Theravance Biopharma has reported positive initial clinical data from the first of a two-part Phase II trial assessing its inhaled COVID-19 drug candidate TD-0903 in patients hospitalized with acute lung injury due to the disease.
All three doses of TD-0903 studied by Theravance 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 six 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.
Among the placebo patients by contrast, just 67% (four of six) were alive and respiratory failure free, while three showed worsening clinical status during a seven-day treatment period, defined as a score of 8, 7 or 6 on the WHO COVID-19 Clinical Status Ordinal Scale. Two placebo patients died, as did one of the 1-mg dose patients, Theravance acknowledged.
The positive topline data—announced by Theravance last week when it released fourth-quarter and full-year 2020 results—will be followed in the second quarter by data from the trial’s second part.
TD-0903 is among candidates GEN is “Keeping an Eye On” of the more than 300 candidates listed in its regularly updated COVID-19 DRUG & VACCINE TRACKER. TD-0903 is a lung-selective, nebulized pan-Janus kinase (JAK) inhibitor designed for delivery by nebulizer into patients’ lungs when the oxygen in their bloodstream begins to drop.
“We know from watching COVID that that’s when the patient has gone from the viral phase into a hyperinflammatory stage in the lung, and we’re trying to put the brakes on that hyperinflammatory stage,” Theravance Chairman and CEO Rick E. Winningham told GEN in an interview during the recent J.P. Morgan virtual 39th Healthcare Conference. “I think if TD-0903 is successful in COVID, it’s a real game changer for the program, and for inhaled JAK inhibition overall.”
One analyst appears to share Winningham’s and Theravance’s enthusiasm for TD-0903.
“This program has tended to be disregarded by investors, but the dose-dependent improvement in outcomes seen in the small trial offer tantalizing hints of real activity and benefit, and are likely to garner considerable attention in coming days,” Geoffrey C. Porges, MBBS, director of therapeutics research and a senior research analyst at SVB Leerink, wrote in a research note.
During the company’s quarterly earnings call, Brett K. Haumann, MD, MBA, Theravance senior vice president and chief medical officer, disclosed that Part 1 of the trial was conducted in the U.K. and Eastern Europe, including Moldova, Romania, and Ukraine, while the geography of participants in part 2 was expanded to countries including the U.S., Argentina, Brazil, and South Africa.
“This change alone, along with much more complex background therapy, are reasons to be cautious about the next trial duplicating the results of this first study,” Porges cautioned.
In an apparent reflection of that caution, SVB Leerink included no revenue from TD-0903 in forecasting Theravance financial results for 2021. Brian P. Skorney, CFA, senior research analyst with Baird, said Theravance could attract investors should another spike in COVID-19 infections emerge later this year.
“While the data are still very early and it is hard to say whether this medication will ultimately prove to be efficacious, we do note the strain-agonstic nature of this approach could provide investors with a nice pandemic hedge should cases start to rise again,” Skorney wrote in a research note. “However, given the rapid rollout of vaccines and recent decline in cases, we believe there are significant uncertainties surrounding the potential commercial opportunity here.”
Two-Part Trial vs. Placebo
TD-903 is under study in a two-part Phase II trial (NCT04402866) designed to compare treatment with TD-0903 versus placebo in addition to standard of care treatment in hospitalized patients with COVID-19 who required oxygen at the time of enrollment.
Part I of the study explored three once-daily doses (1 mg, 3 mg, 10 mg) and matched placebo in a double-blind, multiple-ascending dose (MAD) design. Each cohort consisted of eight patients (six receiving TD-0903 and two receiving placebo), all treated up to seven days with the majority receiving background standard of care therapy, including oxygen, anticoagulation and dexamethasone.
Part 1 results showed TD-0903 to be generally well-tolerated across the three dose levels, with no drug-related serious adverse events. One patient in the 10 mg dose cohort discontinued treatment after four days because of an isolated increase in liver alanine aminotransferase (ALT) that met pre-defined stopping criteria.
“TD-0903 offers the potential for broad pan-JAK anti-inflammatory therapy in the lung without increasing the risk of systemic side effects that are associated with other JAK inhibitors, including the risk of blood clotting, already a high risk in patients with COVID-19,” Haumann said. “TD-0903 also targets the lung inflammation caused by COVID-19 not the Coronavirus itself, so should not be affected by which mutational strains of COVID-19 caused this acute lung injury.”
The 3-mg dose of TD-0903 is now being evaluated in Part 2 of the Phase II trial, designed to evaluate the efficacy and safety of a seven-day course of once-daily nebulized TD-0903 compared to placebo in 198 hospitalized COVID-19 patients.
“We’re very excited because we might be able to make a difference here at this hyperinflammatory state of the lung, and that’s what gets people in real trouble with COVID,” Winningham said.
TD-0903 is one of two nebulized inhaled pan-JAK inhibitor candidates Theravance has advanced for respiratory disorders. The other, TD-8236, is a dry powder lung-selective candidate being developed for asthma.
In November 2020 when it released third-quarter results, Theravance reported that TD-8236 monotherapy failed to meet its primary endpoint of the Phase IIa Lung Allergen Challenge (LAC) study, as the therapy showed no impact on decrease in lung function (FEV1) following the study after 14 days of once-daily dosing at dose levels of 150 µg and 1500 µg.
