The real action started this morning, with the first session of workshops. Brock and I attended the first 2 talks from the workshop CFTR 2013. For the DF508 mutation, there are several issues that cause the ultimate degradation of the CFTR protein, but the primary issue is protein misfolding. To be functional, the CFTR protein must be folded in precisely the right fashion, assemble in the correct order, and be stable enough not to unravel at normal human body temperatures. Researchers are racing to find ways to “fix” each of these issues in DF508. The first talk I attended in this workshop was entitled:
Analysis of CFTR NBD1 Co-Translational Folding Mechanism Using a Novel Solid-State Fret Assay (try saying THAT 5 times really fast!)
Shishido, H.: Yang, Z: Skach, W.R. Dept. of Biochemistry and Molecular Biology, Oregon Health and Science Division.
This was a very technical talk, but basically, this research is focused on finding a precise way to measure how well the CFTR molecule is folding. Understanding this folding mechanism and discovering accurate ways to measure CFTR folding could help researchers find therapeutic pharmaceuticals. This research presented a newly developed technique (solid-state Fret Assay) that successfully measures NBD1 folding (nucleotide binding domain 1—a section of the CFTR molecule that is misfolded in DF508). This technique is currently being adapted for high throughput screening of small molecules that interact with and stabilize NBD1.
The second talk in the workshop was entitled:
The Regulatory Insertion (RI) in NBD1 as a Target for the Stabilization of DF508 CFTR.
Akeksandrov, A.; He, L.; Cui, L.; Caldwell, R.; Dokholyan. N.; Riordan, J.R. Biochemistry and Biophysics, UNC at Chapel, Chapel Hill, NC, USA.
This talk dealt with another issue pertaining to DF508—thermal instability. In healthy individuals without CF, the CFTR protein remains stable enough at human body temperatures to remain functional. With the DF508 mutation, CFTR is unstable and tends to “unravel” at body temp. This research was focused on improving the thermal stability of DF508 by modifying a section of the CFTR protein. They found a certain portion of the protein that has a destabilizing effect on the DF508 mutation. When this section of CFTR (RI) is “immobilized” or deleted from the protein, thermal stability is restored. This concept may not sound groundbreaking, but it represents a deeper understanding of the protein dysfunction, which could lead to therapeutic pharmaceuticals to correct those problems.
After this talk, we moved to a different workshop session called Innovative Approaches to CF Therapy where the effects of Ivacaftor were discussed.
The first talk we heard was:
Results of the G551D Observational Study: The Effect of Ivacaftor in G551D Patients following FDA Approval.
Rowe, S.M., Heltshe, S.L., Gonska, T., Donaldson, S., Borowitz, D., Gelfond, D. Sagel, D.D., Khan, U., Hamblett, N.M., VanDalfsen, J., Joseloff, E. Ramsey, B., 1. UAB, Birmingham, AL, USA; 2. Hospital for Sick Children, Toronto, ON, Canada; 3. Univ. of North Carolina, Chapel Hill, NC, USA; 4. SUNY at Buffalo, Buffalo NY, USA; 5. Univ of Colorado, Aurora, CO, USA; 6. TDN, Seattle Children’s Hospital, Seattle, WA, USA; 7. CFFT, Bethesda, MD, USA.
This was an extension study of Ivacaftor that examined previously unstudied clinical endpoints, and I was really excited to hear their data. The clinical trials that led to the approval of Kalydeco used lung function and sweat chloride as major endpoints. The GOAL study looked at alternate endpoints such as changes in hospitalization rate, and changes in positive Pseudomonas culture. Researchers found that patients on Ivacaftor therapy spent significantly less time in the hospital and also decreased their odds of a positive Pseudomonas a. culture by 35%. These are phenomena that I have heard of in some Kalydeco users, but it is always nice to see the data and make it official! Many people have questioned whether Ivacaftor could make eradication of infection possible—and now we finally have some proof.
After the morning session and lunch, Brock and I made our way to the Milestones II Campaign meet-and-greet with the executive staff of the CFF, then headed to the first Plenary session. The Plenary sessions were streamed live this year, so some of you may have already seen this information! Dr. Beall described 3 challenges that the CFF is stepping up to face:
1) Development of disease modifying drugs for ALL mutations
2) Access to new therapies—The BEST drug in the world is no good if patients don’t have access to it! There must be a balance. We want to encourage biopharmaceutical companies to innovate and bring novel therapies to the market…but that innovation should come at a price that doesn’t restrict access to that new innovative therapy.
3) Maintain access to quality care for ALL CF patients.
While it seems that the majority of CF news is focused on the G551D and DF508 mutations, Dr. Beall offered assurance that the CFF's investment strategy is designed to “leave no mutation behind.” The CFF now has partnerships with several major pharmaceutical companies like Pfizer and Genzyme. I hope they can bring some compounds to the table in the next few years.
