Emphycorp Receives Cystic Fibrosis Orphan Drug Designation for N115
Released: December 27, 2003
The FDA has granted Emphycorp Orphan Drug Designation for investigational drug N115 for the treatment of Cystic Fibrosis. The rest of this document contains part of the submission that was made to the FDA for this designation. This section has been selected for this press release because it explains the pharmacological rationale for the prospective use of N115 for the treatment of cystic fibrosis. Company confidential information has been deleted.
Request for Orphan Drug Designation for a Rare Disease or Condition Pursuant to 21 CFR Part 316 Orphan Drugs, Subpart C Designation of an Orphan Drug.
1. Request for orphan drug designation
(a) This is a request for an orphan drug designation of a previously unapproved drug, i.e. 0.5 mM to 5.0 mM sodium pyruvate in 0.9% sodium chloride solution, administered by inhalation.
(b) This is a request for an orphan drug designation for the rare disease known as Cystic Fibrosis (“CF”).
2. The name and address of the sponsor; the name of the sponsor's primary contact person including title, address, and telephone number; and the generic name of the drug and the name and address of the source of the drug.
Name and Address of Sponsor:
Sponsor's Primary Contact Person:
Generic Name of Drug: Sodium pyruvate (sodium salt of pyruvic acid); CH3COCOO- Na+
C3H3O3Na
Synonyms: sodium salt of 2-oxo-propanoic acid; sodium salt of alpha-keto proprionic acid; Molecular weight = 110 daltons.
Drug Products: Sodium pyruvate in 0.9% sodium chloride solution, where the concentration of sodium pyruvate ranges from 0.5 mM to 5.0 mM. The drug products are sterile and non-pyrogenic.
Source of the Drug:
The sodium pyruvate tested in the pre-clinical, and Phase I and Phase I/II asthma trials was purchased from: The sodium pyruvate utilized in the initial studies was then sent to a GMP-approved facility where it was dissolved in sterile, non-pyrogenic, 0.9% sodium chloride solution. The sodium pyruvate in 0.9% sodium chloride solution was then sterile-filled into Type I Glass vials containing butyl rubber stoppers.
The drug manufacturer for the drug products tested in the pre-clinical, and Phase I and Phase I/II asthma trials was: The sodium pyruvate that was used to produce the drug product for the six-month inhalation study in rats is being used in the present on-going patient responders classification study (“Sodium Pyruvate/Nitric Oxide Pilot Study in Subjects with Lung Disease”), and will be used in future planned trials in asthma patients, COPD patients, ILD patients, and Cystic Fibrosis patients. It was and will be manufactured by:
A Drug Master File describing the chemistry, manufacturing and control of sodium pyruvate has been filed with the Food and Drug Administration, and authorization to reference that Drug Master File has been obtained from
The drug manufacturer for the drug products is:
The drug product is filled into 5.0 cc, 20 mm Type 1 Glass vials containing a gray siliconized 20 mm Stopper and a blue 20 mm Flip Off/Tear Off Seal. These components are supplied by the _________________, and referenced in their Drug Master File _________________. Quality Assurance and specification documents from the West Company, in support of these components were forwarded to FDA in the Information Amendment, October 10, 2001. The vials containing the drug product are labeled appropriately for "Investigational Use Only" per 21CFR 312.6. Batch records for the manufacturing and release of the three drug products (0.5 mM, 1.5 mM, and 5.0 mM sodium pyruvate); and the 0.9% sodium chloride placebo, were previously forwarded to the FDA as part of an Information Amendment, dated September 28, 2001. These batch records consisted of a complete set of the manufacturing documents submitted to ___________________________. These include “Section I – Procedures, Specifications, & Process Flow Charts,” “Section II – Batch Records,” “Section III – Testing, and Section” and “IV – Attachments.”
Stability testing of this drug product is being conducted at:
Sodium pyruvate in 0.9% sodium chloride solution products stored for one, two, three and six months at 40ºC/75%RH; products stored for three, six, and nine months at 25ºC/65%RH; and products stored at six months at 2ºC-8ºC; were chemically and physically stable. The storage studies at 25ºC/65%RH and 2ºC-8ºC are continuing.
3. A description of the rare disease for which the drug will be investigated, the proposed indication or indications for use of the drug, and the reasons why such therapy is needed. Cystic Fibrosis is a well-described disease, and has been the subject of numerous papers, reports, and textbooks. The description of the disease, as presented below, was primarily adapted from The Merck Manual of Diagnosis and Therapy. 1
Description of Rare Disease: Cystic Fibrosis (“CF”)
Cystic fibrosis is a genetic disease afflicting nearly 30,000 persons in the United States and Canada and nearly 250,000 worldwide. It is the most common life-shortening genetic disease in the white population, occurring in the USA in about 1/3,300 white births, in about 1/15,300 black births, and in about 1/32,000 Asian-American births. 1,2
CF is carried as an autosomal recessive trait and there are hundreds of genetic mutations that can produce the disease. In order for the disease to be manifested, the child must inherit the recessive gene from both parents. Heterozygotes may show subtle abnormalities of epithelial transport but are clinically unaffected.
The gene responsible for the disease encodes a membrane-associated protein called the “cystic fibrosis transmembrane regulator” (CFTR). The most common gene mutation, delta F508, leads to the absence of a phenylalanine residue on the CFTR protein and is found on about 70% of CF alleles. Although the exact function of CFTR is unknown, it appears to be part of a cAMP-regulated chlorine channel and appears to regulate chlorine and sodium transport across epithelial membranes. 3,4,5,6
Nearly all exocrine glands are affected in varying distribution and degree of severity. Involved glands are of three types: those that become obstructed by viscid or solid eosinophilic material in the lumen (pancreas, intestinal glands, intrahepatic bile ducts, gallbladder, submaxillary glands); those that are histologically abnormal and produce an excess of secretions (tracheobronchial and Brunner's glands); and those that are histologically normal but secrete excessive sodium and chloride (sweat, parotid, and small salivary glands).
