LittleLab, I always appreciate your informative posts. You always put a lot of time and thought into your responses. Your response here is no exception, but I wanted to share my perspective on how valuable shared information can be. It has been a topic that I’ve been very passionate about since starting off-label Kalydeco in 2014.
I’ve written to multiple people about this topic over the last few years, so I thought I’d copy and paste some of the content of my communications with others. I tend to write a lot when I’m passionate about something so this is going to be a long post : )
I agree that mutations can present differently due to environment, genetic modifiers, and the mutation on 2nd allele. But I think if someone has a significant response to a modulator like Kalydeco, then someone else with the same mutation has a better chance than not of responding in some capacity--not guaranteed by any means, but reason enough to justify a trial of the medicine. Because of the rarity of these mutations, I also think it’s key that these responses are carefully documented in a database for researchers/physicians/and patients to access. If you look at the healthcare/science view of the CFTR2 database, for many of the mutations you can check how the mutation is expected to affect both CFTR quantity and function and, in effect, predict, to an extent, how the mutation MAY respond to a modulator like Kalydeco. The CFTR-2 database should be considered as a tool to track off-label responses to Kalydeco so this information could be disseminated. Although it wouldn’t hold the same weight as a clinical trial because it’s not as controlled as a trial (no placebo); many patients do have pre and post Kalydeco objective data that would be very useful to track (FEV-1, sweat test, BMI, CFQ-R score). This could also serve as documentation considered by insurance companies when deciding coverage for an off-label personal trial. According to Dr. Janet Woodcock of the FDA, these off-label cases can also be very informative to the FDA as long as data is collected in a credible matter, following the patient before and after treatment.
CF research is ahead of the curve with respect to personalized medicine, the FDA hasn’t caught up and they are in the process of deciding how to design clinical trails for rare mutations. While we are in this holding pattern, waiting for the FDA to establish acceptable, sound and reliable protocols for personalized medicine, those with severe disease could be receiving treatment that could prevent further suffering, significantly increase their quality of life, and in some cases, perhaps save their lives.
Real life experience can be very telling and could lead researches to look at these off-label responses when deciding which mutations to include in a clinical trial. I think what needs to be stressed is that a small % increase in CFTR quantity/function (thought to be insignificant) may translate clinically to a life-changing response--far from insignificant. This is the case with my experience with Kalydeco as well as others. My mutation’s in-vitro response to Kalydeco was considered insignificant enough that it wasn’t included in the 661-108 trial for residual function mutations, but I can tell you that with the start of Kalydeco my disease progression has absolutely been slowed and my health has stabilized. Considering that I started it with very low lung function and I felt my disease progression accelerating; it would not be unreasonable to say that there is the possibility that I may have had a lung transplant by now if it wasn’t for Kalydeco. When deciding which mutations to include/exclude, Vertex looked at in-vitro response. The in-vitro results show that my mutation has a 98% quantity of mature CFTR at the cell surface, but because of a defect in CFTR function, it is considered a severe conductance mutation- with only a 1.3% of normal chloride function. With Kalydeco, the function increases to 4.9% of normal. Apparently this is a borderline response because although it was not considered significant enough to be included in residual function trial, the response was significant enough not to be included in trials that have mutations that aren’t expected to have residual function. So there are 403 people with my mutation that have been left out of these clinical trials. It is true that my positive experience may be due to modifier genes but nonetheless; this is data that needs to be documented and accessible. There are others that have had a positive experience with Kalydeco despite poor in-vitro response and vice-versa. This information would be very useful for drug manufacturers and the FDA in that it suggests that a n-of-1 trial is really the only way to be sure that no one is being left out that could respond to this treatment.
Having a database that is tracking individual response to these drugs is critical with rare diseases. Some patients with rare and not so rare mutations (relatively speaking) have been receiving Kalydeco off-label (some as early as 2012). No one is officially tracking these results collectively in a manner that would greatly benefit researchers/physicians/patients. So you have this valuable information essentially being wasted. In any scientific community, sound data that is not shared is unfortunate, but with rare diseases, wasted information multiples this misfortune significantly.
