Shares of San Diego-based Adamis Pharmaceuticals Corp. (NASDAQ:ADMP) fell 51% to close Monday at 62 cents after the FDA issued a complete response letter regarding its high-dose naloxone injection candidate, Zimhi, for the treatment of opioid overdose. The agency raised questions about chemistry, manufacturing and controls (CMC), but not the candidate's safety or efficacy, the company said.

Adamis President and CEO Dennis Carlo said his team will seek a meeting with the regulator to discuss plans to resubmit the NDA and expects to expand the CMC testing it has already provided the regulator. 

Zimhi is manufactured by a third party contract manufacturing organization, and leverages the company’s prefilled Symject syringe, a device already approved by the FDA as part of a separate product, the Symjepi epinephrine prefilled syringe. 

Naloxone is an opioid antagonist used to treat narcotic overdoses. It's generally considered the drug of choice for immediate administration for opioid overdose, according to Adamis, because it blocks or reverses the effects of an opioid, including extreme drowsiness, slowed breathing or loss of consciousness.  

Accidental opioid overdoses continue to be a significant public health problem in the U.S., where more than 700,000 people have died from drug overdoses between 1999 and 2017, according to the CDC. With the more potent opioids such as fentanyl being a significant driver of the current epidemic, "we believe there is a public need for our higher-dose Zimhi product candidate," Ronald Moss, the company's chief medical officer, said during a Nov. 12 investor call. 

Adamis spokesman Mark Flather told BioWorld that the company's team is reviewing the CRL to determine its plan of action, but it's too early to speak to a timeline for resubmission. 

Adamis submitted its NDA for Zimhi, a prefilled single-dose syringe formulation of 5 mg of naloxone in December 2018, leading to FDA acceptance of the application for review in March 2019. But not long after the passing of the application's Oct. 31 PDUFA date, Carlo told investors that "the FDA delivered neither trick nor treat." That left the company in wait-and-see mode as it discussed a proposed commercial agreement with potential commercialization partners. 

Since then, its researchers have showcased data from two studies comparing the pharmacokinetics of Zimhi to current 2-mg doses of other naloxone products. Relative to both 4-mg intranasal naloxone and a 2-mg intramuscular products, they found Zimhi's 5-mg intramuscular dose provided superior pharmacokinetic exposure and more rapid systemic exposure to the drug. That's important , because "fentanyl can result in rapid respiratory failure with resulting brain hypoxia and ultimately, death," said Moss and his co-authors – all Adamis employees – in a recent article published in the Journal of Addiction Research and Adolescent Behavior

While dosing of current naloxone products, such as Kaléo Inc.'s Evzio, Emergent Biosciences Inc.'s Narcan and their generics, may be repeated at two- to three-minute intervals, according to the FDA, researchers at Adamis emphasized the importance of quick high-dose delivery in the recent journal article. "Rapid naloxone systemic exposure and egress to the mu receptors in CNS may mean the difference between life and death. The risks of underdosing with naloxone outweighs any risks particularly because of the more potent synthetic opioids that drive the current epidemic," they said. 

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