emvododstat (PTC299) / PTC Therap - LARVOL DELTA

DHODH is a promising therapeutic target for cutaneous squamous cell carcinoma (ESDR 2025) - "To further assess the therapeutic potential of DHODH inhibition, we evaluated the efficacy of two DHODH inhibitors, leflunomide and PTC299, in immunocompromised mice xenografted with A431 and SCC13 cell lines. They also suggest DHODH may be a promising therapeutic target, at least in a subset of cSCC. Moreover, our data suggest that PTC299 could offer broader therapeutic benefits by potentially overcoming resistance mechanisms associated with metabolic plasticity."

Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

Salvianolic Acid B Promotes Placental and Decidual Angiogenesis by Restoring the Normal Expression of Hypoxia-Inducible Factor-1α/Vascular Endothelial Growth Factor in Mice With Recurrent Pregnancy Loss. (PubMed, Am J Reprod Immunol) - "SalB ameliorates RPL by restoring physiological HIF-1α/VEGF balance and placental angiogenesis. Optimal daily dose was 100 mg/kg, which demonstrated the absence of embryotoxicity or mitigated the embryotoxicity of RPL mice, while higher doses (400 mg/kg) showed lesser improvement and increased hepatotoxicity. The promotion of placental and decidual angiogenesis may be an effective strategy for treating unexplained RPL."

Journal • Preclinical • HIF1A • KDR • VEGFA

Quantitative Systems Toxicology Modeling Informed Safe Dose Selection of Emvododstat in Acute Myeloid Leukemia Patients. (PubMed, Clin Pharmacol Ther) - "Overall, retrospective DILIsym simulations adequately predicted the liver safety liabilities of emvododstat in solid tumor trials and prospective simulations predicted the liver safety of reduced doses in an AML clinical trial. The modeling was critical to enabling regulatory approval to proceed with the AML clinical trial wherein the predicted liver safety was confirmed."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Hepatology • Infectious Disease • Leukemia • Liver Failure • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor

Absorption, metabolism and excretion of C-emvododstat following repeat daily oral dose administration in human volunteers using a combination of microtracer radioactivity and high radioactivity doses. (PubMed, Drug Metab Dispos) - "Significance Statement This study provides a complete set of the absorption, metabolism and excretion data of emvododstat, a potent inhibitor of dihydroorotate dehydrogenase, at close to steady state in healthy human subjects. Resolution of challenges due to slow metabolism and elimination of a lipophilic compound highlighted in this study can be achieved by repeat daily microtracer radioactivity oral dosing followed by a high radioactivity oral dosing at therapeutically relevant doses."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Novel Coronavirus Disease • Oncology

A clinical pharmacokinetic drug-drug interaction study between dextromethorphan and emvododstat, a potent anti-SARS-CoV-2 dihydroorotate dehydrogenase inhibitor. (PubMed, Eur J Clin Pharmacol) - "Emvododstat appears to be a strong CYP2D6 inhibitor. No drug-related treatment emergent adverse effects (TEAEs) were considered to be severe or serious."

Journal • PK/PD data • Immune Modulation • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • CYP2D6

A pharmacokinetic drug-drug interaction study between rosuvastatin and emvododstat, a potent anti-SARS-CoV-2 (COVID-19) DHODH (dihydroorotate dehydrogenase) inhibitor. (PubMed, Pharmacol Res Perspect) - "Emvododstat can be safely administered with other BCRP substrate drugs. Hence, pharmacokinetic DDI mediated via BCRP inhibition is not expected when emvododstat and BCRP substrates are coadministered."

Journal • PK/PD data • Breast Cancer • Immune Modulation • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor

Absorption, Distribution, Metabolism and Excretion of C-Emvododstat following a Single Oral Dose in Rats and Dogs. (PubMed, Xenobiotica) - "Emvododstat was the dominant radioactive component in plasma and faeces.Following a single oral dose of C-emvododstat in dogs, 75.2% of the dose was recovered in faeces while 0.5% of dose was recovered in urine 8 days post-dose. Emvododstat was the dominant radioactive component in faeces, while emvododstat and its two metabolites (O-desmethyl emvododstat and emvododstat amide bond hydrolysis product) were the major circulating radioactivity in dog plasma."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Novel Coronavirus Disease • Oncology

FITE19: A Study to Evaluate Efficacy and Safety of PTC299 (Emvododstat) in Hospitalized Participants With Coronavirus (COVID-19) (clinicaltrials.gov) - P2/3 | N=189 | Terminated | Sponsor: PTC Therapeutics | N=380 ➔ 189 | Recruiting ➔ Terminated; Sponsor decision

Enrollment change • Trial termination • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

SAR studies toward discovery of emvododstat (PTC299), a potent dihydroorotate dehydrogenase (DHODH) inhibitor. (PubMed, Eur J Med Chem) - "Emvododstat (PTC299) is a tetrahydro-β-carboline DHODH inhibitor discovered through the GEMS technology (Gene Expression Modulation by Small-Molecules). Described in this paper is the lead optimization campaign that culminated in the discovery of this highly potent DHODH inhibitor."