Evidence suggests that the lungs are histologically normal at birth. Pulmonary damage is probably initiated by diffuse obstruction in the small airways by abnormally thick mucus secretions. Bronchiolitis and mucopurulent plugging of the airways occur secondary to obstruction and infection. Bronchial changes are more common than parenchymal changes. As the pulmonary process progresses, bronchial walls thicken; the airways fill with purulent, viscid secretions; areas of atelectasis develop; and hilar lymph nodes enlarge. Chronic hypoxemia results in muscular hypertrophy of the pulmonary arteries, pulmonary hypertension, and right ventricular hypertrophy. Much of the pulmonary damage may be caused by immune-mediated inflammation secondary to the release of proteases by neutrophils in the airways. Bronchoalveolar lavage fluid, even early in life, contains large numbers of neutrophils and increased concentrations of free neutrophil elastase, DNA, and interleukin-8. Additionally, it has recently been discovered that the defect in the CFTR affects membrane potential and indirectly regulates the secretion of glutathione into epithelial lung lining fluid. 3,4,5,7,8 Glutathione is an important component of the antioxidant defense in the epithelial lung lining fluid. As a result of this decrease in transport of glutathione and other cellular antioxidant compounds into the surrounding epithelial lung lining, there is deterioration in lung function.
Fifty percent of CF patients present with pulmonary manifestations, usually chronic cough and wheezing associated with recurrent or chronic pulmonary infections. Cough is the most troublesome complaint, often accompanied by sputum, gagging, vomiting, and disturbed sleep. Intercostal retractions, use of accessory muscles of respiration, a barrel-chest deformity, digital clubbing, and cyanosis occur with disease progression. Upper respiratory tract involvement includes nasal polyposis and chronic or recurrent sinusitis. Adolescents may have retarded growth, delayed onset of puberty, and a declining tolerance for exercise. Pulmonary complications in adolescents and adults include pneumothorax, hemoptysis, and right heart failure secondary to pulmonary hypertension.
Early in the course, Staphylococcus aureus is the pathogen most often isolated from the respiratory tract, but as the disease progresses, Pseudomonas aeruginosa is most frequently isolated. A mucoid variant of Pseudomonas is uniquely associated with CF. Colonization with Burkholderia cepacia occurs in up to 7% of adult patients and may be associated with rapid pulmonary deterioration.
Pulmonary function tests reveal hypoxemia and reduction in forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), and FEV1/FVC ratio and an increase in residual volume and the ratio of residual volume to total lung capacity. Fifty percent of patients have evidence of airway hyper-reactivity. The course of the disease, largely determined by the degree of pulmonary involvement, varies greatly. However, deterioration is inevitable, leading to debilitation, respiratory failure, and eventual death. The FEV1, adjusted for age and sex, remains the best predictor of mortality.
Treatment of the disease includes prevention of airway obstruction and prophylaxis against and control of pulmonary infection. Prophylaxis against pulmonary infections consists of maintenance of pertussis, Haemophilus influenzae, varicella, and measles immunity and annual influenza vaccination. In unvaccinated patients, amantadine can be used for prophylaxis against influenza A. There has been no demonstrated increase in susceptibility to or morbidity from pneumococcal infections, and routine use of pneumococcal vaccine is not advocated.
Chest physical therapy consisting of postural drainage, percussion, vibration, and assisted coughing is recommended at the first indication of pulmonary involvement. In older patients, alternative airway clearance techniques such as active cycle of breathing, autogenic drainage, flutter valve device, positive expiratory pressure mask, and mechanical vest therapy may be effective. For reversible airway obstruction, bronchodilators may be given orally and/or by aerosol and corticosteroids by aerosol. O2 therapy is indicated for patients with severe pulmonary insufficiency and hypoxemia. In general, mechanical ventilation is not indicated for patients with chronic respiratory failure. Its use should be restricted to patients with good baseline status in whom acute respiratory failure develops, in association with pulmonary surgery, or in patients awaiting lung transplantation who develop hypercapnic respiratory failure. Noninvasive positive pressure ventilation by nasal or facemask also can be beneficial. IPPB devices should not be used because they may cause a pneumothorax.
Oral expectorants are widely used, but few data support their efficacy. Cough suppressants should be discouraged. Long-term daily aerosol administration of recombinant human deoxyribonuclease has been shown to slow the rate of decline in pulmonary function and to decrease the frequency of severe respiratory tract exacerbations.
Pancreatic insufficiency is clinically apparent in 85 to 90% of patients, usually presents early in life, and may be progressive. Manifestations include the frequent passage of bulky, foul-smelling, oily stools; abdominal protuberance; and poor growth pattern with decreased subcutaneous tissue and muscle mass despite a normal or voracious appetite. Rectal prolapse occurs in 20% of untreated infants and toddlers. Clinical manifestations may be related to deficiency of fat-soluble vitamins.
Excessive sweating in hot weather or with fever may lead to episodes of hypotonic dehydration and circulatory failure. In arid climates, infants may present with chronic metabolic alkalosis. Salt crystal formation and a salty taste on the skin are highly suggestive of CF.
The prognosis for CF has improved steadily over the past five decades, mainly because of aggressive treatment before the onset of irreversible pulmonary changes. Median survival is now 31 years, although long-term survival is significantly better in patients without pancreatic insufficiency. Early colonization with mucoid Pseudomonas, being of female gender, presentation with respiratory symptoms, and airway hyper-reactivity are all associated with a somewhat worse prognosis.
Oral corticosteroids are indicated in infants with prolonged Bronchiolitis and in those patients with refractory bronchospasm, allergic bronchopulmonary aspergillosis, and inflammatory complications (e.g., arthritis and vasculitis). Long-term use of alternate-day corticosteroid therapy can slow the decline in pulmonary function, but because of steroid-related complications it is not recommended for routine use. Patients receiving corticosteroids must be closely monitored for evidence of carbohydrate abnormalities and linear growth retardation.
Ibuprofen, when given at a dose sufficient to achieve a peak plasma concentration between 50 and 100 µg/mL over several years, has been shown to slow the rate of decline in pulmonary function, especially in children 5 to 13 yr. The appropriate dose must be individualized based on pharmacokinetic studies.
