nezulcitinib (TD-0903) / Theravance Biopharma - LARVOL DELTA

Nezulcitinib (TD-0903), an inhaled JAK inhibitor reduces ConA-induced lung inflammation and lung injury in mice (ERS 2023) - "Nezulcitinib blocks ConA-induced inflammation in mouse lung demonstrating therapeutic potential for lung allograft dysfunction and ALI/ARDS.; Pulmonary function testing; Pulmonary rehabilitation; Cell and molecular biology; Endoscopy and interventional pulmonology; Imaging; Surgery; Epidemiology; General respiratory patient care; Respiratory intensive care; Physiology; Transplantation; Palliative care"

Preclinical • Acute Respiratory Distress Syndrome • Critical care • Infectious Disease • Inflammation • Novel Coronavirus Disease • Palliative care • Pneumonia • Respiratory Diseases • Transplant Rejection • Transplantation • CXCL10 • CXCL11 • CXCL9 • CXCR3 • IFNG

Inhaled delivery of nezulcitinib with nasal high-flow oxygen in healthy participants (ERS 2023) - "Nezulcitinib administration conditions and plasma pharmacokinetic data (mean ± SD). Study Period (Subjects) Conditions Cmax (ng/mL) AUC0-inf (hr*ng/mL) A (N=14) 3 mg nasal inhalation via HFNC circuita (30 L/min) 1.7 ± 1.1 7.8 ± 6.9 B (N=14) 3 mg oral inhalationb with low-flow nasal cannula (6 L/min) 14.0 ± 7.2 54.0 ± 28.0 C (N=14) 3 mg oral inhalationb with HFNC (30 L/min) 14.2 ± 8.5 54.7 ± 35.4 D1 (N=7) 3 mg oral inhalationb with HFNC (50 L/min) 14.0 ± 7.7 52.3 ± 29.1 D2 (N=6) 9 mg oral inhalationb with HFNC (50 L/min) 43.7 ± 37.3 152.0 ± 117.3 aAerogen Solo + T-adapter immediately prior to humidifier chamber bAerogen Solo + Ultra handheld device; General respiratory patient care; Respiratory intensive care; Palliative care; Physiology"

Clinical • Acute Lung Injury • Critical care • Infectious Disease • Novel Coronavirus Disease • Palliative care • Respiratory Diseases

Efficacy and safety of an inhaled pan-Janus kinase inhibitor, nezulcitinib, in hospitalised patients with COVID-19: results from a phase 2 clinical trial. (PubMed, BMJ Open Respir Res) - P2 | "Although the prespecified primary, secondary and exploratory efficacy endpoints, including RFF through day 28, change from baseline SaO2/FiO2 ratio on day 7, and 28-day mortality rate, were not met, nezulcitinib was generally well tolerated and had a favourable safety profile. Further studies are required to determine if treatment with nezulcitinib confers clinical benefit in specific inflammatory biomarker-defined populations of patients with COVID-19."

Journal • P2 data • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Outcomes of a phase 2 trial for the inhaled JAK inhibitor, nezulcitinib, in hospitalized patients with acute lung injury due to severe COVID-19 (ERS 2022) - "This is the first report of outcomes for an inhaled JAK inhibitor in COVID-19. Additional trials with nezulcitinb in severe COVID-19 patients are warranted."

Clinical • P2 data • Acute Lung Injury • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

The Pharmacokinetics and Safety of the Inhaled pan-JAK Inhibitor Nezulcitinib in Patients with Symptomatic Acute Lung Injury Associated with COVID-19: Results from a Phase 2 Trial (ATS 2022) - P2 | "Rationale: Severe COVID-19 illness may result in immune overactivation and is treated with systemic anti-inflammatory therapeutics such as dexamethasone, interleukin-6 receptor antagonists, and oral Janus kinase (JAK) inhibitors. Inhaled nezulcitinib was generally well tolerated with no drug-related serious AEs in both parts of the study. Peak plasma concentrations of nezulcitinib were ~10-fold below levels predicted to produce systemic JAK inhibition. Further studies are warranted to determine which patients with COVID-19 may benefit from nezulcitinib treatment."

Clinical • P2 data • PK/PD data • Acute Lung Injury • Acute Respiratory Distress Syndrome • Immune Modulation • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

JAK inhibitors and COVID-19. (PubMed, J Immunother Cancer) - "Significant clinical experience already exists with several JAKi in COVID-19, such as baricitinib, ruxolitinib, tofacitinib, and nezulcitinib, which were suggested by a meta-analysis (Patoulias et al.) to exert a benefit in terms of risk reduction concerning major outcomes when added to standard of care in patients with COVID-19. As for secondary effects of JAKi treatment, the main caution with baricitinib consists in the induced immunosuppression as long-term side effects should not be an issue in patients treated for COVID-19.We discuss whether a class effect of JAKi may be emerging in COVID-19 treatment, although at the moment the convincing data are for baricitinib only. Given the key role of JAK1 in both type I IFN action and signaling by cytokines involved in pathogenic effects, establishing the precise timing of treatment will be very important in future trials, along with the control of viral replication by associating antiviral molecules."

