Prepared Witness Testimony

The House Committee on Energy and Commerce

SARS: Assessment, Outlook, and Lessons Learned

Subcommittee on Oversight and Investigations
May 7, 2003
2:00 PM
2123 Rayburn House Office Building 

Dr. Robert J. Capetola Ph.D.
President & Chief Executive Officer
Discovery Laboratories, Inc.
350 South Main Street, Suite 307
Doylestown, PA, 18901

Written statement of Robert J. Capetola, Ph.D., President and Chief Executive Officer of Discovery Laboratories, Inc., a specialty pharmaceutical company developing its proprietary surfactant technology as Surfactant Replacement Therapies for respiratory diseases including Respiratory Distress Syndromes (RDS and ARDS), Acute Lung Injury (ALI), asthma, Chronic Obstructive Pulmonary Disease (COPD), and upper airway disorders.  Discovery Labs is currently in five late-stage clinical trials of its engineered lung surfactant as a treatment for severe respiratory diseases including Part B of a Phase 2 trial for the treatment of ARDS, the life-threatening respiratory condition that severe SARS suffers deteriorate to. 

Severe Acute Respiratory Syndrome (SARS) is an acute respiratory illness in which patients have difficulty breathing.[i]  The path of SARS is a highly contagious viral infection[ii] that leads to pneumonia, and in severe cases, progresses to life-threatening Acute Lung Injury (referred to as ALI), the most serious manifestation of which is Acute Respiratory Distress Syndrome (referred to as ARDS).  A prominent characteristic of ARDS is the destruction of a patient's lung surfactant.[iii]  Surfactants are produced naturally in the lungs and are essential for breathing. (See Illustration 1).  Should these surfactants degrade or be destroyed, millions of alveoli, or tiny air sacs, in the lung collapse, airflow becomes constricted and the lungs do not absorb sufficient oxygen. (See Illustration 2).

No proven treatment for SARS presently exists.  For now, SARS treatment amounts to keeping patients isolated and dealing with their symptoms while the infection runs its course.  SARS patients are currently getting the same treatments as patients suffering from pneumonia or other respiratory infections, including antibiotics to combat bacterial infections, mechanical ventilation to help them breathe, and treatment for fever.[iv]  With the number of world-wide SARS cases approaching 6,000, the lack of an effective treatment has resulted tragically in at least 400 deaths, or a mortality rate of greater than 6.5%. 

Although public health officials are hopeful that the spread of SARS may have temporarily peaked, at least outside China, most researchers fear that SARS will return in force next winter.[v]  An additional concern is that the virus could be quickly mutating and new SARS strains, possibly more virulent forms, are likely to develop.  Indeed, Hong Kong has recently reported that a dozen former SARS patients had relapsed, indicating that treating the disease may be even more difficult than expected.

World health authorities, including the United States National Institutes of Health, are taking a logical first step to address the SARS virus by searching for an effective antiviral treatment.  They are urgently screening a number of virus-fighting drugs, medicines already on the market or close to it, including protease inhibitors and compounds that block viral replication.  No antiviral presently exists that is specifically aimed at this coronavirus (the form of virus identified by the CDC and the World Health Organization as the cause of SARS).  Even the ribavirin/steroid "cocktail" that doctors in Asia and Canada had been using extensively to treat SARS has been abandoned because of lack of effectiveness in combating the disease and harmful side effects, with many patients suffering anemia and liver inflammation because of it.  Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases, has commented that he hopes to have a possible vaccine ready for human testing in just over a year.  But Dr. Fauci has cautioned that it would still be years before a vaccine would be available for distribution and that its development can never be guaranteed. 

While these efforts need to be continued and supported both scientifically, financially and politically, the harsh reality is that SARS patients have difficulty breathing -- they are suffering the destruction of their essential lung surfactant system and are at risk for life-threatening ALI or ARDS.  No approved therapies for ARDS currently exist.  Current therapy for ARDS patients remains entirely supportive and mechanical ventilation is the present standard of care.  In the face of the SARS crisis, a logical precaution for world health officials to take is to ensure that an adequate number of mechanical ventilators are available.  Indeed, the United States government has recently improved its ability to respond to a SARS outbreak by adding 3,000 mechanical ventilators and has asked the states to identify space for extra hospital beds during an emergency.  However, mechanical ventilation is an unfortunate last resort -- the only way to oxygenate and keep the vital organs functioning.  It is used only to assist in the patient's breathing while an attempt to adequately address the underlying cause of the disease is made. However, mechanical ventilation is very costly and it is axiomatic in critical care medicine that the longer a patient is on mechanical ventilation the higher the likelihood that mortality and morbidity results.  Even with mechanical ventilation, the reported mortality rate for ARDS is between 40-50% worldwide.

