Alidornase alfa (PRX-110)
Alidornase alfa (PRX-110) for the Treatment of Cystic Fibrosis
About Cystic Fibrosis
Cystic fibrosis (CF) is a life-threatening genetic disease affecting the lungs and digestive system. An estimated 70,000 children and adults worldwide have CF. In patients with CF, a defective gene and its protein product cause the body to produce unusually thick, sticky mucus that clogs the lungs. This may lead to lung damage, high exposure to lung infections and loss of respiratory function. Additionally the thickened mucus obstructs the pancreas and stops natural enzymes from helping the body break down food and absorb vital nutrients. Current therapies include multiple daily physiotherapy sessions to improve breathing, various drug therapies, as well as acute and preventive antibiotic therapy. Despite progress in understanding and treating CF, it remains a challenge to significantly improve quality of life and prolong life.
PRX-110 (alidornase alfa)
Alidornase alfa (PRX-110) is a proprietary plant cell-expressed recombinant form of human deoxyribonuclease I (DNase I), that Protalix has designed, through chemical modification, to be resistant to inhibition by actin. DNase I is part of current CF therapy, intended to reduce sputum viscosity that accumulates in the lungs of CF patients, which exposes patients to recurrent infections and compromises lung function. The current therapy is known as Pulmozyme® (dornase alfa). Given actin is a potent inhibitor of DNase I activity, Protalix’s alidornase alfa (PRX-110)
has the potential to enhance the enzyme’s efficacy significantly in CF patients when compared to the currently approved DNase treatment (Pulmozyme®).
However, DNase I activity is compromised by actin, a globular multi-functional protein, found in high concentration in CF patients’ sputum, which is a potent inhibitor of DNase I. Actin may decrease the enzyme’s DNA degradation activity and potentially interfere with the effectiveness of inhaled DNase I in the lungs of CF patients.
In order to reduce the actin-DNase I interaction and the subsequent inhibition of DNase I activity by actin, Protalix developed alidornase alfa by chemically modifying the enzyme forming an Actin Inhibition Resistant DNase I. This novel treatment may result in an improved lung function and decreased incidence of recurrent infections in patients. Inhaled alidornase alfa (PRX-110) was found safe in healthy volunteers. Protalix has begun a phase IIa trial of alidornase alfa (PRX-110) in CF patients, following which Protalix intends to actively seek collaboration with strategic partners for further development.
PRX-110 Clinical Data
We have completed a phase I trial with 18 healthy volunteers. alidornase alfa (PRX-110) was found to be safe and tolerable.
In July 2016, the first patient was dosed in Protalix’s phase IIa clinical trial of alidornase alfa (PRX-110). In January 2017, Protalix announced positive interim results from the phase II clinical trial for the first 13 CF patients enrolled in the study. At that time, 15 patients had been enrolled in, and were expected to complete, the study. The initial primary efficacy result shows that alidornase alfa (PRX-110) improves lung function as demonstrated by a mean absolute increase in the percent predicted forced expiratory volume in one second (ppFEV1) of 4.1 points from baseline. A commercially available small molecule CFTR modulator for the treatment of CF has reported a mean absolute increase in ppFEV1 of 2.5 from baseline in its registration clinical study. This score was achieved while 74% of the patients participating in the trial of the CFTR modulator were also treated with Pulmozyme® on top of the modulator. While this marketed CFTR addresses a certain mutation applicable to less than 50% of CF patients, alidornase alfa (PRX-110) is being developed to treat all CF patients.
Sputa available DNA samples were analyzed for approximately half of the patients. A mean reduction of approximately 60% in DNA content from baseline was observed, and a mean reduction of approximately 90% from baseline was observed for sputa visco-elasticity. This data provides further supportive evidence of improved lung function after treatment with alidornase alfa (PRX-110), as demonstrated by the increase in ppFEV1.
No serious adverse events were reported, and all adverse events that occurred during the study were mild and transient in nature.
The phase II trial is a 28-day switch-over study of 15 CF patients previously treated with Pulmozyme® to evaluate the efficacy and safety of alidornase alfa (PRX-110) in CF patients. Participation in the trial is preceded by a two-week washout period from Pulmozyme® before treatment with PRX-110 via inhalation. The main efficacy endpoint is the change of forced expiratory volume (FEV1) and forced vital capacity (FVC). Additional endpoints include safety and tolerability, immunogenicity and pharmacokinetic data. In the trial, alidornase alfa (PRX-110) is administered through Philips Respironics’ I-neb AAD Inhaler System, for which Protalix has a supply agreement for the exclusive use of the device for the development of an inhaled product based on dornase alfa for the treatment of CF. The I-neb AAD is a small, lightweight, virtually silent device that is fully portable and has a unique vibrating mesh technology that allows for faster administration than conventional jet or ultrasonic nebulizers.
AIR DNase™ (PRX-110) remains active
In vitro assays have shown that that alidornase alfa (PRX-110) remains active in the relevant concentrations of actin and alidornase alfa (PRX-110), as opposed to Pulmozyme® which loses activity.
Reduction in mucus viscosity
Through rheological measurements in human sputa samples, alidornase alfa (PRX-110)
demonstrated a greater reduction in mucus viscosity compared to Pulmozyme®.