Antibiotics should be used in symptomatic patients to treat bacterial pathogens in the respiratory tract, according to culture and sensitivity testing. Aerosol therapy with ribavirin should be considered in infants with respiratory syncytial viral infection.
Proposed Indication:
For the improvement in pulmonary function, and the reduction in pulmonary inflammation, of patients with Cystic Fibrosis.
Reason Why Therapy is Needed:
The course of Cystic Fibrosis disease, largely determined by the degree of pulmonary involvement, varies greatly. However, because there is no known cure, and therapy is essentially confined to getting the patient through successive exacerbations, deterioration is inevitable. Debilitation and eventual death, usually from a combination of respiratory failure and right ventricular enlargement that produces pulmonary artery hypertension (cor pulmonale), are the final consequences of the disease. Thus, any safe therapy that prevents or reduces the decline of pulmonary function must be considered a desirable medical pursuit.
While the prognosis has improved steadily over the past five decades, mainly because of aggressive treatment before the onset of irreversible pulmonary changes, median survival is still only 31 years, and the average age is 14.3 years. Only 40% of adult CF patients are employed - 17% of adults are employed part time, 17% of adults are students, 5% of adults are homemakers, and 21% of adults are not employed. 3
Early colonization with mucoid Pseudomonas, being of female gender, presentation with respiratory symptoms, and airway hyper-reactivity are associated with a somewhat worse prognosis, while long-term survival is significantly better in patients without pancreatic insufficiency. 1
Patients with this disease are challenging to treat and management is considered both difficult and unsatisfactory. An experienced physician in conjunction with other physicians, nurses, nutritionists, physical and respiratory therapists, counselors, and social workers must direct comprehensive and intensive therapy. The goals of therapy are maintenance of adequate nutritional status, prevention or aggressive therapy of pulmonary and other complications, encouragement of physical activity, and provision of adequate psychosocial support.
Treatment of pulmonary manifestations includes prevention of airway obstruction and prophylaxis against, and control of, pulmonary infection. Prophylaxis against pulmonary infections consists of maintenance of pertussis, Haemophilus influenzae, varicella, and measles immunity and annual influenza vaccination. In unvaccinated patients, amantadine can be used for prophylaxis against influenza A.
Chest physical therapy consisting of postural drainage, percussion, vibration, and assisted coughing is recommended at the first indication of pulmonary involvement. In older patients, alternative airway clearance techniques such as active cycle of breathing, autogenic drainage, flutter valve device, positive expiratory pressure mask, and mechanical vest therapy may be effective. For reversible airway obstruction, bronchodilators may be given orally and/or by aerosol and corticosteroids by aerosol. Oxygen therapy is indicated for patients with severe pulmonary insufficiency and hypoxemia. However, in general, mechanical ventilation is not indicated for patients with chronic respiratory failure. Its use is usually restricted to patients with good baseline status in whom acute respiratory failure develops, in association with pulmonary surgery, or in patients awaiting lung transplantation who develop hypercapnic respiratory failure.
Oral expectorants are widely used, but few data support their efficacy. Cough suppressants are discouraged. Long-term daily aerosol administration of recombinant human deoxyribonuclease has been shown to slow the rate of decline in pulmonary function and to decrease the frequency of severe respiratory tract exacerbations.
Pneumothorax can be treated by closed chest tube thoracostomy drainage. Open thoracotomy or thoracoscopy with resection of pleural blebs and sponge abrasion of the pleural surfaces is effective in treating recurrent pneumothoraces.
Inhaled sodium pyruvate will potentially increase the amount of glutathione in the epithelial lung lining, thus reducing inflammation of the lung, and preventing or diminishing the loss of lung function.
4. A description of the drug and a discussion of the scientific rationale for the use of the drug for the rare disease, including all data for nonclinical laboratory studies, clinical investigations, and other relevant data that are available to the sponsor.
The description of the drug, and all non-clinical and clinical investigations, plus other relevant data, including pertinent publications, are included in the Sponsor's IND No. ____________________. Brief summaries of these subjects are addressed below. Also addressed below is a complete discussion of the rationale for the use of sodium pyruvate to treat Cystic Fibrosis.
A Description of the Drug:
Sodium pyruvate is the sodium salt of pyruvic acid. The drug product is prepared by dissolving the sodium pyruvate in sterile, non-pyrogenic 0.9% sodium chloride solution. The sodium pyruvate-sodium chloride solution system is then filtered through a 0.2-micron filter and the resultant drug product is aseptically filled in single dose Type I Glass vials containing butyl rubber stoppers and appropriate closure components. The drug is administered by inhalation therapy. Three ascending doses are under investigation.
0.5 mM sodium pyruvate in 0.9% sodium chloride solution
1.5 mM sodium pyruvate in 0.9% sodium chloride solution
5.0 mM sodium pyruvate in 0.9% sodium chloride solution
Scientific Rationale for the Use of Sodium Pyruvate to Treat Cystic Fibrosis
Premise: The defect in the cystic fibrosis transmembrane conductance regulator gene affects membrane potential and indirectly down-regulates the secretion of glutathione into epithelial lung lining fluid. This reduction in glutathione (and other cellular antioxidants) results in a hastening of destruction of epithelial cells in the lung lining, which in turns hastens reduction in lung function.
Pyruvate helps protect cellular membrane transport systems, and excess pyruvate that is transported into cells should protect and increase cellular levels of glutathione. Inhaled pyruvate in cystic fibrosis patients should provide protection for glutathione in epithelial lung fluids, as well as a protection of the lung tissue from oxygen radicals.
