A Review of the Evolving Landscape of Inclusive Research and Improved Clinical Trial Access.

Current clinical research does not reflect the diversity of patient populations, despite continued recommendations to increase enrollment of under-represented racial and ethnic groups. The ramifications of this lack of trial diversity are important because of potential differences between races and ethnicities in response to therapies, which have been observed for drugs across indications. Nonrepresentative research populations limit the generalizability of study results, which may lead to questions about safety and efficacy in certain subgroups of patients and hinder regulators, healthcare providers, and patients in their ability to adequately consider the benefits and risks of a therapeutic treatment across all populations. Renewed efforts to address healthcare disparities and increase diversity in clinical trials have demonstrated that inclusive trials are achievable and can provide scientifically rigorous results, and, thus, should stimulate greater action across all stakeholders. Ensuring that studies throughout the clinical development process include representative populations is a scientific imperative to advance health equity, racial justice, and trust in the safety and efficacy of medical therapies. This article reviews the long-standing lack of diversity and barriers to enrollment of diverse and representative populations in clinical trials, outlines the current evolving trial landscape and the efforts of stakeholders, and provides examples from scientifically rigorous inclusive trials. The goal is to share learnings in a wider context of opportunities to enhance diversity, equity, and inclusion in clinical development while ensuring the safety and efficacy of medical therapies in all populations of patients, and in doing so, provide wider patient access to therapeutic treatments.

Action for Increasing Diversity, Market Access, and Capacity in Oncology Registration Trials-Is Africa the Answer? Report From a Satellite Session of the Accelerating Anti-Cancer Agent Development and Validation Workshop.

Patients of African ancestry are not well-represented in cancer clinical trials despite bearing a disproportionate share of mortality both in United States and Africa. We describe key stakeholder perspectives and priorities related to bringing early-stage cancer clinical trials to Africa and outline essential action steps. Increasing Diversity, Market Access, and Capacity in Oncology Registration Trials-Is Africa the Answer? satellite session was organized at 2021 Accelerating Anti-Cancer Agent Development and Validation Workshop. Panelists included representatives of African Organization for Research and Training in Cancer, Uganda Cancer Institute, Uganda Women's Cancer Support Organization, BIO Ventures for Global Health, Bill & Melinda Gates Foundation, the US Food and Drug Administration, Nigeria's National Agency for Food and Drug Administration and Control, Bayer, and Genentech, with moderators from ASCO and American Cancer Society. Key discussion themes and resulting action steps were agreed upon by all participants. Panelists agreed that increasing diversity in cancer clinical trials by including African patients is key to ensuring novel drugs are safe and effective across populations. They underscored the importance of equity in clinical trial access for patients in Africa. Panelists discussed their values related to access and barriers to opening clinical trials in Africa and described innovative solutions from their work aimed at overcoming these obstacles. Multisectoral collaboration efforts that allow leveraging of limited resources and result in sustainable capacity building and mutually beneficial long-term partnerships were discussed as key to outlined action steps. The panel discussion resulted in valuable insights about key stakeholder values and priorities related to bringing early-stage clinical trials to Africa, as well as specific actions for each stakeholder group.

Advancing Inclusive Research: Establishing Collaborative Strategies to Improve Diversity in Clinical Trials.

Well-characterized disparities in clinical research have disproportionately affected patients of color, particularly in underserved communities. To tackle these barriers, Genentech formed the External Council for Advancing Inclusive Research, a 14-person committee dedicated to developing strategies to increase clinical research participation. To help improve the recruitment and retention of patients of color, this article chronicles our efforts to tangibly address the clinical research barriers at the system, study, and patient levels over the last four years. These efforts are one of the initial steps to fully realize the promise of personalized health care and provide increased patient benefit at less cost to society. Instead of simply acknowledging the problem, here we illuminate the collaborative and multilevel strategies that have been effective in delivering meaningful progress for patients.

Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia.

BACKGROUND: Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear. METHODS: We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28. RESULTS: A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P = 0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, -5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.).

Using patient-initiated study participation in the development of evidence for personalized cancer therapy.

Personalized cancer therapy offers the promise of delivering the right treatments to the right patients to improve patient outcomes and quality of life, while reducing exposure to ineffective therapies and the cost of cancer care. Realizing this promise depends in large part on our ability to generate timely and sufficiently detailed information regarding factors that influence treatment response. Generating this evidence through the traditional physician investigator-initiated clinical trial system has proved to be challenging, given poor recruitment rates and low compliance with requests for biospecimen collection. As a result, our current understanding of treatment response is inadequate, particularly for cancer therapies that have been in use for many years. Patient-initiated study participation may offer a new model for evidence generation that capitalizes on strong patient interest in furthering research to inform better and more tailored cancer therapies. In this approach, patients are engaged and recruited directly by the sponsor of an Institutional Review Board-approved study, and patients subsequently drive the participation of their health care providers to facilitate collection of required data and tissue samples. The ultimate goal of these studies is to generate evidence of sufficient quality to inform regulatory decisions (i.e., labeling changes for marketed therapies to reflect populations most likely to respond) and treatment selection. Here, we describe a hypothetical prospective observational study in non-small cell lung cancer that could serve as a model for patient-initiated study participation applied to understand molecular determinants of treatment response. Key elements discussed include study design, patient engagement, and data/biospecimen collection and management principles.

