Cohort 3 data is consistent with Cohort 2 of Phase II of VX-809/770
The following observation was written last year after the disclosure of Phase II results. The result of Cohort 3 reported today reinforces the results of Cohort 2 and supports the hypotheses outlined below.
After reviewing Dr. Boyle's slides that were presented at the NACFC 2012 meeting, I found an important point he didn't stress enough, but remarkable because they complement the drug induced improvement in %FEV1.
There appears to be a causal relationship between respiratory symptoms during the mono-phase and absence of FEV1 improvement in the early 4 wks. Respiratory symptoms appeared during the 809 monotherapy phase practically disappeared or greatly reduced during the 809/770 dosing phase. The implication of this point has been overlooked. Please consult the two slides displaying the Adverse Event Summary and its itemized table from Dr. Boyle's talk at the meeting.
Respiratory symptoms of CF patients arise from the insufficient CFTR function on the surface of respiratory cells. Build-up of sticky mucus which does not clear, promoting airways obstruction, and chronic infection. Blocked airways bring about clinical symptoms such as shortness of breath, chest tightness, or dyspnea and pulmonary exacerbation(major causes for pe is most likely infection and inflammation).
Without a drug or other interventions individuals with either G551D or F508del mutation in CFTR experience above respiratory symptoms (except dyspnea). However, when Kalydeco is taken by a G551D person, such symptoms do NOT disappear right away. Instead, additional symptoms can appear. Cough and sputum production can increase in the early 14 days of Kaly dosing as stated by Dr. Peter Mueller at the very end of Q&A session of October 11 webcast. This can be understood because the improved chloride ion conductance through the airways cells decreases the stickiness of mucus so that the mucus can be cleared more easily, resulting in increased production of sputum and cough.
Dr. Mueller hypothesized that the same thing is happening when VX-809 is dosed for 508 persons. Furthermore, these respiratory distress can lead to the depressed lung function measured by FEV1(one of indicators of pulmonary exacerbation is a lowered FEV1). I am saying here that the lowered FEV1 during the monotherapy phase is caused by the drug 809. For example, the dyspnea increases with the 809 dose; none in the placebo and the 200mg arms, 1 out of 21 in the 400mg arm, 7 out of 21 in the 600mg arm, and 4 out of 21 in the heterozygous 508 arm. Subsequently during the combo phase, however, dispnea disappears in all arms but one in the 600mg arm. It must be that the airway mucus becomes more hydrated, can be more easily propelled out, and the patients can breath better.
It is very likely that the early part of the combination phase also suffers from the airways clearing, and the FEV1 does not increase much in the early part, but increases gradually even beyond Day 42. The %FEV1 increase from Day 42 to Day 56 is 20%. It is likely that FEV1 increases further beyond Day 56. Consequently, one underestimates the true effect of VX-809/770 on FEV1 than overestimate it when one measures the Day 56 FEV1 with respect to the Day 1's. You also underestimate it because of the effect of coming off from inhaled antibiotics in the combination phase of the trial.
Dr. Leiden had stated just before Dr. Meuller spoke that the decline of FEV1 during the first 4 wks is not statistically significant. However, Slide #22 of the webcast shows that the 600 mg arm scored -3% on Days 14 and 28 with the former having p value less than 0.05. This may not be a strong case for data significance by itself, but the data from the 400mg arm (see Slide #21) also show a significant depression of FEV1 on Day 14.
To summarize what I wrote, FEV1 actualy decreases in a 809 dose dependent manner in the early going because a partial hydration of dried mucus creates more problems for breathing. However, this difficulty is transient, and FEV1 will return to the base line even without 770 if 809 is dosed long enough, but its effect would be limited. 770 merely extends the 809's work. In in vitro studies CFTR improves with 809 titration alone.
Excellent points third. The preoccupation of some analysts regarding the drop in FEV-1 during days 0-28 dosing in the 809 monotherapy arms of Cohorts 2 and 3 seems to reflect their ignorance of Dr. Boyle's discussion at the NACFC meeting in Orlando last fall. The improvement in the perecentage of patient's with siginificant improvement in FEV-1 from higher drug exposure in Cohort 3 (more than 70% in the fourth quartile of positive repsonse in the 800mg every 12 hr dosing vs. 40% in the fourth quartile in the 600mg once a day dose of VX 809 with 770 in Cohort 2) certainly confirms a strong potenetial for the higher dose to demonstrate even better clinical repsonse in the study population. The six month trial duration and the FDA's willingness to start pediatric trials immediately, shortens the time projections to FDA approval if the Phase 3 studies confirms the safety and efficiacy seen to date. "Breakthrough Drug Designation" fullfill the promise made to the CF community to unlock the door for meaningful improvements in the length and quality of life for CF patients, and reward investors as drug approval for these medications is appreciated by Wall Street as a reality early next year. Add positive Phase 2 results for VX 661 and 509 and 135 later this year, and one can see a lot of upside for Vertex investors as the year progresses.