With 2 important CF clinical trials not showing much success in the last year (Denufosol and KaloBios KB001), it would be easy to be more than a little disappointed. However, there has been some good news as well. Some even around KB001. If you remember, the phase I/II study showed limited efficacy but not enough to make getting an IV worthwhile. They are now reformulating KB001 into a formula that can be self given as a shot every 2 weeks – a few more details can be found here – http://www.xconomy.com/san-francisco/2010/08/17/kalobios-seeking-to-apply-antibodies-beyond-cancer-sets-sight-on-killing-deadly-lung-invader/3/. Hopefully this will be ready for trials by the end of this year.
In other good news, Bronchitol has been successful in all of its required trials and Pharmaxis is preparing to submit for an NDA. Although that will take some time, it should eventually be approved.
Although VX-770 only gets press for the G551D defect (where it has the most efficacy), it may also be beneficial to any missense defect where a reasonable amount of the CFTR protein makes it to the cell surface.
On the antibiotic front, there are a several steps forward. From a convenience perspective, the new Tobi Podhaler will make treatment time dramatically shorter. There is also an inhaled (versus nebulized) Ciprofloaxin antibiotic in the works that will be a much needed alternative to Tobi and offer even quicker treatment times.
Although certainly not new, Azithromycin has also been studied in many small and a few large trials. While everyone is always hopeful of finding a disease modifying solution, Azithromycin may already fit that bill to some degree.
This drug is believed to stimulate the sister protein of CFTR, the multi-drug resistant protein. MRP shares a similar structure of CFTR and may be a pathway for chloride to escape the cell. In addition to chloride, it also allows glutathione to pass out of the cell. When stimulated with Azithromycin, a small in vivo study showed 6 out of 10 CF patients had statistically significant trending of nasal potential difference (another test to determine if someone has CF).
Glutathione status is important as it may be the reason for the anti-inflammatory benefits from Azitthrmycin.
The in vivo studies to date have shown the most benefit for those with Pseudomonas but there is still benefit for those without it as well. Taken at low doses prophylactically, it is relatively safe and has shown to be very effective for some.
- Medscape Today: Therapy With Macrolides in Patients With Cystic Fibrosis: Mechanisms of Action
- Sharktank: MRP and CFTR
- Effects of Azithromycin on Glutathione S-Transferases in Cystic Fibrosis Airway Cells
- Azithromycin increases chloride efflux from cystic fibrosis airway epithelial cells
- Restoration of chloride efflux by azithromycin in CF human airway epithelial cells