Concurrent Stage III Unresectable Duodenal Adenocarcinoma and Metastatic Gastrointestinal Stromal Tumor Treated With Combination of Imatinib and mFOLFIRI.

Cases of concurrent duodenal adenocarcinoma and gastrointestinal stromal tumors (GISTs) are rare, and only a few have been reported. While some cases of other synchronous primary tumors with GIST have been reported, no shared mutations have been consistently found, creating challenges in selecting chemotherapy in cases of inoperable tumors. Here, we presented a case of a stage IIIA locally advanced/unresectable duodenal adenocarcinoma with concurrent metastatic small bowel GIST successfully being treated with combined imatinib and modified folinic acid, 5-fluorouracil, and irinotecan (mFOLFIRI) regimen.

Early identification of SOX17 deficiency in infants to guide management of heritable pulmonary arterial hypertension using PDA stent to create reverse Potts shunt physiology.

Heritable pulmonary arterial hypertension (HPAH) is a rare progressive condition that includes patients with an identified genetic cause of pulmonary arterial hypertension (PAH). HPAH and idiopathic PAH (IPAH) have an estimated combined incidence of 0.5-0.9 cases per million children-years. Several pathogenic variants have been associated with HPAH in children and adults, including genes BMPR2, TBX4, and ACVRL1, and more rarely with variants in genes such as SOX17. HPAH is often difficult to manage and has poor prognosis despite advances in medical therapy with many patients progressing to lung transplantation, right heart failure and death. Surgical and transcatheter Potts shunt creation can reduce systolic burden and has shown reduction in morbidity and mortality in children. Early genetic testing can provide both diagnostic and prognostic value in managing and counseling children with severe PAH and it can guide transcatheter or surgical management in refractory cases despite maximal medical therapies. We describe a patient with HPAH (SOX17 mutation) who underwent percutaneous patent ductus arteriosus stent for right ventricle decompression at 2 months of age with clinical management guidance by genetic testing results.

Myeloid-Derived Suppressor Cells: Therapeutic Target for Gastrointestinal Cancers.

Gastrointestinal cancers represent one of the more challenging cancers to treat. Current strategies to cure and control gastrointestinal (GI) cancers like surgery, radiation, chemotherapy, and immunotherapy have met with limited success, and research has turned towards further characterizing the tumor microenvironment to develop novel therapeutics. Myeloid-derived suppressor cells (MDSCs) have emerged as crucial drivers of pathogenesis and progression within the tumor microenvironment in GI malignancies. Many MDSCs clinical targets have been defined in preclinical models, that potentially play an integral role in blocking recruitment and expansion, promoting MDSC differentiation into mature myeloid cells, depleting existing MDSCs, altering MDSC metabolic pathways, and directly inhibiting MDSC function. This review article analyzes the role of MDSCs in GI cancers as viable therapeutic targets for gastrointestinal malignancies and reviews the existing clinical trial landscape of recently completed and ongoing clinical studies testing novel therapeutics in GI cancers.

Targeted Therapies for Neonatal Pulmonary Hypertension: Beyond Nitric Oxide.

Pulmonary hypertension in the neonatal population can be acute or chronic and carries significant risk for morbidity and mortality. It can be idiopathic but more often is associated with comorbid pulmonary and heart disease. There are several pharmacotherapeutics aimed at pulmonary vasodilation. This review highlights the most common agents as well as those on the horizon for the treatment of pulmonary hypertension in the neonate.

A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir.

Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that is used as an oral antiviral coronavirus disease 2019 (COVID-19) treatment. To sustain unbound systemic trough concentrations above the antiviral in vitro 90% effective concentration value (EC90), nirmatrelvir is coadministered with 100 mg of ritonavir, a pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvir's cytochrome P450 (CYP) 3A4-mediated metabolism which results in renal elimination becoming the primary route of nirmatrelvir elimination when dosed concomitantly. Nirmatrelvir exhibits absorption-limited nonlinear pharmacokinetics. When coadministered with ritonavir in patients with mild-to-moderate COVID-19, nirmatrelvir reaches a maximum concentration of 3.43 µg/mL (11.7× EC90) in approximately 3 h on day 5 of dosing, with a geometric mean day 5 trough concentration of 1.57 µg/mL (5.4× EC90). Drug interactions with nirmatrelvir/ritonavir (PAXLOVIDTM) are primarily attributed to ritonavir-mediated CYP3A4 inhibition, and to a lesser extent CYP2D6 and P-glycoprotein inhibition. Population pharmacokinetics and quantitative systems pharmacology modeling support twice daily dosing of 300 mg/100 mg nirmatrelvir/ritonavir for 5 days, with a reduced 150 mg/100 mg dose for patients with moderate renal impairment. Rapid clinical development of nirmatrelvir/ritonavir in response to the emerging COVID-19 pandemic was enabled by innovations in clinical pharmacology research, including an adaptive phase 1 trial design allowing direct to pivotal phase 3 development, fluorine nuclear magnetic resonance spectroscopy to delineate absorption, distribution, metabolism, and excretion profiles, and innovative applications of model-informed drug development to accelerate development.

Stage 1 and 2 Palliation: Comparing Ductal Stenting and Aorto-Pulmonary Shunts in Single Ventricles with Duct-Dependent Pulmonary Blood Flow.

Patent ductus arteriosus stenting (PDAS) for ductal-dependent pulmonary blood flow (DDPBF) provides a new paradigm for managing neonates with single ventricles (SV). Currently, sparse data exist regarding outcomes for subsequent palliation. We describe our experience with inter-stage care and stage 2 (S2P) conversion with PDAS in comparison to a prior era of patients who received surgical aorto-pulmonary shunts (APS). Retrospective review of 18 consecutive DDPBF SV patients treated with PDAS between 2016 and 2021 was done and compared with 9 who underwent APS from 2010 to 2016. Patient outcomes and pulmonary artery (PA) growth were analyzed. S2P was completed in all 18 with PDAS with no cardiac arrests and one post-S2P mortality. In the 9 APS patients, there was one cardiac arrest requiring ECMO and one mortality inter-stage. Off cardiopulmonary bypass strategy was utilized in 10/18 in the PDAS and 1/9 in the APS group (p = 0.005) at S2P. Shorter ventilation time, earlier PO feeding, and shorter hospital stay were noted in the PDAS group (p = 0.01, p = 0.006, p = 0.03) (S2P). Median Nakata index increase inter-stage was not significant between the PDAS and APS at 94.1 mm2/m2 versus 71.7 mm2/m2 (p = 0.94). Median change in pulmonary artery symmetry (PAS) was - 0.02 and - 0.24, respectively, which was statistically significant (p = 0.008). Neurodevelopmental outcomes were better in the PDAS group compared to the APS group (p = 0.02). PDAS provides excellent PA growth, inter-stage survival, progression along multistage single-ventricle palliation, and potentially improved neurodevelopmental outcomes. Most patients can be transitioned through 2 stages of palliation without CPB.