Public health officials have focused on a search for effective agents to combat SARS and have recognized the need for improving mechanical ventilation resources and attendant facilities.  The next logical step for world health authorities is to fully evaluate therapies that can restore proper lung function in SARS sufferers.  Surfactants are essential for breathing and one of the prominent characteristics of ARDS is the destruction of lung surfactants. (See Illustration 3).  Surfactant Replacement Therapy has the potential to address the SARS crisis.  The goal of Surfactant Replacement Therapy is to maintain or restore proper lung function.  Surfactant Replacement Therapy will not directly address the SARS virus.  However, SARS patients are suffering destruction and degradation of their lung surfactant system.  If the condition of a SARS patient degrades to ARDS, Surfactant Replacement Therapy has the potential to be a treatment by using the same or similar logical approach that we are presently using in our ongoing ARDS trial.  If a SARS patient exhibits symptoms of progressing to ARDS, our engineered lung surfactant, as an inhalable aerosol, has the potential to prevent the widespread surfactant destruction that can occur as a result of SARS.

The remainder of this statement is about the possible benefits of Surfactant Replacement Therapy for the treatment of SARS.[vi]  I will discuss the critical role that lung surfactants play in proper pulmonary function and how Surfactant Replacement Therapy is already being used for the treatment of severe respiratory diseases.  I will also describe our engineered version of human lung surfactant -- its safety and pharmacological profile, our ongoing Phase 2 clinical trial for the treatment of patients suffering from ARDS and the potential for our engineered surfactant as an inhalable aerosol formulation to maintain lung function in SARS patients.  Discovery has the only surfactant technology engineered to mimic the essential properties of human lung surfactant.  We focus exclusively on treating respiratory diseases. 

Lung Surfactant Technology and Current Surfactant Replacement Therapy

Surfactants are produced naturally in the lungs and are essential for breathing.  Should surfactants degrade or be destroyed, the air sacs in the lungs collapse, airflow becomes restricted and the lungs do not absorb sufficient oxygen. (See Illustrations 1 and 2).

Surfactants are protein and lipid (fat) compositions that cover the entire alveolar surface, or air sacs, of the lungs and the terminal conducting airways which lead to the alveoli.  Surfactants facilitate respiration by continually modifying the surface tension of the fluid normally present within the alveoli that line the inside of the lungs.  In addition to lowering aveolar surface-tension, surfactants play other important roles which include lowering the surface tension of the conducting airways and maintaining airflow and airway patency (keeping the airways open and expanded).  Loss of patency leads to compromised pulmonary function. (See Illustration 4).  Human surfactants include four known surfactant proteins, A, B, C and D.  It has been established, through numerous studies, that surfactant protein B (SP-B) is essential for respiratory function. 

Pulmonary surfactants have additional properties such as:

(i)         Physical barrier to inhaled particles and noxious agents;

(ii)        Host defense against infection; and

(iii)       Anti-inflammatory properties

There is a large body of scientific evidence associating the loss or lack of endogenous surfactant function with respiratory diseases. (See, e.g., Illustration 4).  Clinically, all of these diseases are characterized by one or more symptoms such as shortness of breath, chest tightening, and loss of pulmonary function as measured by FEV1, FVC, PO2, and PCO2.  Studies demonstrate that Surfactant Replacement Therapy would be a viable pharmacological approach for patients suffering from respiratory diseases such as Acute Lung Injury, ARDS, asthma, and Chronic Obstructive Pulmonary Disease.

Presently, surfactants are approved as replacement therapy only for Respiratory Distress Syndrome in premature infants, a condition in which infants are born with an insufficient amount of their own natural surfactant.  The most commonly used of these approved replacement surfactants are derived from pig and cow lungs.  Though the animal-derived surfactants are clinically effective, they have drawbacks and cannot readily be scaled or developed to treat broader populations and other respiratory diseases such as ARDS or SARS.

