In January this year, Kalobios informed investors that KB001-A had failed to meet efficacy criteria in a Phase 2 trial of cystic fibrosis (CF) patients. In this well-controlled well-executed placebo-controlled trial of182 patients, the primary endpoint and just about every other efficacy endpoint of interest was missed. Neither did KB001 show a hint of activity in subset analyses.
Why did KB001 miss its primary target of ‘prolonging the exacerbation-free time span’? No explanation was provided by the company nor from the scientific community, nor from the usually astute group of investment advisors that follow VCs and make important Buy/Sell recommendations. Were there any warning signs, dark clouds over the project which could have alerted us to the impending doom?
Let us do a quick post-mortem and review the reasons to believe why KB001-A should have worked. The importance of the pseudomonas TTSS for delivery of virulence factors is and remains solid; the animal models showed clear benefit when PcrV was blocked by KB001; the drug was safe in all clinical studies and at all dose steps tested; the pathogenic role of P. aeruginosa in VAP and CF patients is unquestioned; there were hints of efficacy in the early stages of the program.
The scientific approach was deemed solid and the early clinical data promising enough: On 1/11/2010 Sanofi Pasteur bought into the program and partnered with Kalobios. In the spirit of true collaboration, they took over the “Pseudomonas VAP“ indication while Kalobios concentrated on the CF indication. And on 4/23/2013 the program was given Fast Track status by FDA.
We interpret these actions to mean that nothing was fundamentally wrong from a scientific perspective
We interpret these actions to mean that nothing was fundamentally wrong from a scientific perspective and that the data at the time were convincing enough for Sanofi’s and the FDA’s action. However, on critical review, the data at the time were still rather thin:
- Phase 1/2 study: Ventilated patients colonized with P.aeruginosa ⇒ reduction in VAP in 6/13 patients in the 10 mg/kg dose arm (which Kalobios liked to call “approx. 50% efficacy”) [1]
- Phase 1/2 study: CF patients (N=9 per arm) ⇒ non-significant but consistent dose-dependent reduction in inflammatory markers (elastase, MPO, IL-1, IL-8) [2]
Then came a surprise: On July 28, 2014 Sanofi cancelled the collaboration. Press releases from either company do not give any explanation why Sanofi reversed course and gave up on its admittedly small investment. Were they prescient of things to come?
Sanofi’s exit came exactly at the time when enrollment of the large 182 patient-strong Phase 2 CF study was coming to an end; hence, the bad outcome of this (failed) trial was not known at the time and could not have triggered the decision. Indeed, no new data was generated by the collaboration except for a Global Epidemiological Study on P. aeruginosa in VAP patients, conducted by Sanofi.
As outside observers we are free to speculate about Sanofi’s decision, making some assumptions which could possibly explain Sanofi’s action. This will be detailed in our next blog here at this site.
FOR PART 2, CLICK HERE
As always, you are welcome to weigh in with your opinion and leave us a comment.
References:
[1] Francois Crit Care Med 2012; 40: 2320
[2] Milla Pediatr Pulmonol, 2013; 49: 650
[3] M Kollef Crit Care Med 2014; 42: 2178
