplied in the national markets or in foreign markets, including vaccines with WHO prequalification status. Areas to further strengthen the clinical activities and medical research preparedness were identified. Greater engagements of stakeholders' and investments will be required to expand the clinical basis in vaccine R&D, and to support achieving a high level of preparedness in emerging countries, for development of new vaccines against future regional epidemics and global pandemics.

The unique challenges of clinical trials in rare disease: A regulatory writer’s perspective

Designing clinical trials in rare diseases comes with a specific set of challenges including limited knowledge around the natural history of a disease, small sample size available for trial participation, regulatory guidance that is not calibrated to the rare disease context, manufacturing and supply issues, and safety and financial risks. Here, we discuss some of these potential challenges and how, through proactive early engagement with key opinion leaders, regulatory bodies, and patient groups, a cohesive and strategic clinical development plan can be created to provide the strongest foundations when marketing approval is sought.

Extent of safety database in pediatric drug development: types of assessment, analytical precision, and pathway for extrapolation through on-target effects

ABSTRACT Pediatric patients should have access to medicines that have been appropriately evaluated for safety and efficacy through revised labelling. Given this goal, the adequacy of the pediatric clinical development plan and resulting safety database are critical factors to inform a favorable benefit-risk assessment for the intended use of the medicinal product. While extrapolation from adults can be used to support efficacy of drugs in children, there may be a reluctance to use the same approach in safety assessments, wiping out potential gains in trial efficiency through a reduction of sample size. To address this issue, we explore safety review in pediatric trials, including specific types of safety assessments and precision on the estimation of event rates for specific adverse events (AEs) that can be achieved. In addition, we discuss the assessments which can provide a benchmark for the use of extrapolation of safety that focuses on on-target effects. Finally, we explore a unified approach for understanding precision using Bayesian approaches as the most appropriate methodology to describe or ascertain risk in probabilistic terms for the estimate of the event rate of specific AEs.