EQS-News: Atriva Therapeutics announces Topline Results from the Proof of Concept (POC) / Phase 2a RESPIRE study (zapnometinib) in patients hospitalized with COVID-19

Atriva Therapeutics announces Topline Results from the
Proof of Concept (POC) / Phase 2a RESPIRE study (zapnometinib)
in patients hospitalized with COVID-19

• Atriva Therapeutics GmbH announces high-level results from the Phase 2a RESPIRE study
• Results indicate a clinically relevant efficacy profile for zapnometinib, in terms of the primary endpoint, clinical severity status (CSS) at Day 15, with a favorable safety profile
• Atriva decided to terminate the study early, the decision was based on low recruitment projection as well as the high prevalence of patients infected with the Omicron variant, resulting in fewer hospitalizations
• Results from RESPIRE provide proof of concept for the clinical benefit of zapnometinib
• Atriva has a clear path for the further clinical development of zapnometinib in severe Influenza, COVID-19, and respiratory syncytial virus (RSV) (PanTher Study planned for Q1/23), as well as in other severe viral diseases
• Atriva will report on a detailed analysis of the safety and efficacy data in due course

Tübingen and Frankfurt, Germany, September 20, 2022 – Atriva Therapeutics GmbH, a biopharmaceutical company that is pioneering the development of host-targeting antiviral therapies, announced today the topline findings from the Proof on Concept (POC) / Phase 2a RESPIRE study (zapnometinib) in patients hospitalized with moderate-to-severe COVID-19.

RESPIRE planned to include 220 patients, however, due to recruitment challenges arising from the lower frequency of COVID-19 hospitalizations caused by the Omicron variant compared with previous variants, Atriva Therapeutics GmbH have decided to terminate the study with 104 evaluable patients.

Patients enrolled in RESPIRE were well balanced between groups, with 40% of patients requiring supplemental oxygen in the zapnometinib arm and 41% requiring supplemental oxygen in the placebo arm. A clinically relevant trend for improvement was observed, including the primary endpoint of clinical severity status (CSS) on Day 15 (Odds Ratio (OR) [95% confidence interval] 1.54 [0.72–3.33]). The primary endpoint addresses both efficacy and safety, as the CSS ranges from death as the most severe category to hospital discharge, with and without limitations of activities, as the most favorable categories. Sensitivity and subgroup analyses were defined a priori, including subgroup analysis by the randomization strata of disease severity at baseline (CSS levels 3 or 4). Results from both the primary (improvement on the World Health Organization CSS scale) and key secondary (time to hospital discharge) endpoints in RESPIRE indicate a clear benefit amongst patients with more severe disease activity (CSS 4), confirming the mechanism of action of zapnometinib. In the subgroup of patients with CSS 4 at baseline, a clinically relevant Odds Ratio greater than 2 was observed for the primary endpoint. In addition, in subgroup analyses for the key secondary endpoint, patients infected with the Delta variant of SARS-CoV-2 had significantly better outcomes compared to those infected with the Omicron variant.

Safety data from RESPIRE indicate a favorable profile, with a balanced incidence of treatment-emergent adverse events (TEAEs) between study groups. There was no indication of drug-induced liver injury (DILI), and no cardiac arrhythmia.

These data provide proof of concept for the clinical benefit of zapnometinib in patients with severe COVID-19 and support further evaluation of zapnometinib in influenza, COVID-19, and other severe viral diseases. Atriva and investigators are continuing to evaluate the RESPIRE data and will provide an update on the full dataset in due course as well as next steps for the program.

Prof. Gernot Rohde, M.D., Head of Pneumology and Professor for Respiratory Medicine and Allergology at the Goethe University Hospital, Frankfurt am Main, Germany, (Global Coordinating Investigator RESPIRE) comments: “Despite recent approvals of treatments for patients with severe COVID-19, there remains a significant unmet medical need for targeted, effective therapies in severe viral respiratory infections. The data for zapnometinib from the RESPIRE Study are highly encouraging and suggest that the innovative approach of targeting the intracellular Raf/MEK/ERK signaling pathway may prove to be effective in treating such conditions.”

Dr. Stephan Stenglein, CMO Atriva Therapeutics, adds: “We are pleased to see impressive data from our first clinical study (RESPIRE). The results we obtained show a strong trend for efficacy of zapnometinib in patients with severe COVID-19. In addition, from sensitivity analyses performed, we also have indications of a statistically significant and clinically relevant risk reduction in the subgroup of more severe patients in RESPIRE, along with a favorable safety profile. A detailed analysis of all study endpoints is currently ongoing. Atriva will now continue to develop zapnometinib in a pandemic preparedness Phase 2 study (PanTher) that will include patients with severe disease caused by influenza, SARS-CoV-2, or RSV.”

