Whether this drug combination is successful is a multibillion dollar question. What investors want to know is if the phase 3 trial will show enough improvement for double delta F508 CF patients to get FDA approval and justify a huge price. One way to get some idea of the answers to these questions is to look at the results for Kalydeco monotherapy in 551 mutation CF patients and the response to Ataluren in the 10% of CF patients with "nonsense" mutations. Kalydeco monotherapy in the 551 mutation patients produced dramatic results with about a 10% mean absolute improvement in FEV1 compared to placebo at 48 weeks. It received early FDA approval. Ataluren had poor phase 3 results with about a -2.5% FEV1 change compared to #$%$ FEV1 with placebo. Those not using inhaled antibiotics did somewhat better with Ataluren: -0.2% FEV1 for those on the drug versus -6.9% on placebo. Of course, it is more difficult to show improvement in lung function for CF patients on inhaled antibiotics. Ataluren will not receive FDA approval with these results. Now consider the final phase 3 results for 600 mg VX-809/Kalydeco. These patients had a mean absolute improvement in lung function (FEV1) of 6.7% compared to placebo from day 0 to day 56. Also, 18 of the 21 (86%) patients showing this improvement were on inhaled antibiotics. The results are not as good as those seen with Kalydeco monotherapy in 551 mutation CF patients but they are far superior to the Ataluren results. Even moderate improvements in lung function as seen with VX-809/Kalydeco could add years to the life expectancy of these patients. Of course, these VX-809/Kalydeco results need to be confirmed in a larger and longer phase 3 trial. Remember, if VX-809/Kalydeco is approved after the phase 3 trial, there are 12 times as many CF patients that can be treated with this combination compared to the Kalydeco monotherapy. Even if Vertex charges half what they charge for Kalydeco monotherapy, this could be a drug with multibillion dollar revenue for years to come.
Sentiment: Strong Buy
You are right here in determining the %FEV1 change from Day 1 to Day 56.
It takes a good amount of time to clear airways of clogging thick mucus after the drug starts pumping chloride ions and hydrate dry mucus. According to CSO, there were a great deal of respiratory symptoms during the first 14 days of Kalydeco treatment of 551 patients. The same would be true for 508 treatment. All can lower %FEV1 in the initial dosing periond. After the symptoms clear, FEV1 should increase. It rose 20% even from Day 42 to Day 56, and could rise further from Day 56 to Day 70.
The effect of removal of inhaled antibiotics during the combination treatment should not be as great as for the placebo group because the effect is mediated through increased rate of infection and inflammation. The drug combo should clear some infection without antibiotics. So, the placebo is not a good control for the treatment when the antibiotics is withdrawn. But I think that 5-6% is a good range to shoot for.
Third, I thought the inhaled antibiotics were continued throughout the phase 2 VX-809/Kalydeco trial. There was a presentation by Michael Boyle, MD with a slide showing baseline characteristics for the phase 2 study participants. The 600 mg VX-809/Kalydeco group had 86% on inhaled antibiotics and the placebo group had 91% on inhaled antibiotics. Stopping the inhaled antibiotics at any point during the study would add a confounding variable. The phase 3 Ataluren study showed it was more difficult to show improvement when patients are using inhaled antibiotics. Therefore the 6.7% improvement seen with those receiving the combo compared to placebo is more impressive if most of the patients were using inhaled antibiotics.