zapnometinib (ATR-002) / Atriva Therap - LARVOL DELTA

Antiviral and immunomodulatory effect of zapnometinib in animal models and hospitalized COVID-19 patients. (PubMed, Front Immunol) - "In patients with COVID-19, zapnometinib increased T and plasma B cells. Unlike direct-acting antivirals, zapnometinib's dual effect highlights its therapeutic potential in the treatment of severe acute viral infections, with favorable antiviral and immunomodulatory properties."

Journal • Preclinical • Acute Lung Injury • Immunology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Targeting the MEK1/2 pathway to combat Staphylococcus aureus infection and inflammation in cystic fibrosis. (PubMed, mBio) - "Our previous studies demonstrated anti-inflammatory effects of several MEK1/2 inhibitor compounds, including PD0325901, CI-1040, and trametinib, in human phagocytes from PwCF and a murine S. aureus pulmonary infection model (M. This work also identifies host MEK2 as a specific target that can be modulated to reduce inflammation without impairing host defense against MRSA pulmonary infection. Results from this study can inform future human clinical trials to evaluate the ability of the MEK1/2 inhibitor compound ATR-002 to both combat S. aureus infections and reduce inflammation that accompanies these infections."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • CXCL8 • MAP2K1 • MAP2K2 • TLR2 • TNFA

Influenza H5Nx Viruses are susceptible to MEK1/2 Inhibition by zapnometinib. (PubMed, Emerg Microbes Infect) - "Highly pathogenic avian influenza A viruses (HPAIV) pose a significant threat to both animal and human health. We furthermore could show, that ZMN not only acts antiviral in a standalone treatment but has synergistic potential when used in combination with direct acting antivirals like oseltamivir or baloxavir. Therefore, ZMN treatment offers a promising strategy for future antiviral development."

Journal • Infectious Disease • Influenza • Respiratory Diseases

MEK1/2 inhibitor ATR-002 has dual anti-inflammatory and anti-bacterial effects during S. aureus infection (NACFC 2024) - "To assess the anti-inflammatory-anti-bacterial potential of ATR-002 in vivo, mice were provided intraperitoneal treatment with vehicle or the MEK1/2 inhibitor compound PD0325901 (20 mg/kg) or ATR-002 (10 mg/kg) immediately before intranasal MRSA infection with 1×107 CFU of USA300. We demonstrated that the MEK1/2 inhibitor ATR-002 has in vivo anti-inflammatory and anti-bacterial effects in a MRSA infection model. Our results also demonstrated anti-bacterial effects of ATR-002 on CF S. aureus isolates and the synergistic potential to overcome some antibiotic resistance. Combined, these results highlight the dual anti-inflammatory-anti-bacterial properties of the MEK1/2 inhibitor compound ATR-002."

Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Respiratory Diseases • AURKB • CDK7

MEK-inhibitor treatment reduces the induction of regulatory T cells in mice after influenza A virus infection. (PubMed, Front Immunol) - "Our results demonstrate that CD4+/CD25+FoxP3+ Tregs are involved in the pathogenesis of severe influenza and indicate the potential of the MEK-inhibitor zapnometinib to modulate CD4+/CD25+FoxP3+ Tregs. Thus, making MEK-inhibitors even more promising for the treatment of severe influenza virus infections."

Journal • Preclinical • Immunology • Infectious Disease • Inflammation • Influenza • Respiratory Diseases • CD4 • CD8 • FOXP3 • IL2RA

The host-targeted antiviral drug Zapnometinib exhibits a high barrier to the development of SARS-CoV-2 resistance. (PubMed, Antiviral Res) - "Here we compared the HTA Zapnometinib (ZMN), with direct acting antivirals (DAA) (Remdesivir (RDV), Molnupiravir (MPV), Nirmatrelvir (NTV), Ritonavir (RTV), Paxlovid PAX)), in terms of their potency to induce reduced drug susceptibilities in SARS-CoV-2. Reduced DAA efficacy did not alter the inhibitory potential of ZMN. These results show that ZMN confers a high barrier towards the development of viral resistance and has the potential to act against partially DAA-insensitive viruses."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Efficacy and safety of zapnometinib in hospitalised adult patients with COVID-19 (RESPIRE): a randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial. (PubMed, EClinicalMedicine) - P2 | "Further clinical studies will be required to evaluate the clinical benefit of zapnometinib in this and other indications. Atriva Therapeutics GmbH and the Federal Ministry of Education and Research, Germany."