Chaetocin-mediated SUV39H1 inhibition targets stemness and oncogenic networks of diffuse midline gliomas and synergizes with ONC201.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG/DMG) are devastating pediatric brain tumors with extraordinarily limited treatment options and uniformly fatal prognosis. Histone H3K27M mutation is a common recurrent alteration in DIPG and disrupts epigenetic regulation. We hypothesize that genome-wide H3K27M-induced epigenetic dysregulation makes tumors vulnerable to epigenetic targeting. METHODS: We performed a screen of compounds targeting epigenetic enzymes to identify potential inhibitors for the growth of patient-derived DIPG cells. We further carried out transcriptomic and genomic landscape profiling including RNA-seq and CUT&RUN-seq as well as shRNA-mediated knockdown to assess the effects of chaetocin and SUV39H1, a target of chaetocin, on DIPG growth. RESULTS: High-throughput small-molecule screening identified an epigenetic compound chaetocin as a potent blocker of DIPG cell growth. Chaetocin treatment selectively decreased proliferation and increased apoptosis of DIPG cells and significantly extended survival in DIPG xenograft models, while restoring H3K27me3 levels. Moreover, the loss of H3K9 methyltransferase SUV39H1 inhibited DIPG cell growth. Transcriptomic and epigenomic profiling indicated that SUV39H1 loss or inhibition led to the downregulation of stemness and oncogenic networks including growth factor receptor signaling and stemness-related programs; however, D2 dopamine receptor (DRD2) signaling adaptively underwent compensatory upregulation conferring resistance. Consistently, a combination of chaetocin treatment with a DRD2 antagonist ONC201 synergistically increased the antitumor efficacy. CONCLUSIONS: Our studies reveal a therapeutic vulnerability of DIPG cells through targeting the SUV39H1-H3K9me3 pathway and compensatory signaling loops for treating this devastating disease. Combining SUV39H1-targeting chaetocin with other agents such as ONC201 may offer a new strategy for effective DIPG treatment.

Metastatic retinoblastoma at presentation: Clinical presentation, treatment, and outcomes.

The aim of this study was to retrospectively determine clinical features, treatment outcomes, and overall survival in four patients with metastatic retinoblastoma at presentation. The mean age at diagnosis was 63 months (range: 24-108 months). Three patients had overt orbital disease of at least one eye and one patient had microscopic orbital disease with scleral infiltration on histopathology. Metastatic sites included regional lymph nodes (RLN) (n = 4), bone marrow (BM) (n = 2), and cerebrospinal fluid (CSF) (n = 1). The most common sites of RLN were ipsilateral preauricular nodes (two patients) and contralateral parotid gland involvement (one patient). The treatment administered included primary enucleation (n = 1), high-dose intravenous chemotherapy (n = 4), secondary enucleation (n = 2), orbital external beam radiotherapy (n = 3), and intrathecal chemotherapy (n = 1). High-risk features included massive choroidal and microscopic scleral infiltration in the eye that underwent primary enucleation. At a mean follow-up of 33 months (range, 4-68 months), one patient with CSF involvement deceased in 4 months. The remaining three patients were alive and disease-free at the last mean follow-up period of 43 months (range, 18-68 months). The results of our study showed that RLN and BM metastasis respond well to treatment while CSF metastasis is associated with poor prognosis.

Cancer Biology or Ineffective Surveillance? A multicentre retrospective analysis of colitis-associated post-colonoscopy colorectal cancers.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is associated with high rates of post-colonoscopy colorectal cancer (PCCRC), but further in-depth qualitative analyses are required to determine whether they result from inadequate surveillance or aggressive IBD cancer evolution. METHODS: All IBD patients who had a colorectal cancer (CRC) diagnosed between January 2015 to July 2019 and a recent (<4 years) surveillance colonoscopy at one of four English hospital trusts underwent root cause analyses as recommended by the World Endoscopy Organisation to identify plausible PCCRC causative factors. RESULTS: 61% (n=22/36) of the included IBD CRCs were PCCRCs. They developed in patients with high cancer risk factors (77.8%; n=28/36) requiring annual surveillance, yet 57.1% (n=20/35) had inappropriately delayed surveillance. Most PCCRCs developed in situations where (i) an endoscopically unresectable lesion was detected (40.9%; n=9/22), (ii) there was a deviation from the planned management pathway (40.9%; n=9/22) e.g. service, clinician or patient-related delays in acting on a detected lesion, or (iii) lesions were potentially missed as they were typically located within areas of active inflammation or post-inflammatory change (36.4%; n=8/22). CONCLUSIONS: IBD PCCRC prevention will require more proactive strategies to reduce endoscopic inflammatory burden, improve lesion optical characterisation, adherence to recommended surveillance intervals and patient acceptance of prophylactic colectomy. However, the significant proportion appearing to originate from non-adenomatous-looking mucosa which fail to yield neoplasia on biopsy yet display aggressive cancer evolution highlight the limitations of current surveillance. Emerging molecular biomarkers may play a role in enhancing cancer risk stratification in future clinical practice.

