Savara Pharmaceuticals is stopping its Phase 2a exploratory clinical study of Molgradex (molgramostim nebulizer solution) to treat nontuberculous mycobacterial (NTM) lung infection in people with cystic fibrosis (CF), the company announced in a press release.
The decision to discontinue the open-label ENCORE trial (NCT03597347) stems from an inability to achieve the study’s primary outcome. That goal was to assess the effects of the therapy in converting NTM-positive sputum culture (saliva and mucus from the respiratory tract) to a negative culture.
A proper assessment was not possible due largely to two “confounding factors,” company officials said. One was the COVID-19 pandemic, which limited patient enrollment and “disrupted” study sites. Another was the approval at mid-trial of a triple-combination CFTR (cystic fibrosis transmembrane conductance regulator) therapy, which has become a preferred treatment option for many CF patients.
Savana’s release did not name this therapy, but it is likely to be Trikafta, by Vertex Pharmaceuticals, approved in the U.S. in October 2019, and under the brand name Kaftrio for the European Union in August 2020.
Trikafta (elexacaftor, tezacaftor, ivacaftor) is a next-generation CFTR modulator. As such, it addresses the underlying cause of CF — mutations in the CFTR gene that affect its protein. Trikafta treats patients, ages 12 and older, with at least one F508del mutation, a defect found in an estimated 90% of all with this disease.
The company terminated trial recruitment in early March, after enrolling 14 out of a target 30 patients. Of these 14 adults, nine were using the triple combination; eight started this treatment as ENCORE was underway.
Safety concerns with Molgardex’s use did not play any role in the trial’s termination, Savara reported.
“Discontinuing the exploratory ENCORE study is very disappointing and I extend our sincere gratitude to the patients who participated, especially during the trying times of this pandemic,” said Badrul Chowdhury, the company’s chief medical officer.
While the pandemic made the trial’s recruitment goal unattainable, the triple combination’s approval “transformed the standard-of-care for this patient population,” Chowdhury added. It “further confounded our ability to evaluate the potential effect of Molgradex in this study.”
Molgradex is an inhaled formulation of artificially produced human granulocyte-macrophage colony-stimulating factor (GM-CSF). Certain immune cells normally produce and secrete the GM-CSF protein in response to disease-causing organisms, or pathogens.
A planned 48-week study, ENCORE is ending with 12 patients having more than 20 weeks of Molgradex treatment.
Preliminary data showed five of these 12 reaching a sputum culture conversion, defined as at least three consecutive sputum samples without evidence of NTM growth. All five started on the triple combo therapy after entering ENCORE, and before achieving conversion.
No CF patient treated with Molgradex as a nebulized solution who was not also using the new combo therapy achieved a sputum culture conversion, the release stated.
“[W]e are unable to differentiate which drug was primarily responsible for the observed culture conversions,” Chowdhury said.
Molgradex was also evaluated in non-CF patients who had chronic pulmonary infections not due to NTM in the Phase 2a OPTIMA study (NCT03421743) that finished in March.
Based on the results of both ENCORE and OPTIMA, Savara plans to continue developing Molgradex as a therapy for autoimmune pulmonary alveolar proteinosis, a rare autoimmune lung disorder. It does not plan to investigate Molgradex further in relation to NTM.
“While the results of ENCORE are interesting, additional controlled studies would be required to accurately understand the therapeutic potential of Molgradex in combination with the triple-combination modulator treatment,” Chowdhury said.
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