Journal • P2 data • Infectious Disease • Novel Coronavirus Disease • MAP2K2

Influenza A virus replication has a stronger dependency on Raf/MEK/ERK signaling pathway activity than SARS-CoV-2. (PubMed, Front Cell Infect Microbiol) - "The results suggest that IAV's replication has a stronger dependency on an active Raf/MEK/ERK pathway and, thus, that IAV is more susceptible to treatment with zapnometinib than SARS-CoV-2. With zapnometinib's favorable outcome in a recent phase II clinical trial in hospitalized COVID-19 patients, the present results are even more promising for an upcoming phase II clinical trial in severe influenza virus infection."

Journal • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases

Targeting eukaryotic-like serine/threonine protein kinases in Staphylococcus aureus to combat antimicrobial resistance in CF clinical isolates (NACFC 2023) - "ATR-002 doses as low as 1 μM and 5 μM re-sensitized gentamicin-resistant S. aureus CF isolates to antibiotic treatment. In contrast, 1 μM and 5 μM doses could not re-sensitize S. aureus CF isolates resistant to erythromycin, clindamycin, and nafcillin to antibiotic treatment. Results from these studies demonstrate that the MEK1/2 inhibitor compound ATR-002 affects growth of S. aureus CF clinical isolates and has the potential to synergize with some antibiotics to overcome antibiotic resistance. Future studies will continue to evaluate the ability of ATR-002 to re-sensitize S. aureus CF isolates to antibiotics and will seek to determine the antimicrobial mechanisms of ATR-002."

Clinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases • AURKB • CDK7

MEK inhibition with zapnometinib as a treatment for RNA virus infections: The dual benefit of host immunomodulation and antiviral activity (ESWI 2023) - No abstract available

Immunomodulating • Immunology • Infectious Disease

Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Food Effect and DDI of Ascending Doses of the MEK Inhibitor Zapnometinib (clinicaltrials.gov) - P1 | N=96 | Completed | Sponsor: Atriva Therapeutics GmbH | Recruiting ➔ Completed

Trial completion

MEK inhibitors as novel host-targeted antivirals with a dual-benefit mode of action against hyperinflammatory respiratory viral diseases. (PubMed, Curr Opin Virol) - "Here, we summarize data on a host-targeted strategy using inhibitors of the cellular Raf/MEK/ERK kinase cascade that not only block replication of different RNA viruses but also suppress the hyperinflammatory cytokine response upon infection. In the first phase-II clinical trial of that approach, the MEK inhibitor Zapnometinib shows evidence of clinical benefit."

Journal • Review • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases

Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Food Effect and DDI of Ascending Doses of the MEK Inhibitor Zapnometinib (clinicaltrials.gov) - P1 | N=96 | Recruiting | Sponsor: Atriva Therapeutics GmbH | Trial completion date: Oct 2023 ➔ Jul 2023 | Trial primary completion date: Oct 2023 ➔ Jul 2023

Trial completion date • Trial primary completion date

Establishment of a novel method to assess MEK1/2 inhibition in PBMCs for clinical drug development. (PubMed, Front Cell Dev Biol) - "Furthermore, we showed that treatment with the MEK1/2 inhibitor zapnometinib maintains the MEK1/2 activation at approximately baseline level despite subsequent stimulation with PMA. As our protocol is easy to follow and preserves the cells in an in vivo-like condition throughout the whole handling process, this approach can be a major advance for the easy assessment of MEK1/2 inhibitor target engagement in healthy probands for clinical drug development."

Journal • Infectious Disease • Oncology

Pharmacokinetics, absorption, distribution, metabolism and excretion of the MEK inhibitor zapnometinib in rats. (PubMed, Front Pharmacol) - "Metabolic profiles showed that the main clearance routes were metabolism via oxidative reactions and glucuronidation. These results further strengthen the knowledge of zapnometinib with respect to the clinical development of the drug."

Journal • PK/PD data • Preclinical • Gastrointestinal Disorder • Immune Modulation • Infectious Disease • Inflammation • Influenza • Novel Coronavirus Disease • Respiratory Diseases

Evaluating the antibacterial effects of a MEK1/2 inhibitor compound on Staphylococcus aureus isolates obtained from people with cystic fibrosis (NACFC 2022) - "aureus (USA300) were sub-cultured and treated with vehicle; 5, 25, or 50 µMMEK1/2 inhibitor compound ATR-002 or gentamicin as a control. Our preliminary data suggest that MEK1/2 inhibitors havedirect antibacterial effects on clinically relevant strains of S. aureusin addition to their anti-inflammatory effects on mammalian cells. Futurestudies include evaluating additional S. aureusisolates from PwCF, examining the effects of MEK1/2 inhibitor compounds on S. aureus biofilms, determining if other common CF bacterial pathogens can beinhibited by MEK1/2 inhibitor compounds, and characterizing MEK1/2inhibitor effects in a multi-microorganism co-culture system."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • MAP2K2

