Some annotations follow on the discussion of Vertex's CF drug pipeline in its earnings Press Release issued today. Comments (and some scientific questions!) later on CF drugs based on content of earnings conference call.
U.S. and E.U. Applications for Approval of KALYDECO (VX-770, ivacaftor) Complete : Last week, Vertex submitted an NDA to the U.S. Food and Drug Administration (FDA) and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for KALYDECO, Vertex's cystic fibrosis transmembrane conductance regulator protein (CFTR) potentiator. Vertex requested Priority Review from the FDA and has received agreement from the EMA for accelerated assessment of KALYDECO in Europe.
-Approval: I cannot in my wildest dreams imagine VX770 does not get approved.
-Value: A high price tag on this drug (100k - 200k), will be well-justified. This drug is making life with CF so much easier, better, and longer. You can find story after story on the web of CFers who no longer need their enzymes–after 30 years on them, no longer need Miralax, after years of daily dosing to avoid DIOS, lung function increasing by 10 - 20%.
Phase 2 Combination Trial of KALYDECO and VX-809 Enrolling Patients in Part 2 Vertex today announced the start of the second part of a Phase 2 clinical trial to evaluate combination regimens of KALYDECO and VX-809, a CFTR corrector, in people with the most common mutation in CF, known as F508del. Part Two of this trial will evaluate dosing of VX-809 alone for four weeks followed by dosing of KALYDECO and VX-809 in combination for four weeks. The study is expected to evaluate multiple dose levels of VX-809, including doses higher than those studied in the first part of the trial. The study is expected to enroll approximately 100 people with CF who have one copy or two copies of the F508del mutation. Similar to Part One, the primary goals of the second part of the trial are to evaluate safety and tolerability and the effect of the combination of KALYDECO and VX-809 on CFTR function as measured by sweat chloride. Lung function will be measured as a secondary endpoint. Patient screening for this study is underway.
-Part 2 of Phase 2 is now open to those with only 1 508 mutation. The Part 1 study was limited to those with 2 copies. I theorized earlier that this change will improve the study outcome, see http://messages.finance.yahoo.com/Business_%26_Finance/Investments/Stocks_%28A_to_Z%29/Stocks_V/threadview?bn=19596&tid=37620&mid=37713. I do not see separate arms for those homo and heter for 508. Keeping both groups in the same study I think will definitely improve outcome even without the dosing changes. In conference call, someone asked Vertex about the change and response was merely we need to know how it affects heter 508ers. In response to a follow-up question, Vertex said 551ers would be excluded from study, but I wonder about other gating mutations or those with some residual cell functioning CFTR. Even if all of those are excluded, I still think the results will be better if you go heter b/c of the two-prong defect in folding 508ers have--both folding and sequencing, and I bet other less severe mutations do not have both of those issues or maybe not to the same extent.
-Any thoughts folks on whether 4 + 4 will be long enough to get maximum benefit? 770 showed maximum benefit within 2 weeks. First combo didn’t work that quickly, but did show proof of concept.
The figures I posted were patient population in thousands.
The % figures I came up with were as follows:
66.00% F508 Mutation
2.40% G542X Mutation
1.60% G551D Mutation
1.30% N1303K Mutation
1.20% W1282X Mutation
27.50% All Others
In the CFF conference discussing results of VX770, CFF took questions from CFers and question was posed on cost and CFF explicitly said it was not involved in those discussions/that decision, nor was it allowed to be in the agreement with Vertex re funding.
It is great for you to notice the change in the protocol in the Part II of the trial. I like the 4+4 regimen (= 4 weeks of 809 alone followed by another 4 weeks of 809+770) far better than the 2+2 regimen. I am expecting far better results in FEV1 change than seen with the 150 mg and 250 mg arms of the 2+2 regimen. Look forward to seeing successful trial results coming out from the 809 trial and good results from the VX-661 trial as well about a year from now. As Peter said in the cc, 661 has the property of better reaching to the target organ such as the lung, and also has a longer half-life in the tissue. The value of the CF program will far exceed the value of Hep C program.
"The value of the CF program will far exceed the value of Hep C program."
Even though there are a lot fewer CF patients than HCV, I assume your above statement is due to the fact that CF patients have to take the drugs for their entire lifetime as opposed to HCV patients who just take the HCV regiment for a brief time and then they are cured. Is that correct?
Thanks. I was going to ask you more about what exactly it mean re the tissue and half-life but haven't had chance to re-listen to audio and formulate my thoughts/questions, but hopefully soon and hope you'll be able to help me figure it out. Knowing they are so close gives us such hope, especially when I hear all these wonderful stories of how VX770 has change 551ers lives!
Also, it sounds like they are going higher on dosing, so that too might make an even bigger improvement.
Did you notice one of the questions queried Vertex on why the change from homo to heter? Didn't think the answer said much, though.