Background and Rationale: Glutathione is found throughout the body, and plays several roles in maintaining lung health. Its presence at lung disease sites, including cystic fibrosis, could help mitigate the disease process. Glutathione is a vital antioxidant, a mucolytic, a regulator of inflammation and immune response, and is important in cellular viability. Glutathione is a tripeptide containing the amino acids glutamine, glycine, and cysteine, with cysteine being the rate-limiting constituent. 3 Its sulfur-hydrogen, or thiol, group is a potent reducing agent and thus glutathione is considered one of the body's most important water-soluble antioxidants. 3,4,9
Cystic fibrosis patients typically die of respiratory failure due to profound lung injury secondary to chronic inflammation and chronic pathogen colonization of the lung. While it has long been observed that there is a deficit of extracellular glutathione in cystic fibrosis patients 3,4,5,7,9 , it has only recently been found that the defect in the cystic fibrosis transmembrane conductance regulator gene affects membrane potential and indirectly down-regulates the secretion of glutathione into epithelial lung lining fluid. 3,4,5 Since glutathione is an important component of the antioxidant defense system in the epithelial lung lining fluid the inability to transport glutathione and other cellular antioxidant compounds into the surrounding epithelial lung lining hastens destruction of lung function. Inhaled pyruvate should provide a form of protection to glutathione in epithelial lung fluids as well as providing protection of cells from oxygen radicals in CF patients. Pyruvate helps protect cellular membrane transport systems and excess pyruvate that is transported into cells should protect and increase cellular levels of glutathione.
Recent animal model studies showed that when there was a defect in the CFTR protein, there was a decrease in glutathione concentrations in epithelial lung lining, and an increase in the oxidation of lung lipids and DNA. 5 In asthmatic patients, an increase in oxygen radicals during an asthmatic occurrence decreases already reduced glutathione, and increases oxidized glutathione in the lungs within 10 minutes. 10 These patients have the ability to replenish reduced glutathione rapidly, thus minimizing oxygen radical damage. In pulmonary conditions involving high oxidant stress, extracellular levels of reduced glutathione increase. 6,11,12 Even though plasma levels of antioxidants in cystic fibrosis are normal, cystic fibrosis patients are not able replenish levels of glutathione in the lungs following an oxidative challenge. 3,4,5,7,15 In cystic fibrosis patients; a systemic deficiency of extracellular glutathione develops and progresses over time. 9,13,14
Glutathione is a major component of the cellular defense system against oxidative injury. 3,4,5,7,15,16 In the lungs glutathione is needed for proper lung functions and as a way to protect cells from oxidants that can destroy cell membranes, cause lipid peroxidation and damaged DNA. 3,4,5,7,15,16 The normal level of extracellular glutathione in the epithelial lining fluid is 140 times the normal level of extracellular glutathione in blood plasma. However, it is possible that the lungs, under oxidative stress, and requiring additional anti-oxidants such as glutathione, become net importers of circulating glutathione from many extra-pulmonary sources, including from invading white blood cells. 11 . When glutathione is decreased or depleted in the white blood cells, oxygen radicals are produced. This may, in turn, trigger an inflammatory response, and a depletion of glutathione in the epithelial lung lining fluid would increase the susceptibility of lung epithelium to chronic inflammation such as found in cystic fibrosis, ARDS, COPD, idiopathic interstitial lung disease, and many other lung diseases. 3,16
Another property of reduced glutathione, and one that is vital to the cystic fibrotic patient, is its promotion of mucolysis.3 Glutathione is able to cleave disulfide bonds, which serves to reduce the viscoelasticity of mucus when the glutathione system is functioning normally. 8,11-14,17,18,19,20,21 When glutathione levels are decreased, this reduction in the viscoelasticity in diminished. Increased viscoelasticity of mucus inhibits ciliary beating, and allows for increased opportunity for bacterial colonization of the lung. 19,20,21 Further, oxidant damage to the lung epithelial cells from a diminished extracellular antioxidant, reduces lung function, and also permits greater adhesion of bacteria. 17,18,19
Along with pulmonary dysfunction, evidence of oxidative stress has been found in cystic fibrosis patients. 3,4,7 Cystic fibrosis patients with acute pulmonary exacerbation have abnormally high concentrations of hydrogen peroxide in exhaled air. 16 The continuous presence of bacteria in the lungs induces a strong immune response in the form of a release of inflammatory cytokines, mediators and oxygen radicals. 16 Activated neutrophils and macrophages are major sources of oxygen free radicals including hydrogen peroxide and the production of peroxynitrite from nitric oxide. 3,4,5,7,15,16,22,23,24,25
There a number of mechanistic ways in which pyruvate can intervene in the lung inflammation process, and thus aid patients with Cystic Fibrosis. Pyruvate eliminates hydrogen peroxide and protects glutathione. 23,24 By eliminating hydrogen peroxide, pyruvate protects cells and cellular mitochondria from hydrogen peroxide mediated injury. The protection of glutathione is vital because mitochondrial glutathione plays an important role in the maintenance of lung cell function and viability. 25 Pyruvate also protects thiols like glutathione from peroxynitrite. 26 N-acetylcysteine, a precursor to glutathione is additionally protected by pyruvate. 27 Pyruvate released form astrocytes is also known to protect neurons form cysteine neurotoxicity produced when cysteine reacts with oxygen radicals. 28 In the cell, pyruvate protects essential SH groups from oxidation. Optimum functioning of vital enzymes such a Na+/K+-ATPase and glycerol dehyde-3-phosphate dehydrogenase or metabolite transporters including the specific mitochondrial pyruvate transporter appears to depend on labile SH groups. It is well known that pyruvate has a direct impact on NADPH2. 23 This metabolic pathway produces reducing equivalents in the form of NADPH2 that are normally used for reductive synthesis and importantly, also to keep the glutathione system in its physiologic reduced state. Glutathione in the reduced state is considered the main cellular defense against sudden oxidative stress. Cells also secrete pyruvate as an antioxidant defense to oxygen radicals. Additionally, pyruvate protects membrane transport systems by preventing lipid peroxidation, which impairs membrane functions. Pyruvate also provides protection to cellular DNA and mitochondria membranes. Finally, it was demonstrated that when sodium pyruvate was administered to rats whose lung function was impaired by bleomycin, there was a reduction in inflammation and lung damage in the chronic fibrotic stage of the lung injury. 1
In summary, it is believed that inhalation of sodium pyruvate will reduce the lung damage resulting from the increase in reactive oxygen species associated with the inflammation component of the cystic fibrosis disease, and will enhances nitric oxide's availability to effect bronchodilation by enhancing its synthesis and protecting it from destruction by reactive oxygen species. Inhaled pyruvate in cystic fibrosis patients should provide a form of protection to glutathione in epithelial lung fluids as well as protecting cells from oxygen radicals. Pyruvate helps protect cellular membrane transport systems and excess pyruvate that is transported into cells should protect and increase cellular levels of glutathione. Sodium pyruvate is a reactive oxygen species (ROS) antagonist that has been shown to neutralize oxygen radicals (specifically lowering the overproduction of superoxide anions), regulate the production and level of other inflammatory mediators, and increase the synthesis of nitric oxide. 29 Sodium pyruvate also increases cellular levels of glutathione, a major cellular antioxidant, which is reduced dramatically in antigen-induced lung disease patients. 30
However, neither the dosages of sodium pyruvate, the dosing administration schedule, the preferred route of administration, nor the preferred delivery system, for this disease state, are known at this time.