Clinical • Journal • Review • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Rheumatology • JAK1 • JAK2 • JAK3 • TYK2

The Efficacy and Safety of Janus Kinase Inhibitors for Patients With COVID-19: A Living Systematic Review and Meta-Analysis. (PubMed, Front Med (Lausanne)) - "Based on data from three randomized controlled trials (RCTs), baricitinib treatment significantly decreased mortality by day 28 in hospitalized patients with COVID-19 (RR = 0.64, 95% CI 0.51-0.80) without increasing the incidence of adverse outcomes. The efficacy and safety of other JAK inhibitors, such as ruxolitinib, tofacitinib, and nezulcitinib, await more evidence. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021261414, identifier: CRD42021261414."

Retrospective data • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

TD-0903 Pharmacokinetics Study in Healthy Participants With Supplemental Oxygenation (clinicaltrials.gov) - P1; N=14; Completed; Sponsor: Theravance Biopharma; Recruiting ➔ Completed

Clinical • Trial completion • Acute Lung Injury • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

TD-0903 Pharmacokinetics Study in Healthy Participants With Supplemental Oxygenation (clinicaltrials.gov) - P1; N=14; Recruiting; Sponsor: Theravance Biopharma; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Acute Lung Injury • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

TD-0903 Pharmacokinetics Study in Healthy Participants With Supplemental Oxygenation (clinicaltrials.gov) - P1; N=14; Not yet recruiting; Sponsor: Theravance Biopharma

Clinical • New P1 trial • Acute Lung Injury • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

[VIRTUAL] TD-0903, an inhaled JAK inhibitor in development for COVID-19, blocks ARDS-relevant hyperinflammation and lung injury in primary human immune and airway epithelial cells (ERS 2021) - "TD-0903 blocks specific pathways related to hyperinflammation and resulting lung injury, supporting further development as a potential therapy for ALI and ARDS associated with COVID-19-related cytokine-storm."

Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • CASP3 • CASP7 • IFNG • JAK1 • TNFA • TYK2

Janus kinase inhibitors and major COVID-19 outcomes: time to forget the two faces of Janus! A meta-analysis of randomized controlled trials. (PubMed, Clin Rheumatol) - "We finally pooled data of interest from 4 RCTs in a total of 1338 subjects with documented COVID-19 infection, utilizing the following JAK inhibitors: baricitinib, ruxolitinib, tofacitinib, and nezulcitinib. Herein, we demonstrate a clear benefit with JAK inhibitors added to standard of care in patients with COVID-19 in terms of risk reduction concerning major outcomes. Larger RCTs will elucidate their place in treatment armamentarium against COVID-19."

Journal • Retrospective data • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

Phase 1 study in healthy participants to evaluate safety, tolerability and pharmacokinetics of inhaled nezulcitinib, a potential treatment for COVID-19. (PubMed, Clin Transl Sci) - "No reductions in natural killer cell counts were observed, consistent with the lack of a systemic pharmacological effect and the observed PK. In summary, single and multiple doses of inhaled nezulcitinib at 1, 3, and 10 mg were well tolerated in healthy participants, with dose-proportional PK supporting once-daily administration."

Clinical • Journal • P1 data • PK/PD data • Acute Lung Injury • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A phase 2 multiple ascending dose study of the inhaled pan-JAK inhibitor nezulcitinib (TD-0903) in severe COVID-19. (PubMed, Eur Respir J) - No abstract available

Journal • P2 data • Infectious Disease • Novel Coronavirus Disease

Theravance Biopharma, Inc. Announces Top-Line Results From Phase 2 Study of Nezulcitinib In Patients Hospitalized With Acute Lung Injury Due to COVID-19 (PRNewswire) - P2, N=235; NCT04402866; Sponsor: Theravance Biopharma; "Primary: No statistically significant difference in RFDs from randomization through Day 28 between nezulcitinib and placebo in ITT (median: 21 vs. 21 days; p=0.61); Secondary: No difference in change from baseline at Day 7 in SaO2/FiO2 ratio, proportion of patients in each category of the 8-point Clinical Status scale, and proportion of patients alive and respiratory failure-free at Day 28; Nezulcitinib demonstrated a favorable trend in improvement when compared to placebo for 28-day all-cause mortality (total number of deaths: 6 vs. 13, HR: 0.42, p=0.08) and time to recovery...The Company will share these results with FDA and other regulatory agencies..."

