One study of an immunotherapy for reducing chronic obstructive pulmonary disease (COPD) exacerbations missed its primary endpoint and failed to show a statistically significant benefit even in the subgroup that showed the greatest response. Another study, involving a similar product, showed results so dramatic that an independent expert suspected they were “too good to be true.”
Nevertheless, COPD specialists at the European Respiratory Society’s (ERS) virtual annual meeting said these approaches show real promise and should be pursued.
At a high-profile ERS clinical trials session, researchers presented findings from the two studies. One involved a product called MV130, a cocktail of killed whole-cell bacteria for sublingual administration developed by Inmunotek SL; the other examined an investigational GlaxoSmithKline product for injection incorporating proteins from two specific bacterial species.
Luis Puente Maestu, MD, PhD, of Hospital General Universitario Gregorio Marañón in Madrid, presented the first study. He explained that MV130 consists mainly of heat-inactivated Streptococcus pneumonia and Staphylococcus aureus and epidermis, as well as smaller levels of Klebsiella pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae. These bacterial species are believed to contribute substantially to COPD exacerbations. Hence, mobilizing immune activity against these pathogens could make these events less frequent, if not abolish them entirely.
The phase III trial involved 198 patients, randomized 1:1 to sublingual placebo or the bacterial cocktail, delivered daily for 12 months, followed by 6 months of additional observation.
MV130 was extraordinarily effective: cutting exacerbations during the 18-month evaluation phase by about 30%. Median exacerbation counts during this period were 3 with placebo (interquartile range [IQR] 1-5) versus 2 for the active product (IQR 1-3). Secondary efficacy outcomes also strongly favored MV130, with exacerbation durations reduced by half (median 20 vs 10 days) and antibiotic use by 60% (median 29 vs 12 days during follow-up).
Almost no adverse effects were seen.
The ERS discussant for this presentation, Guy Brusselle, MD, PhD, of Ghent University Hospital in Belgium, called these results “very impressive” — so much so, in fact, that he quickly added, “I’m afraid too good to be true.”
And yet, he went on, they are not unprecedented. A previous study of MV130 as a treatment for chronic wheezing in children also showed similarly dramatic effects. These findings in two considerably different conditions deserve further investigation, Brusselle said.
In the second study, Stefan Andreas, MD, of the University of Göttingen in Germany, reported phase IIb results with the GlaxoSmithKline agent, which includes components from M. catarrhalis and non-typeable H. influenzae along with an adjuvant. Patients (n=606) with at least one moderate or severe exacerbation in the previous year were randomized 1:1 to placebo or the active shot, given in two doses 2 months apart, then followed for 12 months.
On the surface, at least, the product seemed to have failed. For the primary endpoint, prevention of moderate/severe exacerbations, it actually showed negative efficacy (-2.3%). The best efficacy number was seen in the 97 patients with the strongest history of severe exacerbations, in whom vaccine efficacy was 36.5% — but with a P value of 0.075, thus falling short of statistical significance. The product did appear safe, however, and there was a hint of reduced mortality with active treatment (one death, versus 10 in the placebo group, which Andreas said mostly involved respiratory or cardiovascular events).
But discussant Jadwiga Wedzicha, MBBS, MD, of Imperial College London, suggested the study was underpowered and thus the product shouldn’t be written off. “The vaccine works,” she declared, and was safe as well, “with no nasty thromboses or anything like that.”
More generally, she said, the immunotherapy strategy might be misdirected. While Andreas said the goal is to reduce bacterial colonization in airways, Wedzicha said it would be better to deploy vaccines earlier in the COPD progression with an eye to preventing colonization — “the holy grail” for immunotherapy, she said.
She also pressed Andreas for data on the bacteria patients carried in the trial, which he admitted had not been analyzed yet. It would be important to correlate the airway biome profile with treatment responses, she said.
“I would do a larger study with documented colonization,” Wedzicha said. “Ultimately we have a little problem. We still do not quite understand the role of airway bacterial colonization [in COPD exacerbations]…. I would use PCR, we want good quantitative results, and we need more research in this year.”
The MV130 study was sponsored by Immunotek.
GlaxoSmithKline funded the study of its product.
Study authors and the discussants all reported relationships with multiple pharmaceutical companies and other commercial entities; in some cases, grant funds were paid to institutions and not the individuals.