Summary of All Nonclinical Studies, Clinical Investigations, and Other Relevant Data
The safety of sodium pyruvate when administered orally, topically, and parenterally is well documented in the literature, and is appropriately cited in the Sponsor's IND _______________. Prior to the research activities of ______________________, however, there weren't any documented studies describing the effect of inhaled sodium pyruvate on the lungs. The pre-clinical studies supporting the safety of the sterile 0.5mM, 1.5 mM, and 5.0 mM sodium pyruvate in 0.9% sodium chloride solution drug systems are summarized below, and were conducted under the auspices of IND .
Pre-clinical Studies: Five animal studies were conducted to assess the acute, subchronic, and chronic safety of ascending doses of sterile sodium pyruvate in 0.9% sodium chloride solutions administered by inhalation therapy. No untoward results were observed and the drug regimens were judged to be safe as administered. The studies are summarized below.
Rat Study: Effect of Intratracheal Injection of a Single Dose of Sodium Pyruvate on the Lungs :
Twenty rats were administered either sterile 0.9% sodium chloride solution (control) (n=10) or sterile 5mM sodium pyruvate in 0.9% sodium chloride solution (n=10) by intratracheal injection. Five rats from each group were sacrificed four hours after injection, and the remaining five rats were sacrificed 24 hours after injection.
Lung compliance of all animals were similar to that of normal untreated rats at four or twenty-fours hours post injection. There was neither injury nor inflammation to the lungs seen in any of the groups of rats after sacrifice as determined by histological examination, and there weren't any increases in protein or cells in the bronchoalveolar lavage fluid compared to saline controls. It was concluded that sodium pyruvate did not have any harmful effect on lung compliance, that it caused no histological observable alterations in the lung, and had no deleterious effect on the bronchoalveolar lavage fluid.
Rabbit Study: Effect of a Single Dose and Multiple Doses of Inhaled Sodium Pyruvate on the Lungs
New Zealand White rabbits were administered differing concentrations of sodium pyruvate by inhalation therapy to determine the effect of the drug on lung injury as determined by histological examination, bronchoalveolar lavage analysis and arterial blood gas analysis.
In the first subset of acute experiments, rabbits were randomly assigned to one of five groups so that each group contained six rabbits. The first group was administered a single dose of sterile 0.5 mM sodium pyruvate in 0.9% sodium chloride solution. The second and third groups were administered a 1.5 mM and 5.0 mL sodium pyruvate system respectively. A fourth group did not receive any treatment, and a fifth group received only the normal saline vehicle. Four hours after administration of the sodium pyruvate in 0.9% sodium chloride solution, the rabbits were sacrificed.
Three other groups of six rabbits were also administered the ascending sodium pyruvate regimen, and an additional group was administered normal saline, as described above. These rabbits were sacrificed 24 hours after administration of the sodium pyruvate in 0.9% sodium pyruvate solution.
In the second subset of chronic experiments, the groups of rabbits were administered the sterile 0.5 mM, 1.5 mM, and 5.0 mM sodium pyruvate in 0.9% sodium chloride solutions or normal saline vehicle twice daily, five times per week, for three weeks. The rabbits were sacrificed 24 hours after the last administration.
After histological analysis of the lungs, the pathologist's report stated “There were no indications in these sections of any significant lesions or any other conditions of toxicological significance.” Additionally, it was concluded that the administration of single or multiple doses of sodium pyruvate by inhalation did not result in any clinically significant blood gas alterations or changes in whole lung lavages, nor were there any indications of adverse affects due to the drug.
Rat Study: Effect of Multiple Intratracheal Administrations of Sodium Pyruvate on Lung Injury Caused by Bleomycin:
Bleomycin was administered to rats to cause injury to the lungs, which then resulted in decreased lung function. Sodium pyruvate in 0.9% sodium chloride solution or 0.9% sodium chloride (control) was then administered by intratracheal injection to see if the drug regimen had any effect on the progression of the lung injury. The rats were sacrificed 24 hours, 72 hours, one week, and two weeks post injury. The rats sacrificed at two weeks were administered the drug on the third and seventh day post-bleomycin insult, while the other rats received only a single administration of sodium pyruvate.
There was no effect on the progression of the injury in the rats sacrificed at 24 hours, 72 hours or one week. However, significant improvement was observed in the rats administered the sodium pyruvate and sacrificed two weeks after bleomycin insult, compared to the sodium chloride control. There was a significant (p<0.01) reduction in total cells found in the bronchoalveolar lavage, indicating a reduction in airway inflammation. It was concluded that sodium pyruvate was effective in reducing inflammation and lung damage in this chronic fibrotic stage of the lung injury. (It should be noted that the fibrotic infiltration resulting from this type injury is typical of that seen in the fibrosing group of interstitial diseases in humans.)
Rat Study: Effect of Chronic Intratracheal Administrations of Sodium Pyruvate on the Lungs:
Twenty-four male and twenty-four female rats were equally divided among three groups and were administered by inhalation either 0.1 µM/kg/day of the 0.5 mM sodium pyruvate in 0.9% sodium chloride solution, 0.3 µM/kg/day of the 1.5 mM sodium pyruvate in 0.9% sodium chloride solution, or 1.0 µM/kg/day of the 5.0 mM sodium pyruvate in 0.9% sodium chloride solution. The rats had an exposure duration to the drug product of approximately 25 minutes on 15 separate days during a 21 day interval (no exposures were conducted on weekends).