DECIDE: Delphi Expert Consensus Statement on Inflammatory Bowel Disease Dysplasia Shared Management Decision-Making.

BACKGROUND AND AIMS: Inflammatory bowel disease colitis-associated dysplasia is managed with either enhanced surveillance and endoscopic resection or prophylactic surgery. The rate of progression to cancer after a dysplasia diagnosis remains uncertain in many cases and patients have high thresholds for accepting proctocolectomy. Individualised discussion of management options is encouraged to take place between patients and their multidisciplinary teams for best outcomes. We aimed to develop a toolkit to support a structured, multidisciplinary and shared decision-making approach to discussions about dysplasia management options between clinicians and their patients. METHODS: Evidence from systematic literature reviews, mixed-methods studies conducted with key stakeholders, and decision-making expert recommendations were consolidated to draft consensus statements by the DECIDE steering group. These were then subjected to an international, multidisciplinary modified electronic Delphi process until an a priori threshold of 80% agreement was achieved to establish consensus for each statement. RESULTS: In all, 31 members [15 gastroenterologists, 14 colorectal surgeons and two nurse specialists] from nine countries formed the Delphi panel. We present the 18 consensus statements generated after two iterative rounds of anonymous voting. CONCLUSIONS: By consolidating evidence for best practice using literature review and key stakeholder and decision-making expert consultation, we have developed international consensus recommendations to support health care professionals counselling patients on the management of high cancer risk colitis-associated dysplasia. The final toolkit includes clinician and patient decision aids to facilitate shared decision-making.

Universal Genetic Testing vs. Guideline-Directed Testing for Hereditary Cancer Syndromes Among Traditionally Underrepresented Patients in a Community Oncology Program.

Background Detection of pathogenic germline variants (PGVs) has implications for cancer screening, prognosis, treatment selection, clinical trial enrollment, and family testing. Published guidelines provide indications for PGV testing, determined by clinical and demographic factors, but their applicability in an ethnically and racially diverse community hospital population is unknown. This study describes the diagnostic and incremental yield of universal multi-gene panel testing in a diverse population in a community cancer practice. Methods We completed a prospective study of proactive germline genetic sequencing among patients with solid tumor malignancies at a community-based oncology practice in downtown Jacksonville, FL, between June 2020 and September 2021. The patients were unselected for cancer type, stage, family history, race/ethnicity, and age. PGVs identified using an 84-gene next-generation sequencing (NGS) tumor genomic testing platform were stratified by penetrance. National Comprehensive Cancer Networks (NCCN) guidelines determined incremental PGV rates. Results Two hundred twenty-three patients were enrolled, with a median age of 63 years, 78.5% female. 32.7% were Black/African American, and 5.4% were Hispanic. 39.9% of patients were commercially insured, Medicare/Medicaid insured 52.5%, and 2.7% were uninsured. The most common cancers in this cohort were breast (61.9%), lung (10.3%), and colorectal (7.2%). Twenty-three patients (10.3%) carried one or more PGVs, and 50.2% carried a variant of uncertain significance (VUS). Though there was no significant difference in the rate of PGVs based on race/ethnicity, African Americans were numerically more likely to have a VUS reported than whites (P=0.059). Eighteen (8.1%) patients had incremental clinically actionable findings that practice guidelines would not have detected, which was higher in non-whites. Conclusions In this racially/ethnically and socioeconomically diverse cohort, universal multi-gene panel testing (MGPT) increased diagnostic yield over targeted guideline-informed testing. Rates of VUS and incremental PGV were higher in non-white populations.

A quantitative systems pharmacology model of the pathophysiology and treatment of COVID-19 predicts optimal timing of pharmacological interventions.

