New technology to treat CF, disclosed at NACFC 2013
This year’s NACFC meeting disclosed potentially emerging new technologies to treat CF 508 indications, for which CFO Ian Smith expressed his enthusiasm twice during the Vertex conference call Q&A. Ian spoke of possibilities of participation with, in-licensing of, or even buyout of, new technologies.
Then, what are those new technologies which do not involve CFTR “repair” at the protein level? It is curious because people are excited about the potential of these technologies that may compete with protein level modifications that Kalydeco, VX-809, and other correctors are engaged in. I have searched all Symposium Summary abstracts, and came up with one technology that stood out among others.
I said a technology, but it can make up a collection of many technologies. CFTR protein is made from CFTR RNA sequence called mRNA (messenger RNA). The rapidity of CFTR mRNA production is controlled by other RNAs called miRNA(micro-RNA). MRNAs are the codes for proteins, but miRNAs do not code proteins; they are instead controllers of mRNAs. A team based in U. of Iowa (incl. MJ Welsh) found a miRNA called miRNA-138 which increased the production rate of CFTR mRNA. They also found that this miRNA-138 increased the amount of 508del CFTR protein in human airway lining cells of 508 person. They also found that chloride transport across the cell membrane was increased. They also found other miRNAs which produced the opposite effects. Keep in mind that all are bench-top cellular findings, but they are interesting and exciting enough to attract the attention of CFO and Fred Van Goor. It may take 10 or more years before these findings can be translated to clinically meaningful drugs, but Vertex should look into such technologies. There can be a more direct RNA patch work to repair 508del CFTR using antisense technology, Sarepta uses. I am sure that Vertex executives are keenly aware of these potentials, [Contn']
particularly because CFTR “repair” at the RNA level is complementary to the CFTR “repair” at the protein level, and the two approaches can be added together to enhance the outcome.
Both miRNA-138 mimic and antisense technologies would have drug delivery problems to overcome. First, the RNA mimics have to be intravenously injected and then they have to cross the cell membranes without being degraded by cellular enzymes. Great technologies but clinically do not have the convenience of oral drugs like Kalydeco or VX-809.
Third, thank you for all of your analyses of the prior 809/770 Vertex data and the new emerging science using miRNA technologies to correct CFTR function disclosed at the NACF meeting last month. Regardless of the potency demonstrated using 809/770 in earlier clinical trials, analysts like Geoff Porges seem to believe 661 is superior to 809 in combination with 770, even when adjusting dosing of 770 to offset pK drug interactions between 809 and 770. Perhaps as most TRANSPORT AND TRAFFIC patients finish their six months of treatment in the first quarter of next year, investigators will be reporting that as their study patients go off 809/770 at the end of the 24 week treatment protocol, they will no longer have the benefit of the study drugs, and consequently, there will be having a noticeable decline in their health. This should prompt Vertex to report to the FDA the obvious benefit of the study drugs while the study is still underway. Under these circumstances, the FDA has in the past has allowed an earlier than scheduled unblinding of the data on a compassionate use basis, to allow study patients in the control group and those who went off treatment with study drugs after 24 weeks, the opportunity to resume study drugs in long term 'rollover' studies to maintain their health, and accelerate the approval process of these critically needed drugs by allowing earlier NDA submission.