Journal • Immunology • Oncology

FITE19: A Study to Evaluate Efficacy and Safety of PTC299 (Emvododstat) in Hospitalized Participants With Coronavirus (COVID-19) (clinicaltrials.gov) - P2/3 | N=380 | Recruiting | Sponsor: PTC Therapeutics | Trial completion date: Mar 2022 ➔ Jun 2022 | Trial primary completion date: Mar 2022 ➔ Jun 2022

Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Emvododstat, a Potent Dihydroorotate Dehydrogenase Inhibitor, Is Effective in Preclinical Models of Acute Myeloid Leukemia. (PubMed, Front Oncol) - "DHO levels declined as drug levels declined, consistent with the reversibility of DHODH inhibition by emvododstat. These preclinical findings provide a rationale for clinical evaluation of emvododstat in an ongoing Phase 1 study of patients with relapsed/refractory acute leukemias."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Recent advances of human dihydroorotate dehydrogenase inhibitors for cancer therapy: Current development and future perspectives. (PubMed, Eur J Med Chem) - "In recent years, in exploiting novel structural hDHODH inhibitors (hDHODHi), a candidate drug PTC299 has entered clinical trials for treating acute myelocytic leukemia (AML) and other tumors. This review discusses tumor-related research of hDHODH and highlights the structure-activity relationships of hDHODHi, providing insights into new drugs targeting hDHODH for antitumor clinical practice."

Journal • Review • Acute Myelogenous Leukemia • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Hematological Malignancies • Leukemia • Oncology • Squamous Cell Carcinoma

FITE19: A Study to Evaluate Efficacy and Safety of PTC299 (Emvododstat) in Hospitalized Participants With Coronavirus (COVID-19) (clinicaltrials.gov) - P2/3 | N=380 | Recruiting | Sponsor: PTC Therapeutics | Trial completion date: Dec 2021 ➔ Mar 2022 | Trial primary completion date: Dec 2021 ➔ Mar 2022

Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Study of PTC299 (Emvododstat) in Relapsed/Refractory Acute Leukemias (clinicaltrials.gov) - P1b | N=33 | Terminated | Sponsor: PTC Therapeutics | Trial completion date: May 2022 ➔ Dec 2021 | Recruiting ➔ Terminated | Trial primary completion date: Apr 2022 ➔ Dec 2021; Sponsor terminated the study.

Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes. (PubMed, Blood Adv) - "Our results indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells and acts in a synergistic manner with decitabine. This combination therapy may be a new therapeutic option for the treatment of MDS."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • MYC

Inhibition of De Novo Pyrimidine Synthesis Depletes Acute Myleogenous Leukemia Stem Cells (LSCs) Burden and Triggers Apoptosis and Differentiation Associated with Oxidative Stress (ASH 2021) - " Emvododstat treatment in cytarabine-resistant AML cells and primary AML blasts induced apoptosis, differentiation, and reduced proliferation, with corresponding decreased in cell number and increases in annexin V- and CD14-positive cells. Inhibition of de novo pyrimidine synthesis triggers differentiation, apoptosis, and depletes LSCs in AML models. Emvododstat is a novel dihydroorotate dehydrogenase inhibitor being tested in a clinical trial for the treatment of myeloid malignancies and COVID-19. Keywords: AML, emvododstat, DHODH, apoptosis, differentiation."

Acute Myelogenous Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Novel Coronavirus Disease • Oncology • Transplantation • ASXL1 • CASP3 • CD14 • IDH2 • NRAS • TP53

In Vitro Metabolism, Pharmacokinetics and Drug Interaction Potentials of Emvododstat, a DHODH Inhibitor. (PubMed, Xenobiotica) - "Neither emvododstat nor O-desmethyl emvododstat was a substrate for common efflux or uptake transporters investigated.Emvododstat is bioavailable in mice, rats, dogs, and monkeys following a single oral dose. The absorption was generally slow with the mean plasma T ranging from 2 to 5 h; plasma exposure of O-desmethyl emvododstat was lower in rodents, but relatively higher in dogs and monkeys."