A quantitative systems pharmacology (QSP) model of the pathogenesis and treatment of SARS-CoV-2 infection can streamline and accelerate the development of novel medicines to treat COVID-19. Simulation of clinical trials allows in silico exploration of the uncertainties of clinical trial design and can rapidly inform their protocols. We previously published a preliminary model of the immune response to SARS-CoV-2 infection. To further our understanding of COVID-19 and treatment, we significantly updated the model by matching a curated dataset spanning viral load and immune responses in plasma and lung. We identified a population of parameter sets to generate heterogeneity in pathophysiology and treatment and tested this model against published reports from interventional SARS-CoV-2 targeting mAb and antiviral trials. Upon generation and selection of a virtual population, we match both the placebo and treated responses in viral load in these trials. We extended the model to predict the rate of hospitalization or death within a population. Via comparison of the in silico predictions with clinical data, we hypothesize that the immune response to virus is log-linear over a wide range of viral load. To validate this approach, we show the model matches a published subgroup analysis, sorted by baseline viral load, of patients treated with neutralizing Abs. By simulating intervention at different time points post infection, the model predicts efficacy is not sensitive to interventions within five days of symptom onset, but efficacy is dramatically reduced if more than five days pass post symptom onset prior to treatment.

Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability.

MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the molecular and genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. Ctdnep1 ablation promotes the transformation of murine cerebellar progenitors into Myc-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes and activates MYC activity by elevating MYC serine-62 phosphorylation, and triggers chromosomal instability to induce p53 loss and Myc amplifications. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for chromosome segregation and mitotic checkpoint regulators including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting MYC and CHEK1 activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies demonstrate that CTDNEP1 is a tumor suppressor in highly aggressive MYC-driven medulloblastomas by controlling MYC activity and mitotic fidelity, pointing to a CTDNEP1-dependent targetable therapeutic vulnerability.

Olig1/2-Expressing Intermediate Lineage Progenitors Are Predisposed to PTEN/p53-Loss-Induced Gliomagenesis and Harbor Specific Therapeutic Vulnerabilities.

Malignant gliomas such as glioblastoma are highly heterogeneous with distinct cells of origin and varied genetic alterations. It remains elusive whether the specific states of neural cell lineages are differentially susceptible to distinct genetic alterations during malignant transformation. Here, an analysis of The Cancer Genome Atlas databases revealed that comutations of PTEN and TP53 are most significantly enriched in human high-grade gliomas. Therefore, we selectively ablated Pten and Trp53 in different progenitors to determine which cell lineage states are susceptible to malignant transformation. Mice with PTEN/p53 ablation mediated by multilineage-expressing human GFAP (hGFAP) promoter-driven Cre developed glioma but with incomplete penetrance and long latency. Unexpectedly, ablation of Pten and Trp53 in Nestin+ neural stem cells (NSC) or Pdgfra+/NG2+ committed oligodendrocyte precursor cells (OPC), two major cells of origin in glioma, did not induce glioma formation in mice. Strikingly, mice lacking Pten and Trp53 in Olig1+/Olig2+ intermediate precursors (pri-OPC) prior to the committed OPCs developed high-grade gliomas with 100% penetrance and short latency. The resulting tumors exhibited distinct tumor phenotypes and drug sensitivities from NSC- or OPC-derived glioma subtypes. Integrated transcriptomic and epigenomic analyses revealed that PTEN/p53-loss induced activation of oncogenic pathways, including HIPPO-YAP and PI3K signaling, to promote malignant transformation. Targeting the core regulatory circuitries YAP and PI3K signaling effectively inhibited tumor cell growth. Thus, our multicell state in vivo mutagenesis analyses suggests that transit-amplifying states of Olig1/2 intermediate lineage precursors are predisposed to PTEN/p53-loss-induced transformation and gliomagenesis, pointing to subtype-specific treatment strategies for gliomas with distinct genetic alterations. SIGNIFICANCE: Multiple progenitor-state mutagenesis reveal that Olig1/2-expressing intermediate precursors are highly susceptible to PTEN/p53-loss-mediated transformation and impart differential drug sensitivity, indicating tumor-initiating cell states and genetic drivers dictate glioma phenotypes and drug responses. See related commentary by Zamler and Hu, p. 807.

