We are here to extend our lives by THINKING DIFFERENT

Thursday, August 7, 2008

Phase II NAC Trial / Patent Application

Dr. Moss, the author of the Stanford NAC study, has filed for an NAC patent relating to an NAC kit.

This tells me that what he's seeing in his Phase II clnical trials with NAC are very promising. Take a read at what they've found regarding safety in Phase II trials....

If you haven't read Moss' NAC Phase I study, check it out on my blog.

You don't have to read the whole article but it is quite educational....

Methods for treating and monitoring inflammation and redox imbalance cystic fibrosis

The present invention relates to pharmaceutical kits and methods to treat lung inflammation and redox imbalance in human cystic fibrosis patients using pharmaceutical compositions containing N-acetylcysteine (NAC), pharmaceutically acceptable salts of N-acetylcysteine, or N-acetylcysteine derivatives.

In phase I studies, treatment with oral NAC at a dose of from about 1800 mg/day to about 3000 mg/day for a period of 4 weeks produced significant positive effects, namely, it decreased absolute numbers of white blood cells and neutrophils in the sputum and produced concomitant decreases in sputum neutrophil elastase specific activity and sputum interleukin-8 levels, suggesting an amelioration of lung inflammation in the patients.

These effects were associated with an increased total GSH level in whole blood as well increased staining for reduced GSH in blood neutrophils, both of which reflect an amelioration of the redox imbalance in the patients.

In ongoing phase II studies, oral NAC at a dose of about 2700 mg/day administered in double-blind manner for 12 weeks showed excellent safety and significantly decreased white blood cells in sputum as compared to placebo.

Patent Agent: Patent Docket Administrator Lowenstein Sandler PC - Roseland, NJ, US

Patent Inventors: Rabindra Tirouvanziam, Lenore A. Herzenberg, Leonard A. Herzenberg, Carol Conrad, Richard B. Moss

Applicaton #: 20070049641 Class: 514562000 (USPTO)

Related Patents:Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Radical -xh Acid, Or Anhydride, Acid Halide Or Salt Thereof (x Is Chalcogen) Doai, Carboxylic Acid, Percarboxylic Acid, Or Salt Thereof (e.g., Peracetic Acid, Etc.), Nitrogen Other Than As Nitro Or Nitroso Nonionically Bonded, Sulfur Nonionically Bonded
Brief Patent Description - Full Patent Description - Patent Application Claims


[0001] This application claims the benefit of priority to U.S. Provisional Application No. 60/710,807 (filed Aug. 24, 2005) entitled "Methods For Treating And Monitoring Inflammation And Redox Imbalance In Cystic Fibrosis," the entire contents of which are incorporated by reference.


[0002] The present invention relates to pharmaceutical kits and methods for treating lung inflammation and redox imbalance conditions in cystic fibrosis using pharmaceutical compositions comprising N-acetylcysteine, pharmaceutically acceptable salts of N-acetylcysteine, or pharmaceutically acceptable derivatives of N-acetylcysteine and a pharmaceutically acceptable carrier.



[0109] Based on the described phase I results, an Investigational New Drug application was submitted to the Food and Drug Administration (IND #73,410), detailing plans for a phase II trial. This application successfully passed the Food and Drug Administration review process. The phase II trial consists of a 12-wk placebo controlled portion, followed by a 12-wk open label portion, both featuring oral NAC treatment at about 2700 mg/day, administered t.i.d. As of June 2006, the 12-wk placebo-controlled portion of this phase II trial was brought to completion.

[0110] In compliance with guidelines defined in the Investigational New Drug application, safety data and efficacy data for the primary (sputum cellularity) and main secondary (functional expiratory volume in 1 second) outcome measurements were communicated to the Data and Safety Monitoring Board of the Cystic Fibrosis Foundation before unblinding the study.

[0111] 1--Enrollment and Compliance

[0112] Of the 24 CF study patients who underwent screening, 21 were found eligible for enrollment, based on evidence of ongoing lung inflammation (sputum cellularity >0.9, Log.sub.10 scale). Of these 21 patients who received NAC or placebo, 3 were withdrawn for poor compliance before the 12-wk time point. Hence, a total of 18 patients completed the 12-wk time point (% completion=85.7). Among these 18 patients, compliance at the 12-wk time point was excellent, reaching 93.0.+-.1.9% (mean.+-.SE). Compliance was not different between the NAC and placebo groups (93.3.+-.2.3 vs. 92.6=3.2, respectively, N=9 in each group, P=0.9).

[0113] 2--Safety

[0114] The first 12 weeks of this phase II trial (placebo-controlled phase) yielded excellent safety data. No NAC- or placebo-induced serious adverse events were reported. Only 1/18 patients reported adverse events that were likely to be related to treatment (patient in the NAC group), i.e., abdominal discomfort/indigestion which was treated by daily Pepcid AC.RTM.. There was no other GI complaint related to NAC (or placebo). Exacerbations of sinus and lung disease affected 5 and 4 out of 18 patients, respectively. The occurrence of exacerbations did not differ between NAC and placebo groups and was not considered to be linked to the trial. Complete blood count and blood chemistry (including liver enzymes) did not show any significant change for either NAC or placebo groups. Hence, safety of high-dose oral NAC administration over the course of 12 weeks showed even better safety results than the 4-week-treatment tested in phase I.

[0115] 3--Efficacy Data on Lung Inflammation

[0116] In this placebo-controlled phase II, results obtained in phase I were confirmed with regard to the ability of NAC to decrease sputum cellularity significantly (Table 3). There was no significant change in sputum cellularity in the placebo group. The significance of this positive effect of NAC on sputum cellularity was further increased when the 6 patients (3 in each group) with confounding treatments administered during the 12-week trial period (prednisone and tobramycin) were excluded from the analysis (Table 3). With these 6 patients excluded, the difference between NAC and placebo groups was statistically significant upon between-group analysis. Hence, the primary outcome measurement in this phase II trial yielded positive results.

[0117] 4--Efficacy Data on Lung Function

[0118] CF lung disease is characterized by the progressive decline in functional expiratory volume in 1 second (FEV1% predicted). The term "FEV1%" as used herein refers to Forced Expiratory Volume during the first second/FVC, where FVC refers to Forced (ExpiratoryVital Capacity (Liters), meaning the maximum volume of air exhaled as rapidly, forcefully and completely as possible from the point of maximum inhalation. Slowing down, stopping or reversing this decline reflect positive effects of a treatment, which generally requires long-term administration. When the 6 patients (3 in each group) with confounding treatments administered during the 12-week trial period (prednisone and tobramycin) were excluded, the NAC group, but not the placebo group, showed a significant increase in FEV.sub.1 % predicted (Table 3). This effect, however, did not reach significance in the between-group analysis, underlining the necessity for larger patient cohorts to ascertain the potential positive effect of oral NAC treatment on CF lung function. TABLE-US-00003 TABLE 3 Chosen drug effects (post-treatment vs. baseline) during the phase II trial Placebo: Between- Subjects Outcome NAC: Median Median group (N) measurement [interquartile] [interquartile] analysis All Sputum -0.22 -0.16 P = 0.825 cellularity [-0.34; +0.01] [-0.51; +0.35] (Log10) P = 0.030 P = 0.221 6 [Decrease is a -0.27 +0.06 P = 0.025 ex- positive effect] [-0.43; -0.19] [-0.19; +0.77] cluded P = 0.002 P = 0.218 All FEV1 +1.0 +2.0 P = 0.791 (% predicted) [-1.0; +6.0] [-12.0; +10.5] [Increase is a P = 0.150 P = 0.470 6 positive effect] +3.5 -3.0 P = 0.328 ex- [-0.3; +8.5] [-11.0; +7.0] cluded P = 0.037 P = 0.328

[0119] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the Invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

No comments:

Post a Comment