On 4/9/20, Theravance (TBPH) advanced its nebulized pan-JAK inhibitor TD-0903 into the clinic as a potential treatment for severe COVID-19 infections. The drug had previously been presented as a potential treatment against lung transplant rejection. Since scientists see a good chance that the most severe cases are due to an exaggerated immune response, a JAK inhibitor might be a potential treatment:
“TD-0903 has been shown in experimental murine models to have potent, broad inhibition of JAK-STAT signaling in the airways following challenges with multiple cytokines. By its mechanism, TD-0903 has the potential to block release of cytokines and chemokines that may be associated with acute lung injury and the initiation of a cytokine storm syndrome. Preclinical studies suggest that TD-0903 has a very high lung:plasma ratio and rapid metabolic clearance resulting in low systemic exposure, compatible with its lung selectivity. TD‑0903 is administered via nebulized inhalation solution, which further enhances its lung selectivity. Preclinical pharmacodynamic studies indicate that TD-0903 has an extended duration of action that should enable once or twice daily dosing in humans.
Treatment with JAK inhibition is recognized as an important anti-inflammatory mechanism to potentially reduce the hyperinflammation seen in hospitalized COVID-19 patients who develop Acute Lung Injury and Acute Respiratory Distress Syndrome.”
Although Theravance moved rapidly and already has concluded phase 1 and initiated phase 2 studies, the remainder of the clinical program will likely take at least one year to complete. Therefore, if there was a vaccine within 2021, the drug would have a very limited target population.
Moreover, just a few weeks later, Regeneron’s (REGN) anti-inflammatory drug Kevzara targeting the IL-6 pathway (which was mentioned in the Theravance slide above alongside the potential JAK pathway) failed in its first study against COVID-19. Similarly to what Theravance’s JAKi could potentially achieve, researchers hoped the drug would help ease the immune system’s overreaction to the virus, potentially helping to keep patients off of ventilators. Later, this drug also failed in another study evaluating its effects on the 10% of the most severe patients already on ventilators.
Another anti-inflammatory like Actemra (anti-IL-6) also has shown disappointing results in COVID-19.
While Kevzara and Actemra have a different MOA from TD-0903 and are not lung specific (they actually are approved arthritis drugs), just like the Theravance JAK inhibitor they targeted the hypothesis that inhibiting the cytokine storm significant damage in COVID-19 patients could be avoided. Their failure makes this hypothesis a bit more unlikely to be proven correct.
Theravance’s speculation is that this is due to their systemic side effects, which limits dosing and makes doctors more likely to use them only when it’s already too late. In contrast, TD-0903 is lung specific and could provide much more potent anti-inflammatory effects earlier in the course of the disease. On the other hand, some experts believe TD-0903 could be less efficacious due to its localized delivery, as inflammation needs to be fought even outside of the lung tissues.
As the linked article highlights, there’s enormous competition in the field: More than 100 immunomodulators like TD-903 and other immunosuppressants currently are under development against COVID-19. Given the robust pipeline, BARDA has stopped funding this research.
My personal view of Theravance’s effort is that the company is profiting from the occasion to quickly gather insights into TD-0903. While keeping a high-risk option on a potential high-reward COVID-19 treatment, the company probably is more interested in informing a decision on potential other indications for this drug. Effectively, during a recent investor conference at H.C. Wainwright (from min 12), the company played down a bit the importance of TD-0903 for COVID-19, basically confirming my view that it used the occasion to rapidly test this anti-inflammatory drug and understand it better.
Overall, the tepid market reaction to Theravance’s initiative was likely correct. With most of the company’s other trials delayed due to the pandemic, TD-0903 represented a rare chance to accelerate at least one program. But I sincerely doubt its final indication will be to fight COVID-19.
Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.