Human fetal cerebellar cell atlas informs medulloblastoma origin and oncogenesis.

Medulloblastoma (MB) is the most common malignant childhood brain tumour1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.

Single-cell multiomics identifies clinically relevant mesenchymal stem-like cells and key regulators for MPNST malignancy.

Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive Schwann cell (SC)-derived soft tissue sarcoma, arises from benign neurofibroma (NF); however, the identity, heterogeneity and origins of tumor populations remain elusive. Nestin+ cells have been implicated as tumor stem cells in MPNST; unexpectedly, single-cell profiling of human NF and MPNST and their animal models reveal a broad range of nestin-expressing SC lineage cells and dynamic acquisition of discrete cancer states during malignant transformation. We uncover a nestin-negative mesenchymal neural crest-like subpopulation as a previously unknown malignant stem-like state common to murine and human MPNSTs, which correlates with clinical severity. Integrative multiomics profiling further identifies unique regulatory networks and druggable targets against the malignant subpopulations in MPNST. Targeting key epithelial-mesenchymal transition and stemness regulators including ZEB1 and ALDH1A1 impedes MPNST growth. Together, our studies reveal the underlying principles of tumor cell-state evolution and their regulatory circuitries during NF-to-MPNST transformation, highlighting a hitherto unrecognized mesenchymal stem-like subpopulation in MPNST disease progression.

Novel tunnel staining technique to reduce premature entry in manual small-incision cataract surgery.

Mastering manual small-incision cataract surgery (MSICS) for beginner surgeons is difficult. In the initial days of residency or training, surgeons struggle to make a proper scleral tunnel and keratome entry. It commonly results in premature entry and iris prolapse. Most of the literature has shed light on premature entry during tunnel construction by a crescent blade, whereas a significant majority of iris prolapse happens due to improper keratome entry. This novel trypan blue dye-assisted tunnel staining (TBTS) technique helps in proper tunnel demarcation which can reduce the incidence of premature entry with a keratome.

Technique modifications in manual small-incision cataract surgery for left-handed cataract surgeons.

Learning manual small-incision cataract surgery (SICS) is essential for ophthalmic surgeons as it provides an alternative to phaco-emulsification in complicated cases. Nearly 10% of ophthalmic surgeons are left-handed. Left-handed surgeons do face more difficulties because of their laterality, which have been highlighted in various surveys even in other surgical specialities. Surgical training programs, residency programs, and fellowships have traditionally been designed considering the right hand as the dominant hand. Left-handed surgeons (LHSs) are at disadvantage as they are trained by right-handed surgeons (RHSs), which may result in more initial intra-operative errors. Intra-ocular lenses are also designed such that dialing into the bag is relatively difficult for LHSs. Developing customized training modules for LHSs can help them overcome the laterality challenges and enhance their surgical capabilities. In this article, we herein present a brief description of the SICS technique for LHSs, elaborating the crucial steps and customized maneuvers that, if performed differently, may make surgeries easier for them.

Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir.

Coronavirus disease 2019 (COVID-19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) Mpro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. We report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double-blind, placebo-controlled, phase I study. Two interleaving single-ascending dose (SAD) cohorts were evaluated in a three-period crossover. Multiple-ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (b.i.d.) dosing was evaluated over 10 days in five parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase II/III clinical trials were supported by integrating modeling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well-tolerated. Nirmatrelvir exposure and half-life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase II/III trials (300/100 mg b.i.d.), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro. The QSP model suggested that a 5-day regimen would significantly decrease viral load in SARS-CoV-2-infected patients which may prevent development of severe disease, hospitalization, and death. In conclusion, an innovative and seamless trial design expedited establishment of phase I safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase II/III dose selection and accelerated pivotal trials' initiation (NCT04756531).