Animal-derived surfactant products are prepared using a chemical extraction process from minced cow and pig lung.  Because of the animal-sourced materials and the chemical extraction processes, there is significant variation in production lots and, consequently, product quality specifications must be broad.  In addition, the protein levels of these animal-derived surfactants are inherently lower than the protein levels of native human surfactant.  The production costs of these animal-derived surfactants are high, relative to other analogous pharmaceutical products, generation of large quantities is severely limited, and these products cannot readily be reformulated for aerosol delivery to the lungs.

Discovery Labs Surfactant Replacement Therapy

Discovery's engineered version of human lung surfactant is designed to precisely mimic the most essential attributes of natural lung surfactant.  Discovery's surfactant technology contains a proprietary peptide that mimics human lung surfactant protein B (SP-B), the protein in natural pulmonary surfactant known to be the most important surfactant protein for promoting surface-tension lowering and oxygen exchange.[vii]  Discovery's surfactant has anti-inflammatory properties and can be engineered as a liquid instillate or an inhalable aerosol as therapy for specific diseases being treated. (See Illustrations 5 and 6).  Our engineered humanized surfactant can be manufactured less expensively than the animal-derived surfactants, in sufficient quantities, in more exact and consistent pharmaceutical grade quality, and has no potential to cause adverse immunological responses in young and older adults, all important attributes to potentially meet significant unmet medical needs.  In addition, we believe that our engineered humanized surfactants might possess other pharmaceutical benefits not currently found with the animal surfactants such as longer shelf-life, reduced number of administrations to the patient's lungs, and elimination of the risk of animal-borne diseases including the brain-wasting bovine spongiform encephalopathy (commonly called "mad-cow disease").  Our humanized surfactant technology was invented at the world-renowned Scripps Research Institute and was further developed and licensed to us by Johnson & Johnson. 

There is significant scientific and clinical literature establishing the safety and pharmacological activity of our proprietary surfactant technology.  To date, hundreds of subjects have received Surfactant Replacement Therapy with Discovery's lead surfactant product, Surfaxin®, and such treatment has been well-tolerated.[viii]  Surfaxin is in three Phase 3 and two Phase 2 clinical trials addressing critical respiratory indications where there are few or no therapies currently available.  Surfaxin has been shown to remove inflammatory and infectious infiltrates from patients' lungs when used by our proprietary lavage (or "lung wash") and replenish the vital surfactant levels in the lungs. 

Discovery's Surfactant Replacement Therapy for ARDS -- Phase 2 Clinical Trial

Currently, Discovery is developing Surfaxin for the treatment of Acute Respiratory Distress Syndrome in adults (ARDS).  Acute Respiratory Distress Syndrome in adults is a life-threatening disorder for which no approved therapies exist anywhere in the world. (See Illustration 7).  It is characterized by an excess of fluid, inflammatory cells and debris in the lungs that leads to decreased oxygen levels in the patient.  One prominent characteristic of this disorder is the destruction of surfactants naturally present in lung tissue that are essential to the ability to absorb oxygen.  Current therapy for ARDS patients remains entirely supportive and mechanical ventilation is the present standard of care.

Discovery's approach to treating ARDS is based on the scientific rationale supporting Surfactant Replacement Therapy as an effective lavage, or "lung wash," designed to alter the course of this disease by rinsing out damaging infiltrates and debris in the lungs and restoring normal surfactant function. (See Illustrations 8 and 9).  We are presently conducting a Phase 2 open-label, controlled, multi-center clinical trial of Surfaxin for adults in up to 110 patients with Acute Respiratory Distress Syndrome.  This trial will compare the safety and effectiveness of standard of care, including mechanical ventilation, to high concentrations of Surfaxin administered to patients via a proprietary lavage technique that administers the drug sequentially through a tube, called a bronchoscope.

In July 2002, we completed the first part of this trial, a dose escalation safety and tolerability study in 22 patients in four groups (of up to six patients per group).  In consultation with the trial's Independent Safety Review Committee that was comprised of three prominent pulmonologists, we determined that the Part A portion of the trial procedure is generally safe and tolerable and that it was appropriate to proceed onto the larger safety and efficacy portion of the study.  These early results, although in a small number of patients, are encouraging because they suggest that the most effective dosages are the higher Surfaxin concentrations.  In fact, some of the sickest patients were in the highest dose groups and, nevertheless, in these groups we experienced the most promising results, including no mortality and a significant reduction in the number of days on mechanical ventilation. (See Illustration 10). 

The following table presents summary data of certain key clinical endpoints from the dose-ranging part of the trial:

    *  Based on phospholipid content.