The LAC study was the first time an inhaled JAK inhibitor was studied in such a model.
“We’re disappointed about the lung allergen challenge data, yet we were able to see the drug in fact show signs of having suppression of the immune system and the lungs,” Winningham said. “This just part of drug development where we get some results and we’ve got to figure it out. Hopefully, we can find a home for the JAK inhibitors in the lung to treat patients who have asthma and inflammation that’s not adequately resolved through inhaled corticosteroids.”
Theravance met its primary objective, however, for TD-8236 in another clinical trial, the Phase I Part C study in moderate-to-severe people with asthma who took TD-8236 with an inhaled corticosteroid. Decreases in key inflammatory biomarkers of JAK target engagement (pSTAT1 and pSTAT6) were seen in the TD-8236 plus steroid arm vs. the steroid alone arm, based on reduced cellular fractions of bronchoalveolar lavage fluid after 7 days of once-daily dosing at the 1500 µg dose level.
“Put the Puzzle Together”
“We’ll have to look at both the data from TD-0903 and TD-8236, and put the puzzle together to decide where we go next with TD-0903,” Winningham told GEN. “It may be into acute hyperinflammation due to COVID, or it may be to go into acute hyper inflammation in another disease. Originally, this program was designed to prevent lung transplant rejections.”
Indeed, a study in lung transplant rejection may be the next study Theravance carries out for TD-0903, Winningham added: “Where we would go first, I think, is the acute phase, and then work through that to get to the to the chronic phase. We may be able to get into that in late 2021 or early 2022, depending on the data that we have.”
Could TD-0903 be developed for both lung transplant rejections and lung inflammation in COVID? “It could,” Winningham replied. “I think this is why the data are so important coming out of this approximately 200-patient study.”
“We’re pioneers here and in understanding how JAK inhibitors work when directly applied to the lung. But we believe that over time, there is a whole range of conditions in the lung, where it may be beneficial to use an inhaled JAK inhibitor,” Winningham added. “We’ve got to figure it out.”
He said Theravance also needs to decide whether TD-0903 and TD-8236 could both be developed for COVID-19-related indications.
“Clearly the nebulized approach for patients who have had COVID is more attractive, because you’re relying less on the patient’s lung function to deliver the drug with a nebulizer than you are with a dry powder inhaler.”
Last week, Winningham said Theravance has completed additional analysis on gene signature and biomarker data from the Phase 1c study of TD-8236. “The gene pathway analysis and biomarker data are consistent with target engagement in the lung. The robust body of scientific evidence from TD-8236 and TD-0903 provide confidence for us to continue the lung-selective inhaled pan-JAK inhibitor program for asthma,” Winningham said.
But Theravance is pausing its clinical program for TD-8236 in order to refine its formulation and expand the number of inhaled JAK inhibitor molecules in its portfolio that are suitable for dry powder inhalation. A full dataset for TD-8236 will be presented at future scientific meetings.
Net Losses, Market Share Grow
The positive results for TD-0903 followed Theravance reporting results for Q4 and full-year 2020. The company finished 2020 with a net loss of $278 million on revenue of $71.86 million, compared with a $236.5 million net loss on revenue of $73.4 million for 2019, with most of the additional net loss reflecting an additional $41.7 million in R&D expenses last year.
However, Theravanace narrowed its net loss during Q4, to $58.4 million on revenue of $18.7 million, from $65.6 million on revenue of $29.5 million.
Theravance’s 2020 revenue consisted in part of non-cash collaboration revenue of $26.5 million ($7.1 million in Q4), primarily from its up-to-$1 billion global gastrointestinal drug collaboration with Janssen, which is led by Izencitinib (TD-1473), a norepinephrine reuptake inhibitor being developed for ulcerative colitis (Phase IIb/III) and Crohn’s disease (Phase II); and includes TD-5202, a Phase I gut-selective irreversible JAK3 inhibitor candidate being developed for inflammatory intestinal diseases.
Izencitinib is expected to read out both Phase IIb data in ulcerative colitis and Phase II data in Crohn’s in the third quarter. Also expected to read out topline Phase III data in Q3 is another pipeline candidate, Thervanace’s wholly-owned Ampreloxetine (TD-9855) for symptomatic neurogenic orthostatic hypotension (nOH).
2020 revenue also included $43.9 million from collaboration revenue from Viatris, formed last year when Pfizer’s john division merged with Mylan, with which Theravance co-developed Yupelri®, its marketed inhaled maintenance treatment for chronic obstructive pulmonary disease (COPD). Theravance is entitled to 35% of profits and losses on Yupelri; the rest goes to Viatris.
Despite the pandemic, Theravance said, Yupelri achieved year-over-year sales growth of 159%, and increased its share of the nebulized COPD market to 18.6% through November 2020, from 17.4% in September 2020.
“We focus on the hospitals, Viatris focuses on the community. That’s really the drivers of what can grow the product,” Winningham said. “We hope to continue our progress and experience great growth in 2021 because, most importantly, the product delivers on its promise. I think that’s why, even in a respiratory pandemic, we continued to see share growth in both the hospital and the community throughout 2020.”