Approximately 30,000 people in the U.S. are living with cystic fibrosis (CF) — a life-shortening genetic disease characterized by a buildup in the lungs of thick, sticky mucus, chronic lung infections, and gradual loss of lung function.
As the disease progresses, the lungs of CF patients are typically infected with bacteria that are difficult to eradicate. Physicians have been using nebulized antibiotics to treat these infections and have sought new options for treatment in the chronic care setting. The first successful reformulation of an antibiotic into dry powder inhaled therapy is the recently FDA-approved TOBI Podhaler (tobramycin inhalation powder; see below) for Pseudomonas aeruginosa infections in CF patients. Infection by MRSA has become increasingly common with a prevalence of almost 30 percent of CF patients in the U.S.
Pseudomonas aeruginosa, a hardy and adaptable a Gram-negative, nosocomial, aerobic, coccobacillus pathogen with unipolar motility that is found in soil, water, skin flora, and most man-made environments worldwide is the most common lung pathogen in CF patients. P. aeruginosa infection symptoms include generalized inflammation and sepsis, and if colonizations occur in critical body organs, such as the lungs, the urinary tract, and kidneys, they can be fatal.
Methicillin-resistant Staphylococcus (MRSA) is another bacterium resistant to conventional antibiotics that has also become increasingly common, with a prevalence of almost 30 percent of the U.S. cystic fibrosis patient population.
Inhaled antibiotics are becoming the standard treatment for patients with cystic fibrosis and other chronic care patients who experience frequent P. aeruginosa lung infections, but there is no approved inhaled antibiotic therapy for MRSA. Yet. However, a Texas BioTech firm hopes that will soon be changing.
Inhaled Antibiotics vs. Opportunistic Bacteria
Pseudomonas aeruginosa is highly adaptable, can live in both in normal and hypoxic atmospheres, and uses a wide range of organic material for food — characteristics that enable it to thrive in divers natural and artificial environments — even outer space. P. aeruginosa was cultured by Rensselaer Polytechnic Institute scientists funded by NASA scientists during two Space Shuttle Atlantis missions: STS-132 and STS-135, during which spaceflight conditions were observed to increase the number of viable cells, biofilm biomass, and thickness relative to normal gravity controls — the results published in the journal PLOS One (Kim W, Tengra FK, Young Z, Shong J, Marchand N, et al. (2013) Spaceflight Promotes Biofilm Formation by Pseudomonas aeruginosa. PLoS ONE 8(4): e62437. doi:10.1371/journal.pone.0062437). Moreover, P. aeruginosa biofilms formed during spaceflight exhibited a column-and-canopy structure that has not been observed on Earth.
P. aeruginosa’s versatility enables it to opportunistically infect damaged tissues or immunocompromised individuals, and since it thrives on moist surfaces, this pathogen is too often found on and in medical equipment, including catheters, causing cross-infections in hospitals and clinics.
Inhaled antibiotics are becoming the cornerstone of treatment in patients with cystic fibrosis and other chronic care patients who experience frequent lung infections, specifically Pseudomonas aeruginosa infections. The first successful reformulation of an antibiotic into dry powder inhaled therapy is the recently U.S. Food and Drug Administration (FDA) approved TOBI Podhaler (tobramycin inhalation powder) product marketed by Novartis for management of Pseudomonas aeruginosa infections in CF patients with Pseudomonas aeruginosa. TOBI Podhaler is a plastic, handheld inhaler device containing a non-nebulized dry-powder inhaled formulation of tobramycin antibiotic appropriate for treating people with cystic fibrosis and Pseudomonas aeruginosa infections. The powder is inhaled twice daily using the Podhaler device for 28 days. Patients then stop TOBI Podhaler therapy for 28 days before resuming.
TOBI Podhaler’s effectiveness was established in a study of 95 pediatric and adult patients with cystic fibrosis. All patients were 6 years of age or older and infected with P. aeruginosa. Patients were randomly assigned to receive TOBI Podhaler or a placebo for the first 28 days of the study. All patients then received treatment with TOBI Podhaler for the remainder of the study.
Recent reportage indicates that CF patients with chronic MRSA infection have more hospitalizations, faster decline in lung function, and reduced life expectancy.
Persistent MRSA lung infection in CF patients is difficult to eradicate or manage using oral or IV antibiotics, and there is no standard of care to manage MRSA infections, which are associated with poor prognoses and ever-higher rate of complications in CF patients. Physicians using nebulized antibiotics to treat MRSA infections have sought new options for treatment in the chronic care setting. Intravenous vancomycin is the standard antibiotic therapy for MRSA-related bronchopneumonia in CF patients, but the burden of IV administration, poor penetration into the lungs and systemic toxicities limit its use in a chronic setting. There are currently no approved inhaled drugs to treat methicillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis, despite the established practice of treating CF patients’ infections directly at the site of infection — the lungs. As noted in the introduction above, currently there is no approved inhaled therapy for MRSA infections.
However, researchers at Austin-based Savara Pharmaceuticals, an emerging specialty pharmaceutical company developing innovative pulmonary drugs for the treatment of serious and life-threatening conditions, have long been working to devise a therapy to treat methicillin-resistant Staphylococcus aureus, and have developed the product candidate AeroVanc (vancomycin hydrochloride inhalation powder), a proprietary inhaled dry powder form of vancomycin in a capsule-based device designed for convenient self-administration for the treatment of persistent methicillin-resistant Staphylococcus aureus (MRSA) lung infection in cystic fibrosis (CF) patients — the first inhaled antibiotic engineered to address the growing population of MRSA-infected cystic fibrosis patients. By delivering vancomycin directly to the infection site in the lungs, higher vancomycin concentrations are achieved at the site of infection, which is expected to lead to improved clinical efficacy. In addition, direct delivery of the drug into the lungs reduces exposure to the drug elsewhere in the body, and is thereby expected to reduce the risk of systemic drug-related side effects.
