To enter the downtown San Francisco lab space that houses their Nebraska-born biotech startup company, Neurocarrus, Paul Blum and Benjamin Pavlik often pass a collection of people who Blum described as “falling apart from overdose”. The lab is located below a methadone clinic.

“We see the effects of drug addiction and mental illness every single day,” said Arvind Gupta, the founder of IndieBio, an incubator which has invested $250,000 in seed funding and lab space for Neurocarrus because he believes the co-founders might offer a partial solution to a national crisis.

Over the past seven years, Blum and Pavlik have been developing a drug designed to treat the kind of severe and chronic pain frequently treated with opioids. But their drug is missing something – the high.

“I think what our drug could do is make some significant contributions to [combating] the opioid epidemic, and I think that our drug may do a better job to relieve pain than opioids,” said Blum, a University of Nebraska-Lincoln biology professor.

The drug, named N-001 for now, is designed to avoid detrimental side effects of opioid use, addiction among them.

Opioids dull pain in part by binding to opioid receptors found in regions of the brain that not only govern perception of pain, but also pleasure. They also act on receptors found in the brainstem, causing further reduction of pain, but also respiratory depression. For those who become addicted to opioids, and take larger and larger doses to chase the high, that restricted breathing is a key contributor to overdoses.

“That epidemic is getting worse,” Blum told potential investors at an IndieBio demo day event held this week. “Almost five people die every hour in America because they overdose on prescription medications.”



Q&A Why is there an opioid crisis in America? Show Almost 100 people are dying every day across America from opioid overdoses – more than car crashes and shootings combined. The majority of these fatalities reveal widespread addiction to powerful prescription painkillers. The crisis unfolded in the mid-90s when the US pharmaceutical industry began marketing legal narcotics, particularly OxyContin, to treat everyday pain. This slow-release opioid was vigorously promoted to doctors and, amid lax regulation and slick sales tactics, people were assured it was safe. But the drug was akin to luxury morphine, doled out like super aspirin, and highly addictive. What resulted was a commercial triumph and a public health tragedy. Belated efforts to rein in distribution fueled a resurgence of heroin and the emergence of a deadly, black market version of the synthetic opioid fentanyl. The crisis is so deep because it affects all races, regions and incomes

Pavlik said that the years-long process of developing N-001 has been driven by the lack of treatment alternatives to the opioid.

“Doing drug development is one of the hardest things that there is,” he said. “That’s one of the things that keeps me going. There’s all these people out there, and there’s so much suffering in the world.”

A growing number of companies and researchers are seeking to produce a challenger to, or a less addictive version of, opioids. There are multiple efforts to develop drugs that target the brain’s cannabinoid receptors, with the intent of providing pain relief on par with marijuana use, but not the high associated with it or opioids.

Biopharmaceutical company Nektar Therapeutics recently touted hase III trial results of an opioid with low blood-brain barrier penetration, “designed to provide potent pain relief without the inherent high levels of euphoria which lead to abuse and addiction with standard opioids”. Those methods are, like doses of oxycodone, hydrocodone and fentanyl, systemic treatments, exposing tissue throughout the body and brain to their effects due to their presence in the bloodstream.

Unlike those, N-001 is a localized treatment, Blum said, designed to target pain at its source via an injection or a topical solution. (Their drug, unlike the nearly 215 million opioid prescriptions written for Americans in 2016, would not come in pill form.) The Neurocarrus drug would not breach the blood-brain barrier as opioids do, Blum said. The company’s slogan is: “Treat the pain, not the brain.”

To create their drug, Pavlik and Blum found inspiration in a wrinkle-reducer. While getting his PhD at the University of Nebraska-Lincoln, Pavlik researched proteins, and how they can be manipulated to serve vital functions.

N-001 developed from interest in a specific kind of bacterial protein found in a toxin class called Clostridium botulinum. The protein is highly effective when it comes to delivering information into a cell. Botulinum toxins, though among the most poisonous biological substances, have proved useful in treating an array of medical conditions, including migraines and spastic movement disorders, by causing muscle paralysis. It also brought us Botox.

“Both Ben and I were tuned into Botox,” Blum said. “It’s an injection, and people get it and it freezes motor neurons. What if we could do that to sensory neurons? That was the gee-whiz moment. And then we came up with a way to do it.”

The drug binds to sensory neurons, enters the cells – “None of the other drugs do that,” Blum said – and deposits a payload that quiets much of the electrical noise that pain produces in the peripheral nervous system.

“We’re trying to develop a drug that locally turns down pain signals in order to prevent them from ever being transmitted to the brain,” Pavlik said. “And that will be useful for lots of localized, painful conditions.”

Since publishing promising in vitro test results in a 2016 Scientific Reports journal article, N-001 has been tested in animals, with mice receiving either injections of the experimental drug or an opioid. Blum said the mice that received N-001 showed signs of pain control that wore off after three days, compared to about one day for the mice in the control group that received an opioid dose. And, he said, the mice given N-001 showed no loss of muscular control.

They hope to begin US Food and Drug Administration-approved testing in humans by the end of 2019. They’re preparing to test it on people suffering from osteoarthritis.

Neurocarrus has received funding and recognition in the form of an award from the National Institute on Drug Abuse, which in February awarded it $10,000, saying the startup shows promise in furthering an understanding of substance use disorders. Now, the two are working on a sales pitch to venture capitalists with deeper pockets.

After graduating from Nebraska last year, Pavlik headed west to begin the four-month accelerator program at IndieBio along with a group of 13 other biotech startup founders. This week, the duo pitched Neurocarrus to a theater full of potential investors at a demo day.

The results of their pitch efforts will likely guide their next steps.

“I think we’re in a position to do a lot of good for people, and society,” he said. “The road is long and difficult, and I think that we’re a team to take this thing forward because we both believe in the mission, and it’s as simple as that.”