Inside the FDA: Insys Therapeutics Inc. (NASDAQ:INSY) and Sublingual Naloxone

If any one thing that can be pinpointed as of #1 paramount importance in an FDA approval, it is a risk/benefit ratio. If a drug can be proven to be risk-free and have benefit, the overwhelming chances are that it will be approved at some point. No matter where you fall on the regulatory spectrum and no matter how suspicious you may be of political and/or pharmaceutical-industrial pressures levied on the FDA or if you believe that there are any in the first place, an overwhelmingly obvious risk/benefit ratio will override all of that.

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Here we come to Naloxone sublingual spray, being trialed by Insys Therapeutics Inc. (NASDAQ:INSY) with a briefing document published by on the FDA website on September 27th.  Naloxone is an opiate antagonist that has been around since the early 1970’s, and it has one of the strongest safety profiles that can possibly be established. The drug has no known pharmaceutical effects whatsoever in the absence of opioids. Meaning, it does pretty much nothing other than counteract opioids in the system.

Insys is currently trialing a new sublingual formulation of naloxone. Currently, the drug is available in the event of opiate overdose which includes both heroin and prescription overdose. The issue with overdose is that it suppresses oxygenation of the blood by slowing respiration. Addicts tend to need more and more opiates of whatever form in order to achieve the same effects, and eventually the chemicals suppress breathing to the point that users literally suffocate and die. Naloxone binds to opiate molecules and knocks them off from suppressing respiration, leading to almost immediate regaining of consciousness and withdrawal, which though extremely painful in some cases, does save their lives.

The drug is currently available in intravenous, intramuscular, subcutaneous, and intranasal formulations. Statistics to date show that Naloxone has been used to reverse 10,000 opioid overdoses since its first use in the United States. That means the drug has saved 10,000 lives, which is great, but on the other hand, there were a total of 47,055 drug overdose deaths in 2014 alone in the United States.

That means we have a serious problem. We have a drug that works, and has been known to work for almost half a century, and yet people are still dying from drug overdoses in droves every year. This drug has no known side effects even at extremely high doses in people with no opiates in their systems. It has an almost perfect safety profile. So why are people still dying of opiate overdoses?

For one, overdoses need immediate treatment. Often there is no time to call 911 and wait for an ambulance to arrive. To do so is nearly equivalent to allowing a choking victim to lay unconscious on the floor turning blue without performing the Heimlich maneuver or tracheotomy, and instead just call 911 and see if they can get to the scene in time. Sometimes they can’t. Death from respiratory depression from opioid overdose can take 1 to 3 hours, and this is not taking into account drug interactions or other issues.

The issues with IV, subcutaneous, or intramuscular naloxone even though they are effective are four. First, there is a significant issue of taboo associated with carrying needles around at all times for your fellow addict who you may be ashamed of. Carrying a needle around in your pocket at all times seems off and can be difficult to get access to, and like it or not, people just don’t want to do it. Second, even if a friend or family member of an addict does carry one around, IV administration requires training to find a vein, and this in a considerable situation of emotional duress. Subcutaneous and intramuscular are easier, but taboo persists here. Third, when it comes to addicts, there may be significant skin and vascular damage from repeated injections of opiates, making injection harder to administer. Fourth, there is the danger of infection with any injection due to possible blood exposure, and 80% of the injection drug user population in large metropolitan areas is either Hepatitis C positive or HIV positive (see briefing document).

How can we stop the death? Legislation does not seem to work. In fact, according to the Insys briefing document, “The pathophysiology and acute medical management of an opioid overdose is similar irrespective of whether the opioid that was taken was legally prescribed or illegally bought on the street.” So regardless of whether an opiate was acquired legally or not, an overdose is equally life threatening. The mere existence of naloxone is not enough, as it has been around for nearly 50 years and people are still dying of overdose. It has to be available first hand immediately and not only via first responders, who often cannot arrive at the scene fast enough. Just like the Heimlich maneuver is taught to everyone in the case of choking, naloxone needs to be as available and as easily useable as possible in order to stop overdose death, just like the Heimlich.

There is another route available for naloxone administration besides injection and that is intranasally. This was approved by the FDA in November and is effective in about 83% of cases. The other 17% in a 2005 study were either suffering from nosebleeds at the time, or stuffed noses, or other nasal trauma or septal abnormalities, meaning people with deviated septums sometimes due to cocaine abuse. None of those who responded to intranasal naloxone had any nasal abnormalities. The common cold can be enough to render intranasal naloxone completely ineffective in a potentially life threatening situation. 83% is good, but it’s not good enough, and besides, a person being treated with intranasal naloxone has to be conscious enough to snort or at least breathe with minimal pressure, which is not always the case.

A sublingual spray would at once be both more convenient to administer than either injectable formulations or intranasal formulation of naloxone, and answer the problems inherent in both formulations. Carrying around a spray bottle that you can spray under the tongue is more convenient and frankly less scary and safer than a needle and independent of any nasal obstructions or abnormalities. Even if a person has stopped breathing altogether, a sublingual formulation can still enter the bloodstream and save lives whereas intranasal formulations still require that a victim be at least breathing somewhat.

Insys plans to submit an NDA for sublingual naloxone in 2017. The FDA has already granted Fast Track designation for it, and its sublingual technology already has an approval under its belt for fentanyl spray, brand name Subsys. That means the technology works enough for it to gain approval, and will probably work for naloxone just as well.

The only catch here is the lack of information surrounding the trial. According to the Insys website, sublingual naloxone is at Phase III development, but there is no record of it on Whether this has to do with the difficulties of proceeding in a clinical pathway for emergency drugs or something else we are not sure. Nevertheless, the evidence threshold that Insys will have to meet to get this approved is pretty low, as there is no reason for the FDA to reject or even delay it unless it is obviously less effective than nasal or injectable formulations. In that case, the FDA may delay it for fear that mass adoption may discourage the use of more effective formulations.

If it is equivalent or nearly equivalent however, the chances of sublingual naloxone being approved are extremely high. And if approved, it will continue to validate Insys’ sublingual technology. The company is also pursuing sublingual formulations with the same tech for ondansetron (Zofran), sildenafil (Viagra), diclofenac (an NSAID pain reliever), epinephrine (adrenaline) and ketorolac (another NSAID).

If sublingual naloxone is approved, that increases the chances that more or even all sublingual formulations that the company is now pursuing have increased chances of approval. Given that Insys is near its lows, it looks like a good buy at these levels if indeed an NDA will be filed in 2017. We assume that if it is, the FDA will approve it quickly, as this is a life and death issue and naloxone has no side effects. In fact, the only side effects it does have are not inherent to the drug itself, but in the opiate withdrawal symptoms it causes in addicts by neutralizing the drugs in their systems. It could be then that a sublingual formulation could be less intense in terms of indirect side effects than naloxone injections, which act within minutes 2 – 5 minutes generally, and have caused cardiac arrest in some due to the shock of sudden opiate withdrawal.

Arguments have been made along the lines that effective antidrugs like naloxone will encourage more drug use. Whether or not this is true is a matter of debate and conjecture. The fact is though, people are dying and more easily usable antidrugs can save lives in emergency situations. Opiate abuse is on the rise, and oftentimes only a near-death experience can inspire people to stop abusing drugs, so it can just as easily be said that more available naloxone may inspire more people to quite using after bringing them back from the brink of death.

Bottom line, if the NDA is filed in 2017, it will almost certainly be approved, and Insys will get a jump.

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