The target deposited dose for the 0.5 mM, 1.5 mM, and 5.0 mM sodium pyruvate drug product was 0.02 µM/kg/day, 0.06 µM/kg/day, and 0.20 µM/kg/day, respectively. Eight male and eight female control rats were treated similarly in all regards except they were exposed to the 0.9% sodium chloride solution vehicle. Observations for appearance, activity, and behavior patterns were made at the beginning of the study and immediately after exposures to the drug.
After the 21-day experimental period, the rats were sacrificed and ten rats in each group (five male and five female) were necropsied, except only four male and five female rats that received the sodium chloride vehicle were necropsied. The lungs, mediastinal lymph nodes, nasal cavity/turbinates including respiratory and olfactory epithelium, trachea, larynx, pharynx/nasopharynx, and gross lesions were collected and processed for microscopic and histopathologic evaluation.
After microscopic and histopathologic evaluation, it was concluded that there were no treatment-related microscopic changes observed in any of the tissues collected from the respiratory tract or the mediastinal lymph nodes of either the male or female rats exposed to any of the three aerosolized sodium pyruvate doses.
Rat Study: Effect of Chronic Intratracheal Administrations of Sodium Pyruvate on the Lungs After Six Months of Treatment:
A study titled “180-Day Nose-Only Inhalation Study of Sodium Pyruvate in Rats,” which included a 90-day sacrifice of half the animals, was initiated and completed at ________________________________. The protocol was submitted to the FDA prior to initiation of the study for comment (Information Amendment, June 28, 2001, Submission 004).
The study was concerned with evaluating the toxicity of sodium pyruvate in normal saline when administered to 16 male and 16 female CDF® (F-344)/CrlBr by nose-only inhalation, for a 180-day duration. Each rat was exposed to the drug system every day for 85 minutes per day. Sterile normal saline was the control, and was administered in a similar manner to an equal number of rats.
The dosage received by each rat, based on comparable body weights, was calculated to be ten times higher than the maximum anticipated human dose when humans are administered three doses per day. The rationale for dose exposure concentrations is described in detail in both the 90-Day Interim Report (submitted to the FDA, March 20, 2002, Submission 006) and the final 180-day report (submitted to the FDA, September 5, 2002, Submission 007).
After 90 days, six males and six females from each group were sacrificed. At necropsy, gross morphological observations on lung, liver, kidney, heart, and body weights were recorded. Histopathological evaluations were performed on lung, trachea, larynx, nose, liver, heart, and kidneys. The Study Director concluded, “The animals displayed no clinical signs of toxicity attributable to sodium pyruvate inhalation. Terminal body weights, organ weights, and organ to body weight ratios were unaffected by exposure to sodium pyruvate for 90 days. There were minimal histopathological findings. Lesions of interstitial infiltrates in the lung were observed among control and pyruvate exposed rats and could not be attributed to the test article.”
After 180 days, the remaining males and females from each group were sacrificed. At necropsy, gross morphological observations on lung, liver, kidney, heart, and body weights were recorded. Histopathological evaluations were performed on lung, trachea, larynx, nose, liver, heart, and kidneys.
The Summary section of the final report stated: “The purpose of this study was to evaluate the potential respiratory tract and systemic toxicity in rats of a sodium pyruvate formulation inhaled daily for up to 180 days at 10 times the anticipated human dose. Equal numbers of male and female CDF® (F-344)/Cr1BR rats were exposed for 85 minutes/day, 7 days/week for up to 180 days to target concentrations of 0 and 5.76 mg sodium pyruvate/m3. The interim and final sacrifices were conducted after 90 and 180 days of exposure, respectively.
“The rats were exposed to target concentrations of test material and vehicle control.
“The rats remained free of diseases common to rodents, and the sodium pyruvate aerosol concentration used in this study was not toxic to rats. Except for sodium pyruvate-exposed females after 30 days of exposure, body weights were not adversely affected by exposure. The animals displayed no clinical signs of toxicity attributable to inhalation of sodium pyruvate. At the 90-day interim sacrifice terminal body weights, organ weights, and organ-to-body weight ratios were unaffected by exposure to sodium pyruvate. After 180 days of exposure only terminal body weight and percent kidney to body weight ratio for females were significantly below control values. There were minimal histopathological findings. Lesions of interstitial infiltrates in the lung were observed among control and sodium-pyruvate-exposed rats and could not be attributed to the test article.
The study report concluded: “…inhalation of target concentrations of 5.76 mg sodium pyruvate/m3, 85 minutes/day, 7 days/week for 180 days resulted in no clinical signs of toxicity attributable to administration of the test article, minimal effects on body weight in females, and no compound-related microscopic lesions.”
It is concluded by the Sponsor that rats exposed to an inhalation regimen of sodium pyruvate calculated to be ten times the level of the maximum dose (based on body weight) that will be administered to humans when taken three times per day did not experience any drug-product related toxicity or adverse reactions. These data suggest that the levels of sodium pyruvate intended for multiple therapeutic administration to humans is safe.
Clinical Studies:
Human Volunteer Phase I Safety Study: During this Phase I study, the safety of sterile sodium pyruvate in 0.9% sodium chloride administered via inhalation using a nebulizer was evaluated in healthy volunteers. Sterile 0.9% sodium chloride solution was employed as the control (vehicle). Vital signs (heart rate, respiratory rate, blood pressure, and lung function were determined for the volunteers before, and 15, 30, 60, 120, and 240 minutes after the single dose administration. Lung function was determined by measuring Forced Expiration Volume During the First Second (“FEV1”), and Peak Expiratory Flow Rate (“PEF”). Blood chemistries and the concentration of hydrogen peroxide in breath condensate were also measured. Hydrogen peroxide is now generally considered a marker of acute airway inflammation of patients with asthma and other lung diseases. 30,31,32,33,34,35
A diverse group of 15 normal subjects were treated with a single dose of saline placebo (vehicle), and safety parameters and lung function were measured over the 240-minute experimental period. At a later date these subjects were administered either 0.5 mM, 1.5 mM or 5.0 mM sodium pyruvate in 0.9% sodium chloride solution, and the safety and lung function measurements were again recorded.
