Candidate: Nezulcitinib (TD-0903)

Type: Lung-selective, nebulized Janus kinase inhibitor (JAKi)

2021 Status: Mixed Phase IIb/III Trial Results–Theravance acknowledged August 23 that Izencitinib (TD-1473), a norepinephrine reuptake inhibitor being co-developed with Johnson & Johnson’s Janssen Biotech, failed a Phase IIb/III trial in patients with ulcerative colitis by missing its primary endpoint: A change in the total Mayo score at week eight, relative to placebo. Izencitinib also failed a key secondary endpoint of clinical remission at week 8, relative to placebo. Based on the disappointing topline results, Theravance said it would minimize future expenses associated with the program.

Phase II Success–TD-0903 “showed potential for treatment of patients with severe COVID-19” in the first part of a two-part Phase II trial (NCT04402866), researchers concluded in a preprint posted March 12 on medRxiv. In a study assessing the JAK inhibitor on patients hospitalized with acute lung injury due to the disease, patients randomized to TD-0903 showed improved 8-point clinical status, shortened hospitalization, improved oxygenation, and fewer deaths: Overall mortality was 33% in placebo-treated patients vs 5% in patients treated with any dose of TD-0903.

Part 1 explored three doses of TD-0903 (1, 3, and 10 mg once-daily for 7 days) and placebo in a randomized, double-blind, ascending-dose study. Each dose cohort comprised eight hospitalized patients (6 who received TD-0903: two who received placebo) with PCR-confirmed COVID-19 requiring supplemental oxygen and receiving background standard-of-care therapy. Key objectives included safety and tolerability, pharmacokinetics, and oxygen saturation/fraction of inspired oxygen ratio; clinical outcomes were also explored.

In reporting fourth-quarter and full-year 2020 results on February 23, Theravance announced the positive initial clinical data, saying that all three doses of TD-0903 studied in the placebo-controlled trial generated high percentages of patients who were alive and free of respiratory failure 28 days after once-daily treatment administered over seven days. The study defined free of respiratory failure as a score of 1, 2, 3 or 4 on the World Health Organization (WHO)’s COVID-19 Clinical Status Ordinal Scale.

Among the six patients who received the highest dose (10 mg), all were alive and respiratory failure free on day 28. Similar positive results also occurred in 86% (six of seven patients) receiving the 3 mg dose, and 83% (five of six patients) receiving the 1 mg dose.

The positive topline data will be followed in the second quarter by data from the trial’s second part, in which a 3 mg dose of TD-0903 is being evaluated in 198 hospitalized patients with COVID-19. “I think if TD-0903 is successful in COVID, it’s a real game changer for the program, and for inhaled JAK inhibition overall,” Theravance Chairman and CEO Rick E. Winningham told GEN in an interview.

2020 Status: Theravance said June 25 that the first COVID-19 patient had been dosed in a Phase II trial (NCT04402866) designed to evaluate TD-0903 compared with a matching placebo in combination with standard of care (SOC) in hospitalized patients with Acute Lung Injury (ALI) caused by COVID-19. The study, which is expected to enroll 159 participants, is being conducted in the same clinical setting in the U.K. as the Phase I study; the U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA), approved the Phase II study in May.

The Phase II study consists of two parts. The first part is designed to assess the safety, tolerability, and clinical response to treatment in sequential ascending dose cohorts of hospitalized COVID-19 patients, with each patient being dosed for seven days. Patients will be enrolled if they demonstrate hypoxia (lack of oxygen in the blood) since that is believed to be a marker of underlying cytokine storm in the lung. The second part will be a larger, multi-center study conducted at hospital-based clinical sites in the U.K., as well as other European countries and in the U.S., pending appropriate Ethics Committee and regulatory approvals.

The Phase II trial, like the Phase I study, is being conducted by Prof. Ashley Woodcock, Associate Dean for Clinical Affairs, Professor of Respiratory Medicine, University of Manchester and Consultant Physician, NW Lung Centre, Manchester University NHS Foundation Trust.

In April, Theravance dosed the first healthy volunteer in a Phase I study assessing TD-0903 in hospitalized patients with ALI caused by COVID-19 (NCT04350736). The study was designed to assess the safety, tolerability and pharmacokinetics of single- and multiple-ascending doses of TD-0903 in healthy volunteers and was set to enroll 54 volunteers and be completed in June.

Theravance reasons TD-0903 has the potential to inhibit the cytokine storm associated with ALI and prevent progression to Acute Respiratory Distress Syndrome (ARDS), since the drug has been shown in preclinical studies to have broad pan-JAK inhibition. TD-0903 was initially disclosed in 2018, with Theravance at the time exploring an initial clinical application of preventing/delaying graft rejection among individuals receiving lung transplantation. That is still a potential application, though Theravance added its priority for the drug is development as a COVID-19 treatment.

COVID-19: 300 Candidates and Counting

To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:

FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.

DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data.

KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.

TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.

GEN has also tagged the most common treatment types:



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