Roche’s current Phase 2 program is strangely ambiguous. RG-7929 has not made it into www.clinicaltrials.gov yet, only POL7080 is listed. An uncontrolled open label study in “patients with non-CF acute exacerbation of bronchiectasis due to P. aeruginosa requiring IV treatment” is enrolling. Well, good luck finding those patients! At best, this is a safety study; an assessment of efficacy (by measuring reduction in CFU) will not be possible in such a small cohort (N= 20).
More to the point is a Phase 2 VAP study. This is also a small open-label uncontrolled trial (N=25) for patients with “suspected or possible” P. aeruginosa lung infection. This study will provide some useful PK information in the target population. With POL7080 given together with SoC, it will not permit an efficacy assessment either.
Interestingly, no dosing information is provided for any Phase 2 study; it seems that the appropriate dose is still in question.
In summary, we cannot expect more than PK/PD information and tiny bit more safety data from the current Phase 2 program. This is not enough to jump into a costly and – we would argue – highly risky Phase 3 program. It would make sense for Roche to add a mid-size Phase 2 trial to get a preliminary read-out on efficacy. This would give the team time to structure the path for Phase 3 and the submission package.
The POL7080 development program is very difficult and getting it right will take imagination. We wish the Roche/Polyphor team all the best for their Health Authority meetings. VABP has proven to be a mine field for many drugs already, even for those where we would have expected a home run. Think about doripenem and tigecycline, but they are not alone. Nowadays, recruitment has become more difficult as cases of VAP are disappearing, partly because of the CMS penalties for hospitals reporting VABP cases, partly because the VAP ‘bundle’ of preventative measures has really made a difference.
Let’s also be clear: there is no other indication for POL7080 to pursue than VABP. P. aeruginosa infection in skin infections or burns, UTI and malignant external otitis are just too rare for prospective study. CF patients are routinely receiving so many drugs, including IV and aerosol antipseudomonas agents, making it impossible to study POL7080 in this polypharmacy environment. POL7080 is a drug for serious P. aeruginosa infection, not for folliculitis or hot tub rash. But bacteremia / sepsis is also not an indication anyone would want to tackle with a new antibiotic coming right from the start.
Cubist proved that a narrow-spectrum drug like daptomycin can be developed: Their S. aureus endocarditis trial was highly innovative in design, difficult to execute and high risk overall but the payback for these efforts was enormous. Somehow I doubt that any large pharma company could have done what this small dedicated VC company could pull off. Hats off to Francis Tally and his team of trailblazers at Cubist.
In contrast to MRSA endocarditis, P. aeruginosa endocarditis is no longer common – not even in the Detroit area. Such a study would require a huge effort and strong commitment, and still take too long to execute.
Unfortunately, “exacerbation of bronchiectasis due to P.aeruginosa in need for IV therapy” is not the sweet spot for POL7080. Let’s hope that Roche develops a quick diagnostic test and comes up with a workable plan for Phase 3 quickly.
Part 3 to follow shortly – HHR
Abbreviations:
SoC standard-of-care
CF cystic fibrosis
VAP/VABP ventilator-associated (bacterial) pneumonia
CMS Center for Medicare/Medicaid Services