Savara Pharmaceuticals CEO Rob Neville welcomed the TOBI Inhaler’s FDA approval in 2013, affirming that he was “delighted that the FDA has approved a very necessary product.” Mr. Neville noted that “We hope to provide similar benefits to MRSA infected patients that tobramycin provides for the treatment of Pseudomonas The response from the cystic fibrosis community has been very encouraging,” so much so “that physicians like to refer to AeroVanc as the ‘TOBI for MRSA.'”
Last October, Savara announced on the opening day of the 27th annual North American Cystic Fibrosis Conference that it had received a $1.7 million research award from Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT), the nonprofit drug discovery and development affiliate of the CF Foundation, to help advance AeroVanc development.
“An inhaled dry powder form of vancomycin for MRSA infection will be a logical addition to this and other treatment options available for CF patients,” says Mr. Neville. “We are further encouraged by the strong interest and support of key opinion leaders, and the feedback that AeroVanc is exactly what the CF care community has been waiting for.” Mr. Neville adds that “The support of the CF Foundation is yet another acknowledgment that AeroVanc addresses an unmet need for people with CF suffering from MRSA infection…. The $6 million in support that Savara has received from the CF Foundation and the National Institutes of Health not only provides critical funding to advance the AeroVanc program, but is also a strong endorsement of the quality and promise of our program.”
Savara has been enrolling patients for a Phase II clinical trial of AeroVanc — a randomized, double-blind, placebo-controlled study in 80 CF patients with persistent MRSA lung infection being conducted at 40 CF study centers nationwide. Patients will receive either 32 mg or 64 mg doses of AeroVanc or a corresponding placebo twice daily for 28 days. The study’s primary objective is to evaluate AeroVanc’s efficacy in reducing the quantity of MRSA colony forming units in sputum cultures. Secondary objectives include evaluation of the safety of repeat dosing with AeroVanc and efficacy of AeroVanc in improving lung function, reducing respiratory symptoms, and prolonging the time to pulmonary exacerbations and the need for other antibiotics.mIn Phase I studies of AeroVanc in healthy volunteers and cystic fibrosis patients, AeroVanc was well tolerated and demonstrated an excellent pharmacokinetic profile. The AeroVanc Inhaler is a plastic device used for inhaling the AeroVanc and Placebo powders. For the study, AeroVanc and Placebo capsules are supplied in aluminum foil laminated blisters, and the blister strips are packaged into a wallet that contains one week’s supply of study drug. To use the delivery system, an AeroVanc or Placebo capsule is placed in the well of the AeroVanc Inhaler, and the capsule is pierced by pressing and releasing the buttons on the sides of the device. The AeroVanc or Placebo powder is dispersed into the air stream when the patient inhales rapidly and deeply through the mouthpiece. Study centers will provide detailed instructions on the use of the study drug capsules and the inhaler to each patient. More details on the AeroVanc Phase 2 study can be found at http://www.clinicaltrials.gov (study identifier NCT01746095).
In the meantime, Savara announced in December that the FDA has designated AeroVanc, as a Qualified Infectious Disease Product (QIDP), and approved Fast Track designation for AeroVanc pursuant to section 506(a)(1) of the Food and Drug Administration Safety and Innovation Act (FDASIA).
The QIDP and Fast Track designation provide AeroVanc access to certain incentives, including priority review associated with a New Drug Application (NDA) submission and an additional five years of exclusivity under the Hatch-Waxman Act upon FDA approval of AeroVanc. Last year AeroVanc received orphan designation, which provides the product seven years of market exclusivity, and various other incentives.
“The recent QIDP status forms an important part of our market exclusivity strategy,” comments Rob Neville, adding, “This designation along with Orphan Drug status, our formulation patent protection, and our inhalation device exclusivity creates a very robust protection from competition.”
“Savara’s AeroVanc is a much needed investigational product, as none of the current inhaled antibiotics address the growing problem of MRSA infection,” says Dr. Bonnie W. Ramsey, Director of the Center for Clinical and Translational Research at Seattle Children’s Research Institute, and one of the pioneers and lead investigators of TOBI, an inhaled form of tobramycin used to treat chronic Pseudomonas aeruginosa infection in CF. “TOBI has become the cornerstone of treatment in CF, and AeroVanc has the potential to become analogous to TOBI for MRSA.”
The Cystic Fibrosis Foundation is the world’s leader in the search for a cure for cystic fibrosis. The Foundation funds more cystic fibrosis research than any other organization, and nearly every CF drug available today was made possible because of Foundation support. Based in Bethesda, MD, the Foundation also supports and accredits a national care center network that has been recognized by the National Institutes of Health as a model of care for a chronic disease. The CF Foundation is a donor-supported nonprofit organization. For more information, visit:
Established in 2000, Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) is the non-profit drug discovery and development affiliate of the Cystic Fibrosis Foundation. CFFT supports and governs activities related to cystic fibrosis (CF) drug discovery through the many stages of drug development and clinical evaluation.
For more information about Savara Pharmaceuticals, see Savara’s websites at:
ClinicalTrials.gov service of the U.S. National Institutes of Health
The U.S. Food and Drug Administration
Cystic Fibrosis Foundation
Seattle Children’s Research Institute