The last part of this Phase 2 trial, Part B, will evaluate safety and efficacy of Surfaxin in direct comparison to standard of care at approximately 50 centers in the United States and Canada.  The primary endpoint of this part of the trial is to determine the incidence rate of patients being alive and off mechanical ventilation at the end of day 28 with one of the key secondary endpoints being mortality. 

The FDA has granted Fast-Track Approval Status and Orphan Drug Designation for Surfaxin for the treatment of Acute Respiratory Distress Syndrome for adults.  The European Medicines Evaluation Agency has granted Orphan Product designation for Surfaxin for the treatment of Acute Lung Injury in adults (which in this circumstance encompasses Acute Respiratory Distress Syndrome).

If the necessary activities and , coupled with the adequate resources, could be properly organized, including, but not limited to, (1) training of medical personnel in the bronchopulmonary segmental surfactant lavage procedure, (2) regulatory procedures, and (3) supply of sufficient drug, this program could be positioned to evaluate Surfactant Replacement Therapy for the most severe SARS patients on mechanical ventilation by mid-to late-summer of 2003.

Discovery's Inhalable Aerosol Surfactant -- Positioned to enter Phase 1b / 2a Clinical Trials

Discovery recently prepared its proprietary engineered version of lung surfactant as an inhalable aerosol formulation that successfully retained the critical therapeutic properties of fully-functioning natural lung surfactant.  This development now evolves surfactant therapy to the point where inhalable aerosol formulations of engineered lung surfactant have the potential to be developed to treat respiratory diseases that so far have been unable to benefit from Surfactant Replacement Therapy.  The immediate focus of our aerosol development program is on surfactant-based therapy to help restore lung function of hospitalized patients suffering from severe respiratory conditions (for example, SARS), hopefully avoiding the progression to ARDS, the need for mechanical ventilation, thereby preventing respiratory conditions from becoming severe, even life-threatening events.

Discovery's lung surfactant was aerosolized as a liquid formulation that exhibited all of the essential pharmacological properties of a functioning surfactant, including the surface-tension lowering abilities necessary to restore lung function and keep the airways open and expanded.  An aerosolized Surfactant Replacement Therapy may be effective as a preventive measure for patients at risk for Acute Lung Injury by providing a functioning surfactant to act as an anti-inflammatory and to maintain proper lung function.

Importantly, our inhalable aerosol surfactant could be readily administered to ambulatory patients with a number of already-available devices or could be used with aerosol generators designed for in-line use with mechanical ventilators.  With a highly communicable disease such as SARS, this could be a closed system reducing the risk of disease transmission to health care workers and others.  We have every reason to expect that our inhalable aerosol Surfactant Replacement Therapy would demonstrate the same safety and pharmacological profile exhibited throughout our surfactant pre-clinical and clinical programs to date, including our five ongoing Phase 3 and Phase 2 studies.  Our present development plan calls for us to enter Phase 1b /2a clinical trials to evaluate our inhalable aerosol Surfactant Replacement Therapy by late-2003 or early-2004.  However, with a concerted effort by all necessary parties, this program can be positioned to evaluate the possible benefits of Surfactant Replacement Therapy for SARS patients by early-fall of 2003.

Conclusion

Scientists around the world have moved with unprecedented speed to identify the SARS virus and screen potential treatments.  Public health officials have employed intense efforts to contain its spread and are exploring numerous medical treatments, focusing on antivirals, vaccines, and mechanical ventilation.  The logical next step is for world health authorities to fully evaluate pulmonary therapies aimed at restoring or maintaining proper lung function in SARS sufferers.  SARS patients have difficulty breathing and are suffering degradation and destruction of their lung surfactant system.  Surfactants are critical for breathing and the goal of Discovery's Surfactant Replacement Therapy is to maintain or restore proper lung function. 

Surfactant Replacement Therapy has the potential to play an important role in addressing the SARS crisis.  Discovery's surfactant technology, engineered to mimic the essential properties of human lung surfactant, is the only surfactant technology that could play this role.  We focus exclusively on treating respiratory diseases.  I respectfully ask that this Committee consider taking appropriate actions to ensure . . . [Bob - please outline what next crucial steps you would want taken]In summary, Discovery and its medical advisors are convinced that Surfactant Replacement Therapy has the potential to be an effective therapy to treat a variety of respiratory diseases, including SARS.  We ask this Committee to be a catalyst in conveying the message that Surfactant Replacement Therapy be included in the assessment of therapies currently under consideration by the various health authorities.

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