The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs. (PubMed, Pharmaceutics) - "Treatment combinations of ATR-002 with nucleoside inhibitors Molnupiravir and Remdesivir or 3C-like protease inhibitors Nirmatrelvir and Ritonavir, the ingredients of the drug Paxlovid, were examined in Calu-3 cells to evaluate the advantage of their combinatory use against a SARS-CoV-2 infection. Synergistic effects could be observed for all tested combinations of ATR-002 with DAAs, as calculated by four different reference models in a concentration range that was very well-tolerated by the cells. Our results show that ATR-002 has the potential to act synergistically in combination with direct-acting antivirals, allowing for a reduction in the effective concentrations of the individual drugs and reducing side effects."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Food Effect and DDI of Ascending Doses of the MEK Inhibitor Zapnometinib (clinicaltrials.gov) - P1 | N=109 | Recruiting | Sponsor: Atriva Therapeutics GmbH

New P1 trial

RESPIRE: Clinical Trial to Evaluate the Safety and Efficacy of ATR-002 in Adult Hospitalized Patients With COVID-19 (clinicaltrials.gov) - P2 | N=133 | Terminated | Sponsor: Atriva Therapeutics GmbH | N=220 ➔ 133 | Recruiting ➔ Terminated; general circumstances around COVID-19 and current availability of hospitalized patients

Enrollment change • Trial termination • Infectious Disease • Novel Coronavirus Disease

Pharmacokinetics, Pharmacodynamics and Antiviral Efficacy of the MEK Inhibitor Zapnometinib in Animal Models and in Humans. (PubMed, Front Pharmacol) - "However, the period of reduced phosphorylated extracellular-signal regulated kinase (pERK), a measure of MEK inhibition, was maintained even after elimination of zapnometinib from plasma, suggesting a sustained effect on MEK consistent with regulatory effects or a slow off-rate. These data suggest a target plasma C of at least 10 μg/ml zapnometinib in further clinical studies."

Journal • PK/PD data • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

RESPIRE: Clinical Trial to Evaluate the Safety and Efficacy of ATR-002 in Adult Hospitalized Patients With COVID-19 (clinicaltrials.gov) - P2 | N=220 | Recruiting | Sponsor: Atriva Therapeutics GmbH | Trial completion date: Jun 2022 ➔ Sep 2022 | Trial primary completion date: Apr 2022 ➔ Jul 2022

Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease

The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses. (PubMed, Cell Mol Life Sci) - "We also observe that ATR-002 treatment impairs the SARS-CoV-2-induced expression of pro-inflammatory cytokines, and thus might prevent COVID-19-associated hyperinflammation, a key player in COVID-19 progression. Thus, our data suggest that the Raf/MEK/ERK signaling cascade may represent a target for therapeutic intervention strategies against SARS-CoV-2 infections and that ATR-002 is a promising candidate for further drug evaluation."

Journal • Fibrosarcoma • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Sarcoma • Solid Tumor

RESPIRE: Clinical Trial to Evaluate the Safety and Efficacy of ATR-002 in Adult Hospitalized Patients With COVID-19 (clinicaltrials.gov) - P2; N=220; Recruiting; Sponsor: Atriva Therapeutics GmbH; Trial completion date: Mar 2022 ➔ Jun 2022; Trial primary completion date: Dec 2021 ➔ Apr 2022

Clinical • Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease

Clinical trial, conducted at multiple trial sites, to test the safety and effectiveness of ATR-002 in hospitalized patients diagnosed with the lung disease COVID-19. Ensayo clínico, realizado en múltiples centros de ensayo, para probar la seguridad y eficacia de ATR-002 en pacientes hospitalizados diagnosticados con la enfermedad pulmonar COVID-19. (clinicaltrialsregister.eu) - P2; N=220; Ongoing; Sponsor: Atriva Therapeutics GmbH

Clinical • New P2 trial • Infectious Disease • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases

RESPIRE: Clinical Trial to Evaluate the Safety and Efficacy of ATR-002 in Adult Hospitalized Patients With COVID-19 (clinicaltrials.gov) - P2; N=220; Recruiting; Sponsor: Atriva Therapeutics GmbH; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Infectious Disease • Novel Coronavirus Disease