He also described the major strategic planning effort that has taken place over the last year to offer insight and solutions to problems faced by the CF community. For example, our CF specialists should not be bogged down with hours of paperwork and prior auths in order for a patient to gain access to a necessary Rx. I think I speak for everyone when I say it would certainly be wonderful to have a more streamlined process! Sometimes I feel like insurance companies put all these hoops in our way because they are COUNTING ON us giving up. The CFF is working on creative ways to remove this barrier and make the whole process easier for physicians as well as patients. I have had the privilege of working on the strategic planning committee for patient adherence, and I know there are several programs in the works designed to help patients overcome the obstacles to adherence--whatever those obstacles may be. Maintaining appropriate, quality care for all patients is a growing challenge due to the increasing size and special needs of the adult CF population (a great problem to have!). The CFF has established a task force to help them work toward solutions for issues specific to adult CF care. The overall message that I took from Dr. Beall's presentation at the Plenary is that the CFF cares about all aspects of care and understands that improvements in quality of life may come from avenues other than genetic modification. While it seems that the CFF has its sights firmly set on clinical trials and the science of CURING this disease, they truly are working behind the scenes to make sure the needs of every CF patient can be addressed in a positive fashion by the Foundation.
The main speaker at the first plenary was Dr. Scott Donaldson from the University of North Carolina at Chapel Hill. His talk was entitled: Restoring CFTR Function, Road to a Cure Part 1
Dr. Donaldson began by describing the term "cure"--which is to fully relieve a person of the symptoms of a disease or condition. What does a cure for CF look like? How will we know when we have arrived? First, he went through a brief history of the advancements through the years that have led us to where we are today. He described the detail in which we now understand CFTR function, and the combinations of correctors and potentiators that might take us much closer to that cure (no new information was given on the VX-770/VX-809 combination). He then went on to describe which CFTR functions are essential and must be corrected to restore health: pancreas, intestine, and lung.
Then he launched into the detail of the dysfunction that CF causes in each of these organs. In the pancreas, CFTR is found in the surface lining the ducts that secrete digestive enzymes into the small intestine. When CFTR is dysfunctional here, thick mucus accumulates and blocks these ducts, leaving the digestive enzymes trapped inside the organ. In essence, the pancreas begins to digest itself, rather than your food. CF disease in the intestine develops much in the same way it does in the lung (impaired bicarb secretion and chloride channel function results in retention of mucus, bacterial overgrowth, and inflammation). In the lung, CFTR dysfunction also manifests as decreased airway surface liquid, impaired mucociliary clearance, and decreased pH (CFers are overly acidic--pH is too low). He described how lungs that exhibit appropriate pH have superior bacterial killing power vs. the overly acidic environment in the CF lung. Regulating airway surface liquid pH could be a therapeutic target in the future.
Dr. Donaldson went on to discuss the need for new and improved assays to prove clinical benefit in all these areas. In other words, are there tests that could be developed to more accurately measure CFTR function? There isn't a direct correlation between sweat test test and lung function, so it may not be the best clinical endpoint to use if we are trying to prove the benefits of new drugs. I know several patients taking Kalydeco who haven't seen huge sweat test changes, but have still seen big improvements in lung function. Perhaps their CFTR is working better than we imagine, but we are simply measuring the wrong thing! One new method that was discussed was the use of intestinal organoids to measure CFTR function. A biopsy from the patient's rectum would yield a personal tissue sample. The intestinal tissue contains small "organoids" that are designed to swell and draw in water. In contrast, the intestinal organoids exhibit reduced ability to swell in individuals with impaired CFTR function. This new technique may yield a new/better way to measure CFTR function than the sweat test.
Another new technique was discussed that also uses a patient's own tissues for testing. A nasal scrape provides epithelial tissues that are then cultured and available for testing. While developing new "tests" may not be as exciting as developing new drugs, these new techniques are going to be an absolutely crucial piece of the puzzle as we move into a new era of truly personalized medicine--where you are treated based on your personal physiological response. Cool.
At this point, Dr. Donaldson reported some of the data from the GOAL study (that extension study of Kalydeco that I reported a bit on earlier in this blog). In addition to showing reduced rates of positive pseudomonas cultures and reduced hospitalizations, the study also revealed that patients taking Kalydeco were able to normalize pH in the gut. He described the ideal pH range for enzymes to be effective and hypothesized that this is part of the reason why patients taking Kalydeco have seen weight gain and better absorption. The overly acidic environment prevents enzymes from working properly in many individuals with CF (which is why most of them are on acid blockers). The pH changes seen in the intestine of patients taking Kalydeco means that they are able to move to the optimal range for enzyme function.
Dr. Donaldson also showed data on improved mucociliary clearance in both the whole lung and also in the peripheral lung--where disease often begins. He showed this really cool video showing a patient attempting to clear their lungs, measured over 30 coughs. In the untreated CF lung, very little clearance was seen. In the CF lung treated with Ivacaftor, there was a dramatic difference in the ability to clear mucus in the entire lung. Typically, lung clearance in the periphery can be very difficult once small airways are blocked. Because Kalydeco is a systemic therapy, it can reach tissues inhaled therapies couldn't, and have a greater impact on the small airways.
Finally, he discussed how we might improve moving forward. He didn't give specific information on when the trial of Ivacaftor in 2-5 year olds might be completed, but he did remark that they have a good indication that the earlier you are able to start this type of therapy, the better the outcome might be. Another way to improve on this would be to treat BOTH of a patients mutations (for example, Brady is G551D/DF508. He may receive increased benefit from a future combination therapy vs. Kalydeco alone). Lastly, we must continue the pursuit of better, more effective compounds.
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