Characterization of 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (JNJ-39729209) as a novel TRPV1 antagonist.

As an integrator of multiple nociceptive and/or inflammatory stimuli, TRPV1 is an attractive therapeutic target for the treatment of various painful disorders. Several TRPV1 antagonists have been advanced into clinical trials and the initial observations suggest that TRPV1 antagonism may be associated with mild hyperthermia and thermal insensitivity in man. However, no clinical efficacy studies have been described to date, making an assessment of risk:benefit impossible. Furthermore, it is not clear whether these early observations are representative of all TRPV1 antagonists and whether additional clinical studies with novel TRPV1 antagonists are required in order to understand optimal compound characteristics. In the present study we describe 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (JNJ-39729309) as a novel, TRPV1 antagonist. JNJ-39729209 displaced tritiated resiniferotoxin binding to TRPV1 and prevented TRPV1 activation by capsaicin, protons and heat. In-vivo, JNJ-39729209 blocked capsaicin-induced hypotension, induced a mild hyperthermia and inhibited capsaicin-induced hypothermia in a dose dependent manner. JNJ-39729209 showed significant efficacy against carrageenan- and CFA-evoked thermal hyperalgesia and exhibited significant anti-tussive activity in a guinea-pig model of capsaicin-induced cough. In pharmacokinetic studies, JNJ-39729209 was found to have low clearance, a moderate volume of distribution, good oral bioavailability and was brain penetrant. On the basis of these findings, JNJ-39729209 represents a structurally novel TRPV1 antagonist with potential for clinical development. The advancement of JNJ-39729209 into human clinical trials could be useful in further understanding the analgesic potential of TRPV1 antagonists.

JNJ-26070109 [(R)4-bromo-N-[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide]: a novel, potent, and selective cholecystokinin 2 receptor antagonist with good oral bioavailability.

JNJ-26070109 [(R)4-bromo-N-[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide] is a representative of a new chemical class of competitive antagonists of cholecystokinin 2 (CCK2) receptors. In this study, the primary in vitro pharmacology of JNJ-26070109 was evaluated along with the pharmacokinetic and pharmacodynamic properties of this compound in rat and canine models of gastric acid secretion. JNJ-26070109 expressed high affinity for human (pK(I) = 8.49 ± 0.13), rat (pK(I) = 7.99 ± 0.08), and dog (pK(I) = 7.70 ± 0.14) CCK2 receptors. The selectivity of JNJ-26070109 at the CCK2 receptor versus the CCK1 receptor was species-dependent, with the greatest degree of selectivity (>1200-fold) measured at the human isoforms of the CCK1 receptor (selectivity at CCK2 versus CCK1 receptors: human, ∼1222-fold; rat, ∼324-fold; dog ∼336-fold). JNJ-26070109 behaved as a surmountable, competitive, antagonist of human CCK2 receptors in a calcium mobilization assay (pK(B) = 8.53 ± 0.05) and in pentagastrin-stimulated gastric acid secretion in the isolated, lumen-perfused, mouse stomach assay (pK(B) = 8.19 ± 0.13). The pharmacokinetic profile of this compound was determined in vivo in rats and dogs. JNJ-26070109 was shown to have high oral bioavailability (%F rat = 73 ± 16; %F dog = 92 ± 12) with half lives of 1.8 ± 0.3 and 1.2 ± 0.1 h in rat and dog, respectively. The pharmacodynamic properties of this compound were investigated using two in vivo models. In conscious rat and dog chronic gastric fistula models of pentagastrin-stimulated acid secretion, JNJ-26070109 had oral EC(50) values of 1.5 and 0.26 µM, respectively. Overall, we have demonstrated that JNJ-26070109 is a high-affinity, selective CCK2 receptor antagonist with good pharmacokinetic properties.

1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines as TRPV1 antagonists with improved properties.

Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure-activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 ≥237 µg/mL and SIF=11 µg/mL) was significantly improved over compound 1 (pH 2=5 µg/mL and SIF=0.5 µg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL=0.7 L/kg/h) compared to compound 1 (CL=3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats.

Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepines as novel TRPV1 antagonists.

Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of TRPV1. The tetrahydro-pyrimdoazepines have been identified as having good in vitro and in vivo potency and acceptable physical properties.

Discovery of potent cholecystokinin-2 receptor antagonists: elucidation of key pharmacophore elements by X-ray crystallographic and NMR conformational analysis.