P2 data • Infectious Disease • Novel Coronavirus Disease

[VIRTUAL] Inhaled pan-Janus kinase inhibitor TD-0903 in patients with COVID-19-associated acute lung injury: part 1 results of a two-part, phase II, randomised, double-blind, placebo-controlled study (ECCMID 2021) - No abstract available

Clinical • P2 data • Acute Lung Injury • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

TD-0903 for ALI Associated With COVID-19 (clinicaltrials.gov) - P2; N=235; Completed; Sponsor: Theravance Biopharma; Recruiting ➔ Completed

Clinical • Trial completion • Acute Lung Injury • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Theravance Biopharma, Inc. Reports First Quarter 2021 Financial Results and Provides Business Update (PRNewswire) - "Q2 2021: Nezulcitinib (nebulized lung-selective pan-Janus kinase (JAK) inhibitor) Phase 2 for acute hyperinflammation of the lung in COVID-19 (study 0188) – enrollment complete...Quarterly Highlight: YUPELRI® (revefenacin) inhalation solution, the first and only once-daily...continued to increase its share of the long-acting nebulized COPD market, increasing to 19.0% in January 2021, up from 18.6% in December 2020. TRELEGY (first once-daily single inhaler triple therapy for COPD and asthma)...posted first quarter 2021 global net sales of $341 million (up from $249 million, 36.9%, in the first quarter of 2020); Theravance Biopharma is entitled to tiered royalties of 5.5% to 8.5% of TRELEGY global net sales."

Commercial • Enrollment status • Sales • Asthma • Chronic Obstructive Pulmonary Disease • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Theravance Biopharma, Inc. Reports Fourth Quarter and Full Year 2020 Financial Results and Provides Business Update (PRNewswire) - P2, N=222; NCT04402866; Sponsor: Theravance Biopharma; "Part 1 Safety:TD-0903 was generally well-tolerated across the three dose levels; There were no drug-related serious adverse events; One patient in the 10 mg dose cohort discontinued therapy after four days because of an isolated increase in liver alanine aminotransferase...TD-0903 showed numerical improvements in clinical outcome and duration of hospital stay and fewer deaths compared to placebo (n=25); Part 1 Biomarkers and Pharmacokinetics (PK): Evidence of improvement in several relevant inflammatory biomarkers....The 3 mg dose is currently being evaluated in Part 2 of the Phase 2 study...The Company expects to announce data from Part 2 in Q2 2021."

Biomarker • P2 data • PK/PD data • Infectious Disease • Novel Coronavirus Disease

TD-0903 for ALI Associated With COVID-19 (clinicaltrials.gov) - P2; N=222; Recruiting; Sponsor: Theravance Biopharma; Trial primary completion date: Dec 2020 ➔ Apr 2021

Clinical • Trial primary completion date • Acute Lung Injury • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Glens Falls Hospital joins study on treating long-term COVID lung damage (The Post-Star) - "Glens Falls Hospital is the first site in the United States studying a treatment for COVID-19 lung injuries. The hospital has joined a Phase 2 study that will treat local patients....The first Glens Falls Hospital patient joined the study last week. The hospital may have many more takers for the program: There are 15 patients with coronavirus at the hospital now, more than at any one time before during the pandemic....The study will recruit about 200 participants at sites in multiple countries....The hospital also entered into a study for remdesivir."

Trial status • Infectious Disease • Novel Coronavirus Disease

Theravance Biopharma, Inc. Reports Third Quarter 2020 Financial Results and Provides Business Update (PharmiWeb) - P1, N=54; NCT04350736; Sponsor: Theravance Biopharma; "Completed Phase 1 study....Data provided confidence to continue dosing patients in a Phase 2 study; Favorable safety and tolerability profile across the full range of nebulized doses from 1 to 10 mg after once-daily dosing for 7 days....Initiated Phase 2 study....Part 1 was a multiple dose-ascending study (from 1 to 10 mg doses) conducted in 24 hospitalized COVID-19 patients that has now completed dosing. Part 2 is a randomized, double-blind, parallel-group study...in approximately 200 hospitalized COVID-19 patients; the Company expects to report results of the Phase 2 study in Q2 2021."

P1 data • P2 data • Trial status • Acute Lung Injury • Infectious Disease • Novel Coronavirus Disease

TD-0903 for ALI Associated With COVID-19 (clinicaltrials.gov) - P2; N=222; Recruiting; Sponsor: Theravance Biopharma; N=159 ➔ 222; Trial completion date: Oct 2020 ➔ Feb 2021

Clinical • Enrollment change • Trial completion date • Acute Lung Injury • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pneumonia

First in Human SAD and MAD Study of Inhaled TD-0903, a Potential Treatment for ALI Associated With COVID-19 (clinicaltrials.gov) - P1; N=54; Completed; Sponsor: Theravance Biopharma; Recruiting ➔ Completed

Clinical • Trial completion • Acute Lung Injury • Infectious Disease • Novel Coronavirus Disease

TD-0903 for ALI Associated With COVID-19 (clinicaltrials.gov) - P2; N=159; Recruiting; Sponsor: Theravance Biopharma; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Acute Lung Injury • Immunology • Infectious Disease • Novel Coronavirus Disease