Dr. Rainer Lichtenberger, CEO Atriva Therapeutics, concludes: “These very encouraging study results provide a perfect foundation for the company's further strategic positioning as a pioneer in delivering novel, broad-based and highly effective therapies against severe viral diseases with pandemic potential.”

About the RESPIRE study

RESPIRE¹ is a randomized, double-blind, placebo-controlled, international, multi-center POC (Proof of Concept) / Phase 2 clinical trial in adult patients with moderate-to-severe COVID-19. Hospitalized patients with or without supplemental oxygen at the time of screening or randomization were enrolled. On top of standard of care, patients were randomized to receive zapnometinib (ATR-002) 900 mg tablets, once daily on Day 1, followed by zapnometinib 600 mg once daily on Days 2 to 6, or to receive placebo in a matching scheme.

The study is designed to establish the efficacy of zapnometinib; the primary endpoint is CSS on Day 15, using a seven-point ordinal scale as recommended by the WHO COVID-19 Therapeutic Trial Synopsis.² Secondary endpoints include time to hospital discharge, changes in clinical signs and symptoms and other relevant clinical parameters. All patients have been followed-up for 90 days.

About zapnometinib

The Atriva lead product zapnometinib (ATR-002) was specifically developed to treat diseases caused by RNA viruses, such as influenza and COVID-19. Zapnometinib is a MEK inhibitor targeting the intracellular Raf/MEK/ERK signaling pathway. Many RNA viruses need to activate this pathway to ensure replication, including influenza viruses,³ hantaviruses,⁴ the respiratory syncytial virus (RSV),⁴ and coronaviruses,⁴ including SARS-CoV-2. Zapnometinib inhibits cellular MEK (MAPK/ERK kinase), blocking the formation of functional virus particles in the host cell, ultimately reducing the viral load in the body.^5,6 In SARS-CoV-2 infected cells, inhibition of MEK1/2 by zapnometinib significantly reduces virus production.⁷

In addition, zapnometinib has the potential to modulate the host immune response and avoid an excessive cytokine/chemokine response that can be caused by viral infections.^8,9 This second host-targeting effect may therefore mitigate the overactive inflammatory response, e.g., as seen in the lungs of patients who are severely ill with COVID‑19 or influenza.^7,10 In SARS-CoV-2 infected cells, inhibition of MEK1/2 by zapnometinib significantly impairs pro-inflammatory cytokine production.⁷ Zapnometinib is under advanced clinical development as a treatment for patients with influenza or COVID-19. For the treatment of hantavirus infections, zapnometinib has been granted Orphan Drug Designation (ODD) by the U.S. Food and Drug Administration (FDA).

About Atriva Therapeutics

Atriva Therapeutics’ mission is to develop an antiviral therapy platform against severe respiratory and systemic diseases with a high unmet medical need induced by RNA viruses, e.g., influenza and COVID-19. The clinical-stage biopharmaceutical company is pioneering the development of host-targeting antiviral therapies, making development of resistance unlikely, and thereby significantly contributing to pandemic preparedness. The Atriva lead product zapnometinib (ATR-002) is a first-in-class, host-targeting agent that aims to inhibit viral replication and to favorably modulate the body’s immune response to RNA viruses. Eleven patent families with broad international coverage grant protection for the use of MEK inhibitors and other kinase inhibitors for antiviral therapies through 2041. Atriva Therapeutics was founded in 2015 by a team of leading scientists in viral research and seasoned industry experts and is based in Tübingen and Frankfurt, Germany.

Atriva is a founding member of the BEAT-COV initiative. www.beat-cov.de

For further information, please visit www.atriva-therapeutics.com and follow us on LinkedIn and Twitter.

References

^[1]  Atriva Therapeutics GmbH. 2022. A Randomized, Double-Blind, Placebo-Controlled, Multi-Centre Clinical Trial to Evaluate the Safety and Efficacy of ATR-002 in Adult Hospitalized Patients with COVID-19 (RESPIRE).

^[2]  https://www.who.int/publications/i/item/covid-19-therapeutic-trial-synopsis.

^[3]  Pleschka S et al. Nat Cell Biol 2001 Feb 3:301-5.

^[4]  Pleschka S. 2008. Biol Chem. 389, 1273–1282.

^[5]  Haasbach E et al. Antiviral Res 2017 Jun 142:178-4.

^[6]  Laure M et al. Antiviral Res 2020 Jun 178:104806.

^[7]  Schreiber A et al. 2022. Cell Mol Life Sci. 79(1):65.

^[8]  Planz O Antiviral Res 2013 Jun 98(3):457-68.

^[9]  Pinto R et al. Antiviral Res 2011 Oct 92(1):45-56.

^[10]  Ragab D et al. 2020. Front Immunol. 11, 1446 (2020).