Journal • PK/PD data • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Novel Coronavirus Disease • Oncology • CYP2C8 • CYP2D6

Study of PTC299 (Emvododstat) in Relapsed/Refractory Acute Leukemias (clinicaltrials.gov) - P1b; N=39; Recruiting; Sponsor: PTC Therapeutics; Trial completion date: Jun 2021 ➔ May 2022; Trial primary completion date: May 2021 ➔ Apr 2022

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

FITE19: A Study to Evaluate Efficacy and Safety of PTC299 (Emvododstat) in Hospitalized Participants With Coronavirus (COVID-19) (clinicaltrials.gov) - P2/3; N=380; Recruiting; Sponsor: PTC Therapeutics; Trial completion date: Jul 2021 ➔ Dec 2021; Trial primary completion date: Jul 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

[VIRTUAL] Emvododstat (PTC299) Targets De Novo Pyrimidine Synthesis in Acute Myeloid Leukemia (SOHO 2021) - " Emvododstat treatment in cytarabine-resistant AML cells and primary AML blasts induced apoptosis, differentiation, and reduced proliferation, with corresponding increases in annexin V- and CD14-positive cells. Inhibition of de novo pyrimidine synthesis triggers differentiation, apoptosis, and/or inhibition of proliferation in AML models. Emvododstat is a novel dihydroorotate dehydrogenase inhibitor being tested in a clinical trial for the treatment of myeloid malignancies and COVID-19."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CASP3 • CD14 • TP53

Antiviral treatment of COVID-19: An update. (PubMed, Turk J Med Sci) - "The main drug groups include inhibitors of viral entry into the human cell (convalescent plasma, monoclonal antibodies, nanobodies, mini proteins, human soluble ACE-2, camostat, dutasteride, proxalutamide, bromhexin, hydroxychloroquine, umifenovir nitazoxanid, niclosamide, lactoferrin), inhibitors of viral proteases (lopinavir/ritonavir, PF-07321332, PF-07304814, GC376), inhibitors of viral RNA (remdesivir, favipiravir, molnupiravir, AT-527, merimepodib, PTC299); inhibitors of host proteins supporting virus (plitidepsin, fluvoxamine, ivermectin) and agents supporting host natural immunity (Interferons)...Additional studies are needed to define the role of remdesivir, favipiravir, interferons, ivermectin, dutasteride, proxulutamide, fluvoxamine, bromhexine, nitazoxanide and niclosamid in the treatment of COVID-19. Finally, the results of phase trials are waited to learn whether or not the newer agents such as molnupiravir, PF-07321332, PF-07304814, plitidepsin and AT-527..."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

[VIRTUAL] The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines Implicated in COVID-19 Disease and Is Currently Being Evaluated in the Multinational FITE19 Phase 2/3 Clinical Trial in Hospitalized Patients (WMF 2021) - P2/3 | "PTC299 is being studied in the FITE19 Phase 2/3 clinical trial for the treatment of COVID-19 (Clinicaltrials.gov NCT04439071). The FITE19 trial will enroll 380 patients globally, with a primary endpoint of time from randomization to respiratory improvement."

Clinical • P2/3 data • Acute Respiratory Distress Syndrome • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases • IL17A • IL6

PTC Therapeutics Reports Fourth Quarter and Full Year 2020 Financial Results and Provides a Corporate Update (GlobeNewswire) - "Strong continued revenue growth for the DMD franchise, with total net product revenue of $331 million for Translarna™ (ataluren) and Emflaza® (deflazacort) in 2020: Translarna growth was driven by broader uptake due to new patients in existing geographies, geographic expansion and label updates; Emflaza experienced strong 38% year-over-year revenue growth in 2020 due to increased new prescriptions and high compliance....The second stage of the FITE19 Phase 2/3 clinical trial to assess PTC299 in patients with COVID-19 has been initiated. Data from this study is expected in the second half of the year."

P2/3 data • Sales • Duchenne Muscular Dystrophy • Infectious Disease • Novel Coronavirus Disease

PTC Therapeutics Reports the Initiation of the Second Stage of the FITE19 Phase 2/3 Clinical Trial Evaluating PTC299 for the Treatment of COVID-19 (PRNewswire) - "PTC Therapeutics, Inc. (NASDAQ: PTCT), today announced the initiation of the second stage of the FITE19 clinical trial to assess PTC299 in COVID-19 patients....Enrollment for the second stage of the trial has been initiated in multiple centers outside of the US. 'Completion of the first stage of the FITE19 trial is an important milestone that triggers the final stage of the trial to begin,'..."

Trial status • Infectious Disease • Novel Coronavirus Disease

Study of PTC299 in Relapsed/Refractory Acute Leukemias (clinicaltrials.gov) - P1b; N=39; Recruiting; Sponsor: PTC Therapeutics; Trial completion date: Dec 2020 ➔ Jun 2021; Trial primary completion date: Nov 2020 ➔ May 2021

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology