This month’s Journal of Aerosol Medicine and Pulmonary Drug Delivery features positive Phase Ib clinical trial results for PARI Pharma’s L-CsA, inhaled liposomal cyclosporine A. In May, PARI Pharma received Orphan Drug Designation from the Food and Drug Administration for L-CsA, delivered via an Investigational eFlow Nebulizer System, for the prevention and treatment of bronchiolitis obliterans, a devastating, incurable disease of the small airways affecting approximately 60,000 patients worldwide.

“PARI’s encouraging results show that it is feasible and well tolerated to deposit relevant amounts of L-CsA into transplanted lungs. This has the potential to prevent and treat bronchiolitis obliterans in a more efficient way compared to current oral standard treatment. Inhaled L-CsA has a favorable drug distribution to the target sites in the lung, which should lead to lower side effects than associated with systemic cyclosporine exposure,” stated Prof. Jurgen Behr, head of the Division of Respiratory Disease at the Ludwig Maximilians University, Klinikum Grosshadern, Munich, Germany.

“The long-term survival rate for lung transplant patients could be greatly improved through an effective inhaled liposomal cyclosporine therapy. Using our proprietary liposomal technology we created an inhaled formulation that is free from irritating solvents and optimized for administration via an Investigational eFlow Nebulizer System without destroying the liposome,” stated Dr. Manfred Keller, executive vice president and chief scientific officer of PARI Pharma GmbH. “We had a very encouraging pre-IND meeting with the FDA, and their recent Orphan Drug Designation for L-CsA, which follows a similar designation in Europe, encourages us to move forward to solve this unmet medical need.”

PARI Pharma’s Phase Ib clinical trial for L-CsA studied 12 lung transplant recipients, where five patients had double lung transplants and seven patients had single lung transplants. Patients were given a single dose application of 10mg or 20mg of liposomal L-CsA, which was well tolerated. Deposition data showed a peripheral lung deposition of 2mg for a nominal, 10mg dose that was nebulized in less than ten minutes. Once daily administration of a nominal dose of 10mg L-CsA with an Investigational eFlow Nebulizer System would give approximately 14 mg L-CsA/week. Mean values for C(max) and AUC(0-inf) were up to 20ng/mL and 110 h ng/mL, respectively. These results are significantly lower compared to oral therapy. In comparison, oral CsA (Neoral(R)) therapy in lung transplant patients leads to highly variable C(max) and AUC(0-12h) values of approximately 1,800ng/mL and 8,000 h ng/mL, respectively when given twice daily in a dose of up to 250mg [Knoop 2003]. L-CsA’s favorable and significantly lower pharmacokinetic values were obtained for both dose strengths tested. Phase Ib study results for L-CsA are published in the June 2009 volume of the Journal of Aerosol Medicine and Pulmonary Drug Delivery [Behr et al., Vol. 22, No. 2, p.121-129].

About PARI Pharma’s Inhaled L-CsA Formulation

PARI Pharma’s L-CsA is a low-dose, inhaled, liposomal cyclosporine A formulation that aims to improve the pharmacological profile, the highly variable bioavailability, and the severe side effects of oral CsA. (Severe side effects of oral CsA include kidney and brain damage, cancer, and vulnerability to infections.) L-CsA is an investigational, proprietary, liposomal formulation of 10mg CsA/2.5mL for inhalation delivery via a customized Investigational eFlow Nebulizer System. The L-CsA formulation is based on an artificial lung surfactant carrier. It is free of any irritating organic solvents and consists of unilamellar liposomes of about 100nm. The unilamellar liposomes are obtained via a high-pressure homogenization process using standard pharmaceutical equipment followed by sterile filtration and lyophilization. The product has been scaled up to production batch sizes, and preliminary stability data indicate that a shelf life of more than 2 years at room temperature is feasible.

About the Investigational eFlow Nebulizer System and eFlow Technology

The Investigational eFlow Nebulizer System uses eFlow Technology to enable highly efficient aerosolization of liquid medications via a vibrating, perforated membrane that includes thousands of small holes that produce the aerosol mist. Compared to other nebulization technologies, eFlow Technology produces aerosols with a very high density of active drug, a precisely defined droplet size, and a high proportion of respirable droplets delivered in the shortest possible period of time. Combined with its silent mode of operation, small size (it fits in the palm of your hand), light weight, and battery use, products incorporating eFlow Technology reduce the burden of taking daily, inhaled treatments. The Investigational eFlow Nebulizer System and eFlow Technology are proprietary to PARI Pharma.

About Bronchiolitis Obliterans

According to the International Society of Heart and Lung Transplantation Registry, development of bronchiolitis obliterans is the single most important risk factor for five-year mortality among lung transplant patients. Bronchiolitis obliterans is an incurable small airways disease, which manifests as chronic allograft rejection and results in airflow obstruction. The disease is also a factor in other lung diseases such as collagen vascular diseases, inhalation of toxic fumes, and respiratory tract infections. Bronchiolitis obliterans affects approximately 60,000 patients worldwide, and once it develops, most patients die of respiratory failure within 5 years.

About PARI Pharma

PARI Pharma focuses on the development of aerosol delivery devices, drug formulations, and therapies for upper and lower respiratory indications. PARI Pharma partners with pharmaceutical companies to develop new or improved therapies with eFlow Technology and other advanced delivery platforms. Investigational eFlow Nebulizer Systems are optimized and customized per investigational drug product and are currently in clinical trials for cystic fibrosis, asthma, COPD, respiratory syncytial virus (RSV) infection, and treatments for lung transplant patients among other indications.

PARI Pharma provides comprehensive inhalation drug development, including nebulizer formulation development and optimization, analytics, aerosol characterization, clinical protocol development, and regulatory guidance, all in compliance with CMC/GCP guidelines. PARI Pharma has several clinical development programs ongoing, either partnered or on its own. Proprietary programs in different development stages will be offered for licensing partnerships.

Source: PARI Pharma

Interim results from an ongoing phase 2, randomized, placebo-controlled trial of the investigational drug TMC207 for the treatment of multidrug-resistant tuberculosis (MDR-TB) were published in the New England Journal of Medicine. TMC207 is being developed by Tibotec BVBA. The data show that the addition of TMC207 for eight weeks to a 5-drug background regimen, in patients with multidrug-resistant tuberculosis (MDR-TB), resulted in a significant increase in the proportion of patients achieving a negative sputum culture and a shorter time to sputum culture conversion compared with the background regimen alone.

“The results of this study are highly encouraging news for the treatment of tuberculosis,” said Peter Donald M.D., Professor Emeritus, Stellenbosch University in Capetown, South Africa. “Not only is this an agent with a radically different means of action, but it shows potential to shorten the treatment of tuberculosis in the foreseeable future, something the tuberculosis community has been hoping for years.”

Treatment of TB is protracted and burdensome. MDR-TB is currently responsible for an estimated 490,000 incident cases of TB and 110,000 fatalities worldwide each year1. MDR-TB requires extended treatment for at least 18 months with second-line drugs that are less effective and associated with more side effects than first line regimens2. This underscores the need for effective drugs with the potential to shorten and improve MDR-TB treatment outcomes.

TMC207 is being investigated as part of a combination therapy for the treatment of MDR-TB. The results reported are from the first stage of a two-stage Phase II randomized placebo-controlled trial. Forty-seven hospitalized patients with newly diagnosed multidrug-resistant pulmonary TB were randomized to receive TMC207 (400 mg daily for 2 weeks, followed by 200 mg three-times weekly for 6 weeks) (n=23) or placebo (n=24) in combination with a standardized 5-drug background second-line antituberculosis regimen. Six subjects (3 in each treatment group), discontinued the study prematurely. This first stage was conducted in South Africa, where the prevalence of MDR-TB is particularly high.

The results of bacterial culture of sputum showed more patients were TB culture-negative at 8 weeks in the TMC207 group, 47.6% versus 8.7% in the placebo group. In addition TMC207 reduced the time to culture conversion. The probability of becoming culture negative on any given day within the 8-week treatment period was 11.8 times higher in the TMC207 group, versus in the background regimen alone hazards ratio (95% CI): 11.8 (2.26, 61.3); p=0.003 by Cox regression analysis. Mean sputum colony-forming units (CFU) count declined more rapidly in the TMC207 than in the placebo group. Most adverse events were mild to moderate and only nausea occurred more frequently with TMC207 than with placebo (26% vs. 4 %). One subject in each treatment group experienced a serious adverse event, neither of which was considered to be related to the study medication. The data obtained validate ATP synthase as a viable target for the treatment of TB.