There were no significant differences observed in vital signs, blood chemistries, hydrogen peroxide, FEV1, or PEF after treatment with any of the doses of sodium pyruvate in the subjects when compared to their values after receiving placebo. There were no abnormalities detected in vital signs, hydrogen peroxide, and clinical laboratory values that would indicate that sodium pyruvate caused any adverse effects. There were no Serious Adverse Events reported for any of the subjects. There were three Non-Serious Adverse Events reported, two were not related to the study and one was "very likely related" to the study. The related event was a dry mouth. No action was taken and the subject recovered without sequelae.
Unexpectedly, even though this was a safety study of normal subjects, when the fifteen subjects reported for their placebo treatment (zero time), eight had positive hydrogen peroxide readings in their breath condensate. The presence of positive hydrogen peroxide readings is considered indicative of lung inflammation. The “post-treatment” placebo readings indicated that four subjects had increased hydrogen peroxide and four subjects had decreased hydrogen peroxide values. There were no statistical differences seen in the levels of hydrogen peroxide when the pre- and post-saline treated values were compared (p=0.4, t-Test).
When these same subjects reported for their sodium pyruvate treatment (zero time), twelve of the fifteen volunteers had positive hydrogen peroxide readings in their breath condensate. A number of these subjects had values consistent with the level of inflammation associated with that of “mild asthmatics.” After treatment with the Reactive Oxygen Species antagonist sodium pyruvate, eleven of the twelve positive hydrogen peroxide subjects had significantly reduced hydrogen peroxide readings (1:12, p<0.05, binomial test). An analysis of the "pre minus post" delta values for the sodium pyruvate group revealed that the “post” readings were significantly lower than the "pre" readings (p<0.01, H0:delta=0, t-Test).
When the “pre minus post” scores of the fifteen subjects administered sodium pyruvate and placebo treatments were compared, sodium pyruvate was shown to be significantly more efficacious in reducing the hydrogen peroxide content in the subjects' breath condensate (p=0.02, t-Test, two sample, unequal variances). Thus the ROS antagonist sodium pyruvate was shown to decrease acute airway inflammation in subjects who were previously considered disease-free.
Phase I/IIa Study With Mild Asthmatics: The primary objective of this phase of the study was to evaluate the safety of single administrations of escalating doses of sodium pyruvate in mild asthmatics. The secondary objective was to determine if efficacy of these doses, as determined by lung function and reduction of reactive oxygen species (e.g. hydrogen peroxide) could be demonstrated in these patients.
Fifteen mild asthmatics, as previously determined to have no less than 85% lung function, were assigned to receive 0.5 mM sodium pyruvate in 0.9% sodium chloride solution by inhalation therapy. The patients were tested for lung function by determining their FEV1 and their PEF. They were also tested for hydrogen peroxide content in their breath condensate as an indicator of reactive oxygen species in the lung. The patients were then randomly assigned to receive either a single administration of the drug or the 0.9% sodium chloride solution vehicle. Lung function tests and hydrogen peroxide tests were conducted at 0 (pre-administration), 15, 30, 60, 120, and 240 minutes. Several days later the patients were brought back and administered the other treatment in accordance with the same testing protocol.
When the first fifteen patients had completed the study, a second group of mild asthmatics were enrolled. These patients received a single administration of 1.5 mM sodium pyruvate in 0.9% sodium chloride solution in accordance with the protocol. Following the completion of this portion of the study, a third and final group of fifteen patients were enrolled in this study and received a single administration of 5.0 mM sodium pyruvate in 0.9% sodium chloride solution.
Sodium Pyruvate/Nitric Oxide Screening Study in Subjects with Lung Disease: This study is presently being conducted, and is almost completed. A total of 105 subjects will be enrolled in this study. Fifteen control subjects and sixty subjects with diagnosed lung disease will receive the sodium pyruvate experimental drug. Ninety subjects with diagnosed lung disease (sixty with emphysema, chronic bronchitis or moderate bronchial asthma and thirty with interstitial lung disease) will be studied at two clinical centers.
Twenty subjects with COPD, ten subjects with ILD, and five control subjects will receive a 0.5 mM dose of sodium pyruvate. The same subject stratification will be repeated for the 1.5 mM and the 5.0 mM sodium pyruvate doses.
The purpose of this pilot study is to classify and identify those lung disease patients that will benefit from sodium pyruvate inhalation therapy. A single inhaled dose of sodium pyruvate, if efficacious, should alter NO levels in expired breath of individuals with lung disease and should improve spirometry values.
Safety:
There were no serious or moderate side effects or adverse reactions related to the administration of sodium chloride (control) or any of the three doses of sodium pyruvate to the forty-five mild asthmatics enrolled in the study. Six Non-Serious Adverse Events were recorded. Three were regarded as Possibly Related and three as Doubtful. No therapeutic action was taken with any of these events and each resolved without sequelae. The three Possibly Related events consisted of a dry mouth, a decrease in FEV1 and PEF, and a skin rash. The three Doubtful events consisted of a palpitations, transient lightheadedness, and a dry mouth. In four subjects Non-Serious Adverse Events were documented which showed decreases in FEV1 or PEF. Each of these occurrences were post inhalation of sodium chloride solution (control).
During this trial, any mild asthmatic patient that did not respond to either sodium pyruvate or saline (control), and was judged by the physician to be in sufficient pulmonary distress, was removed from the study and administered a “rescue therapy.” Six mild asthmatics administered saline were removed from the trial and given rescue therapy. Significantly, none of the patients administered any of the doses of sodium pyruvate required rescue therapy.
