According to the National Heart Lung and Blood Institute sleep apnea affects some 18 million Americans. In fact, according to the National Sleep Foundation, about one in ten adults reports experiencing pauses in breathing during sleep. Approximately 4% of the men and 2% of the women suffer from sleep apnea, and untreated sleep apnea may cause $3.4 billion in additional medical costs.
Sleep apnea is generally defined as the repeated cessation of breathing during sleep, at times for as little as a few seconds and at other times for a minute or more and often hundreds of time per night. This leads to oxygen desaturation (hypoxia) of the blood, poor sleep and excessive daytime sleepiness. Chronic hypoxia due to sleep apnea is associated with increased incidence of hypertension (high blood pressure), stroke, vascular inflammation and other morbidities, including heart failure and death.
The most common type, obstructive sleep apnea (OSA), is due to blockage via relaxation or collapse of the smooth muscles of the upper airway during inspiration while asleep. Several factors increase the risk of airway blockage. Among these are an anatomically narrow airway; excess weight (obesity) including excessive neck fat; large tongue and tonsils; receding chin. While these features may predispose to OSA, it is the weakening of muscular tone in the pharyngeal muscles, particularly the genioglossus muscle, during sleep, especially REM sleep, which leads to a relaxation of the tongue and throat muscles, causing airway restriction.
Another form of sleep apnea, central sleep apnea (CSA) occurs because of alterations in brain centers responsible for generating breathing. CSA can be caused by certain drugs, such as opioids or anesthetics, or by damage to the brain or spinal cord. Some individuals have a mixed type of sleep apnea which results from both obstructive and central features.
There is currently no drug treatment option available for sleep apnea. The current standard of care requires the use of a medical device, the Constant Positive Airway Pressure (CPAP) device. While effective, the compliance rate of patients is typically less than 50%. Many OSA patients find it difficult to tolerate wearing a CPAP mask that is connected via an airhose to a positive pressure machine while they sleep. There are variations on the CPAP theme in an attempt to increase patient compliance, but to date there is no optimal solution. Adaptive servo-ventilation (ASV) and BiPaP devices have been used, but ASV has been found to adversely affect CSA patients and BiPap is primarily used for other indications and was not originally developed for sleep apnea. Thus the sleep apnea market is a large market opportunity in which the competition is a medical device with poor compliance.
RespireRx is exploring two different pharmacological approaches for treating sleep apnea. One approach involves the use of dronabinol, or synthetic THC (D9-tetrahydrocannabinol), which has shown positive effects on reducing the apnea-hypopnia index (AHI) in OSA patients in a 22 patient pilot clinical trial.
The second approach uses RespireRx’s Ampakine compounds in the treatment of central and, possibly, mixed sleep apnea. Central sleep apnea is due to a reduction of neural signaling to the lungs from the respiratory rhythm generating center in the medullary area of the brain, called the PreBötzinger Complex. RespireRx has shown that several different Ampakine compounds can restore relatively normal breathing patterns in animals suffering from opioid-induced respiratory depression. Opioids reduce breathing rates by acting directly on the respiratory rhythm generating PreBötzinger Complex neurons in the medulla, the same neurons that are not properly signaling the lungs to breath in central sleep apnea. For this reason, RespireRx believes that its Ampakine compounds may be effective in restoring breathing in central sleep apnea. Early clinical data support this notion. CX717, an older Ampakine was shown in human volunteers to normalize breathing that is otherwise depressed due to opioid administration. CX1739, a new, more potent Ampakine was tested in a pilot clinical study in sleep apnea patients with varying types of apnea. While the overall effect of a single dose of CX1739 was not statistically effective in reducing sleep apnea measurements, there was an intriguing hint of activity in reducing central sleep apnea in a few patients who also had significant levels of CSA prior to CX1739 treatment and in patients with mixed sleep apnea.
Central Sleep Apnea and Heart Failure
As noted above, about 2-4% of the overall population has sleep apnea. Obstructive sleep apnea is much more prevalent than central sleep apnea: about 80% are predominantly of the OSA type, 5% predominantly CSA, and 15% have a mixed type of sleep apnea with obstructive and central characteristics. However, cardiovascular disease, and in particular heart failure, is increasingly being recognized as intertwined with sleep apnea. Having moderate-severe sleep apnea increases the risk of developing heart failure in otherwise healthy middle-aged men by almost 60% over the ensuing decade (Gottlieb et al 2010). Similarly, within the heart failure patient population, more patients have sleep apnea than those who don’t. In one study of 700 patients, 40% had central sleep apnea and another 36% had obstructive sleep apnea (Oldenburg et al. 2007). A few key studies have linked reduced lifespan with the presence of central sleep apnea in heart failure patients. Reduction of sleep apnea, especially central sleep apnea, in the heart failure patient is a very attractive pharmaceutical indication that, if effective, would provide significant benefit to the patient.
Furthermore, a recent study of over 100 cardiac patients admitted to a hospital system with untreated sleep breathing disorders showed that only those patients that adhered strictly to a CPAP regimen had significantly reduced 30-day rehospitalization for the same indication. As noted earlier, CPAP has a very low compliance rate. A drug therapy that could reduce 30-day rehospitalizations would have a significant favorable pharmaco-economic impact.