“The nearly half a million estimated new cases of MDR-TB annually highlights the urgent need for a paradigm shift in the way this disease is being tackled,” said Roger Pomerantz, President, Tibotec Research & Development. “The development of TMC207 is a tribute to the dedication of our scientists, to innovation and to the commitment of our company to accelerating the development of new drug regimens for tuberculosis.”

TMC207 is a diarylquinoline that offers a novel mechanism of action by specifically inhibiting mycobacterial ATP-synthase3, responsible for the cell’s energy production. In vitro, TMC207 potently inhibits both drug-sensitive and drug-resistant M. tuberculosis isolates and is bactericidal against both actively replicating tubercle bacilli and non-replicating bacilli4. The safety and efficacy of TMC207 are being further evaluated in ongoing and future trials. The second stage of the study, which will evaluate efficacy following 24 weeks of treatment, is currently ongoing with active recruitment in South Africa, Peru, Latvia and Russia. Results from the second stage of the study are expected to be available in 2010.

Notes:

1. World Health Organization. Global tuberculosis control: surveillance, planning, financing. Geneva, WHO, 2007

2. Matteelli A, Migliori GB, Cirillo D, Centis R, Girard E, Raviglion M. Multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis: epidemiology and control. Expert Rev Anti Infect Ther 2007; 5: 857-71
3. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307: 223-7
4. Koul A, Vranckx L, Dendouga N, et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed homeostasis. J Biol Chem 2008; volume 283, number 37, pages: 25273-80

Source:
Karen Manson, Tibotec

Porter Novelli

The first-ever national estimate among a nationally representative sample of U.S. children revealed that 3 out of every 1,000 children between the age of 6 and 17 in the United States have been diagnosed with Tourette Syndrome (TS), according to a study by the cdc.gov/” rel=”nofollow”>Centers for Disease Control and Prevention (CDC) released in the Morbidity and Mortality Weekly Report.

The study, “Prevalence of Diagnosed Tourette Syndrome in Children in the United States, 2007,” found that a TS diagnosis is three times more common in boys than in girls, and approximately twice as common in children between 12-17 years as those aged 6-12 years. Among children with TS, 27% were reported as having moderate or severe TS and 79% of children had also been diagnosed with at least one additional mental health or neurodevelopmental condition.

Tourette Syndrome is a neurological disorder that typically begins during early childhood, with symptoms being most severe between the ages of 10 and 12 years. TS is characterized by recurring multiple motor tics and at least one vocal tic. Tics are involuntary, repetitive, stereotyped, usually sudden and rapid movements or vocalizations that may be suppressed for short periods of time.

“TS and tic disorders have been linked to higher rates of Attention Deficit/Hyperactivity Disorder, obsessive-compulsive disorder, and impairments associated with these conditions, such as learning disabilities and problems with peer relations,” said Dr. Rebecca Bitsko, Health Scientist at the Centers for Disease Control and Prevention. “Given the high number of children diagnosed with TS who have another mental health or neurodevelopmental condition, it is necessary to further study the relation between these conditions.”

Further, the data showed that non-Hispanic white children were more than twice as likely as non-Hispanic black children or Hispanic children to have a parent-reported TS diagnosis.

“Having an estimate of the number of U.S. children who are diagnosed with TS is a first step toward understanding the overall impact of this condition in the population,” said Dr. Bitsko. “Further research must examine differences in access to health care for children with TS in different population groups, the impact of TS on the quality of life, long term outcomes for children with TS, and strategies for reducing the impact of conditions associated with TS.”

The study analyzed data from interviews with parents (or guardians) from 91,642 households from April 2007 through July 2008 collected through the National Survey of Children’s Health (NSCH). The NSCH is the first large, national, population-based survey of U.S. children up to 18 years old that included questions on TS. This random-digit-dialed telephone survey is sponsored and directed by the Health Resources and Services Administration’s Maternal and Child Health Bureau and conducted by CDC through the State and Local Area Integrated Telephone Survey program. Interviews were completed in 66.0% of identified households with children which represents a 46.7% response of all possible eligible households.

Source: Centers for Disease Control and Prevention