At the 1.5 mM dose of sodium pyruvate, patients with mild bronchial asthma demonstrated a significant improvement in PEF at 240 minutes post-inhalation as compared to the inhalation of physiological saline. However, these same individuals also had a significant decrease (p=0.04) in the percent change in FEV1 at 15 minutes. Since this change was only about 4% the decrease was not deemed clinically significant. Of the 15 patients receiving the 1.5 mM dose of sodium pyruvate, five showed improvements in FEV1 of greater than 10%. A statistically significant (p<0.02) decrease in H2O2 levels in expired breath was observed in these subjects when compared to post-inhalation values of physiological saline.
Patients with mild bronchial asthma that received the 5.0 mM dose of sodium pyruvate showed no significant alteration post-inhalation when compared to the physiological saline post-inhalation values.
The beneficial effect seen during the first two hours post-inhalation suggests that the inhalation of sodium pyruvate may have a bronchodilator effect in addition to its proposed Reactive Oxygen Species Antagonist (anti-inflammatory) properties. The mechanism of this bronchodilator effect is unclear, but it may be a result of the ability of inhaled sodium pyruvate to modulate ROS and Reactive Nitrogen Species such as hydrogen peroxide and nitric oxide. These species have both been shown to be elevated in expired breath of patients with bronchial asthma and thus implicated in the pathogenesis of this disorder. This phenomenon will be better studied in patients with more severe lung disease. It can be concluded that a single dose of 0.5 mM, 1.5 mM and 5.0 mM sodium pyruvate in 0.9% sodium chloride solution is safe to use in patients with mild bronchial asthma. Further, that these data indicate that 0.5 and 1.5 mM sodium pyruvate was capable of improving lung function in these patients.
Pertinent Unpublished and Published Papers:
All pertinent unpublished and published papers are referenced at the end of this Orphan Drug Designation Request. Additionally, abstracts or full text versions of the most important references are appended at the end of this Designation Request.
5. Where the sponsor of the drug that is otherwise the same drug as an already approved orphan drug seeks orphan drug designation for the subsequent drug for the same rare disease or condition, and explanation of why the proposed variation may be clinically superior to the first drug.
The sponsor is seeking orphan drug designation for sodium pyruvate in 0.9% sodium chloride solution. This drug has never been approved as an orphan drug for the treatment of cystic fibrosis, nor has an orphan drug designation ever been requested for this indication.
An Orphan Drug Designation (#00-1409) has been granted for the use =5.0 mM sodium pyruvate in 0.9% sodium chloride solution to treat Interstitial Lung Diseases.
6. Where a drug is under development for only a subset of persons with a particular disease or condition, a demonstration that the subset is medically plausible.
The drug is not under development for only a subset of patients with Cystic Fibrosis. The inflammation process followed by increased lung damage and diminishing pulmonary function, appears to be characteristic of patients with this class of disease. Therefore, all patients with this disease would be candidates for this therapy.
7. A summary of the regulatory status and marketing history of the drug in the United States and in foreign countries.
IND and Marketing Application Status and Dispositions
An IND, No._____________, is on file with the Division of Pulmonary and Allergy Drug Products, Office of Drug Evaluation II, Center for Drug Evaluation and Research. Additionally, two copies of the amended IND were forwarded to the Office of Orphan Products Development on December 9, 2000, in support of the Sponsor's Request for Orphan Drug Designation for Interstitial Lung Disease. Accompanying this document are the Information Amendments to IND No ________________, submitted on September 28, 2001, October 8, 2001, and February 22, 2002, and September 5, 2002).
A Phase I trial that studied the safety of inhaled 0.5 mM, 1.5 mM, and 5.0 mM sodium pyruvate in 0.9% sodium chloride solution in normal volunteers, and a Phase I/II trial that studied the safety and efficacy of inhaled 0.5 mM, 1.5 mM, and 5.0 mM sodium pyruvate in 0.9% sodium chloride solution in patients with mild bronchial asthma, have been completed. A Phase I/II study in which patients with different lung diseases are being treated with single doses of 0.5 mM, 1.5 mM or 5.0 mM sodium pyruvate in 0.9% sodium chloride solution to determine responders to the therapy, and a Phase II Asthma study, a Phase II COPD study, and a Phase II Interstitial Lung Disease study are planned.
Uses Under Investigation in Any Country:
The use of sodium pyruvate in 0.9% sodium chloride solution to treat pulmonary diseases, or any other diseases, by inhalation therapy, is not under investigation by _____________ in any country other than the United States. _______________________ is not aware of any other company investigating the use of inhaled sodium pyruvate solutions to treat pulmonary diseases, or any other diseases, in any country.
Approved Indications in Any Country:
The Sponsor is not aware of any approved indications for the use of sodium pyruvate solutions to treat pulmonary disease, or any other disease, by inhalation therapy, in any country.
Adverse Regulatory Actions Taken Against the Drug in Any Country:
There have not been any adverse regulatory actions taken against the Sponsor's drug(s) (0.5 mM, 1.5 mM, and 5.0 mM sodium pyruvate in 0.9% sodium chloride solution) in any country.
8. Documentation, with appended authoritative references, to demonstrate that the disease or condition for which the drug is intended affects fewer than 200,000 people in the United States. Cystic fibrosis is now known to be among the most common genetic diseases. It is the most common life-shortening genetic disease in the white population, occurring in about 1/3,300 white births, compared to 1/15,300 black births, and 1/32,000 Asian-American births. 1 One child in approximately 2,500 of European descent carries two defective copies and has the disease. In the U.S. such numbers translate into about 1,000 new cases a year and a total of some 30,000 people who live with the disorder today.2 About 30% of the patients are adults. Worldwide, there are believed to be about 250,000 CF patients. 3
Welsh and Smith 2 report that about 5 percent of white Americans are asymptomatic carriers, harboring a single mutant version of the gene in their cells, and Cystic Fibrosis Foundation 36 states that one in 31 Americans (one in 28 Caucasians) - more than 10 million people - is an unknowing, symptomless carrier of the defective gene.
The most recent CF Patient Registry 37 provides the following data: Reported patients in the U.S. is 19,517 with 1,062 known but not seen at a CF center. 96% are Caucasian; the median survival age is 28.3 years, but the average age of CF patients is 14.3 years. Percent of adults over age 18 is 33.9%. Only seven patients in the United States were 60 to 70 years old in 1994.
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