A novel series of cholecystokinin-2 receptor (CCK-2R) antagonists has been identified, as exemplified by anthranilic sulfonamide 1 (pK(i)=7.6). Pharmacokinetic and stability studies indicated that this series of compounds suffered from metabolic degradation, and that both the benzothiadiazole and piperidine rings were rapidly oxidized by liver enzymes. A combination of synthesis, computational methods, (1)H NMR conformational studies, and X-ray crystallographic analyses were applied to elucidate key pharmacophore elements, and to discover analogs with improved pharmacokinetic profiles, and high receptor binding affinity and selectivity.

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516), a novel, potent, and selective cholecystokinin 1 receptor antagonist: in vitro and in vivo pharmacological comparison with dexloxiglumide.

3-[5-(3,4-Dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionate (JNJ-17156516) is a novel, potent, and selective cholecystokinin (CCK)1-receptor antagonist. In this study, the pharmacology of JNJ-17156516 was investigated both in vitro and in vivo, and the pharmacokinetic profile was evaluated in rats. JNJ-17156516 expressed high-affinity at the cloned human (pK(I) = 7.96 +/- 0.11), rat (pK(I) = 8.02 +/- 0.11), and canine (pK(I) = 7.98 +/- 0.04) CCK1 receptors, and it was also highly selective for the CCK1 receptor compared with the CCK2 receptor across the same species ( approximately 160-, approximately 230-, and approximately 75-fold, respectively). The high affinity of JNJ-17156516 at CCK1 receptors in vitro was confirmed in radioligand binding studies on fresh human gallbladder tissue (pK(I) = 8.22 +/- 0.05). In a functional in vitro assay of guinea pig gallbladder contraction, JNJ-17156516 behaved as a competitive antagonist, with a pK(B) value of 8.00 +/- 0.07. In vivo, JNJ-17156516 produced a parallel, rightward shift in the CCK-8S-evoked contraction of the guinea pig gallbladder. The dose required to shift the CCK-8S dose-response curve was 240 nmol kg(-1) i.v. In the anesthetized rat, JNJ-17156516 produced a dose-related decrease in the number of duodenal contractions evoked by infusion of CCK-8S, with an ED(50) = 484 nmol kg(-1). Pharmacokinetic analysis of JNJ-17156516 in rats, revealed that JNJ-17156516 had a half-life of 3.0 +/- 0.5 h and a very high bioavailability (108 +/- 10%) in this species. Overall, we have demonstrated that JNJ-17156516 is a high-affinity selective human CCK1 receptor antagonist with good pharmacokinetic properties in rats.

Identification and optimization of anthranilic sulfonamides as novel, selective cholecystokinin-2 receptor antagonists.

A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK-2R) ligands resulted in the discovery of a novel series of antagonists, represented by 1-[2-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-5-chlorobenzoyl]-piperidine (1; CCK-2R, pK(I) = 6.4). Preliminary exploration of the structure-activity relationships around the anthranilic ring and the amide and sulfonamide moieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-fold selectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identification of 4-[4-iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpholine, 26d, a compound that demonstrates promising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oral bioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat when dosed orally.

A novel, quantitative bio-assay for cholecystokinin type-1 receptor activity in the anaesthetised rat.

INTRODUCTION: Cholecystokinin type-1 (CCK(1)) receptors mediate many of the physiological functions of CCK including delay of gastric emptying, pancreatic enzyme secretion, intestinal motility and gallbladder contractility. Existing in-vivo assays for the quantitative measurement of CCK(1) receptor mediated function are generally variable, limited in precision and require a relatively large number of animals to obtain statistically meaningful data. We found that they did not provide robust pharmacokinetic-pharmacodynamic data for profiling compounds acting at these receptors. Accordingly, here we describe a novel rat duodenal contractility assay that addresses these problems. METHODS: Rats were anaesthetised and a saline-filled balloon was inserted through the body of the stomach and secured in the duodenum approximately 1 cm from the pyloric sphincter for measurement of intra-lumenal pressure. Studies were performed to determine a dose, rate and frequency of administration of CCK8S that produced a readily quantifiable response. RESULTS: Initial experiments revealed that sustained exposure to CCK8S resulted in the rapid development of tachyphylaxis. After investigating different dosing paradigms, it was found that pulsatile delivery of CCK8S (intravenous infusion for 1 min every 10 min) produced a readily quantifiable contractile response that did not exhibit tachyphylaxis. The assay response output was defined as the number of contractions >5 mm Hg over baseline. The contractions were blocked in a dose-dependent manner by intravenous bolus injections of the CCK(1) receptor antagonists, dexloxiglumide (2 and 20 micromol/kg), and devazepide (3-100 nmol/kg) but not by the CCK(2) receptor antagonist gastrazole (10 micromol/kg). CONCLUSION: A novel, simple, high quality assay for the quantification of the in-vivo activity of CCK(1) receptor ligands is described. CCK8S delivered by pulsatile intravenous infusion to anesthetized rats produced a burst of contractile activity of the duodenum mediated by CCK(1) receptors. This activity was highly reproducible and sustained for more than 3 h providing an assay that circumvents problems associated with agonist-induced tachyphylaxis.