In San Francisco, United States, it is easy to spot individuals stumbling through the streets, behaving like zombies. These so-called “drug zombies” have become addicted to fentanyl, a painkiller prescribed by doctors. The misuse and illegal distribution of this highly addictive opioid painkiller have caused serious social problems.
Many major pharmaceutical companies have attempted to address the severe side effects of opioid painkillers by developing non-opioid alternatives but have faced repeated failures. However, a South Korean firm, Vivozon Pharmaceutical, has achieved a breakthrough. Last month, the Korea Ministry of Food and Drug Safety approved the nation’s 38th novel drug, Unafra injection.
Unafra, with the active ingredient opiranserin hydrochloride, is an injectable medication developed for managing moderate-to-severe acute pain following surgery. It works through a different mechanism than existing opioid or non-steroidal anti-inflammatory painkillers. Moderate-to-severe pain includes post-surgical pain, accident-related pain, third-degree burn pain, neuropathic pain (where normally non-painful stimuli are perceived as painful due to nervous system abnormalities), and cancer pain.
Until now, opioid-based drugs were the only option for treating this level of pain. However, they come with serious side effects, such as high addiction potential and tolerance. As tolerance builds, the same dose becomes ineffective, often requiring increased dosages, which can lead to overdose and fatalities.
In an interview with ChosunBiz at Vivozon’s office in Seoul on Jan. 7, Vivozon Chairman Lee Doo-hyun said, “Unafra is the world’s first multi-receptor-targeted non-opioid painkiller and the first non-opioid medication for moderate to severe pain. It has significant development potential in the global market.”
Lee, who holds a Ph.D. in biopsychology from Korea University, worked as a researcher at major pharmaceutical companies such as Amgen, Johnson & Johnson, and Eli Lilly from the late 1990s through the 2000s, participating in painkiller development. He concluded that the failure of large pharmaceutical companies to develop non-opioid painkillers was due to their focus on drugs targeting a single receptor. In simple terms, pain is caused by multiple factors, and a drug targeting only one cannot effectively manage it.
He founded Vivozon to develop non-opioid painkillers targeting multiple receptors. Unafra injection shows pain control effects comparable to opioid painkillers, without the side effects of addiction or tolerance. The company reports virtually no side effects, except for nausea and vomiting.
According to the Korea Health Industry Development Institute (KHIDI), the global market for non-opioid painkillers is projected to reach approximately 100 trillion won by 2030. Vivozon Pharmaceutical is also developing an oral version of the non-opioid painkiller as a follow-up to the Unafra injection.
The company plans to develop VVZ-2471 as an oral pain treatment in Korea and as a drug addiction treatment in the United States. If successful, it could become a game-changer in the global painkiller and addiction treatment markets.
“VVZ-2471 is currently undergoing Phase 2 clinical trials,” Lee said. “It has shown effectiveness for substance abuse, including drug addiction, and we are working closely with U.S. addiction specialists to advance clinical development.” Below is a Q&A with Chairman Lee.
What motivated you to establish a company and embark on developing non-opioid painkillers?
“While working at U.S. pharmaceutical companies, there was an urgent need to develop new painkillers that could match opioids’ effectiveness without side effects like addiction or gastrointestinal bleeding, as problems with opioid and anti-inflammatory painkillers emerged. Despite advancements in genetic engineering and molecular biology that uncovered numerous pain-related genes and receptors, many pharmaceutical companies failed in drug development. I also led several studies over 10 years but faced repeated failures. We identified a pivotal factor behind our earlier setbacks. At the time, the prevailing approach in drug development prioritized designing treatments targeting a single receptor. However, pain management is inherently complex, involving multiple mechanisms that cannot be effectively addressed by drugs with a singular focus. This insight led us to recognize the need for a drug capable of simultaneously targeting multiple receptors. In pursuit of this goal, we developed an innovative methodology to rapidly screen potential compounds using electrophysiological techniques. I presented this concept to Professor Jung Kyung-woon from the Department of Chemistry at the University of Southern California (USC). Professor Jung not only endorsed the idea but also encouraged me to establish a company to advance this research. In 2008, I returned to South Korea and founded Vivozon. During its formative years, Professor Jung played a crucial role in securing approximately 3 billion won (around $2.1 million) in funding over three years.”
How was Opiranserin discovered?
“In 2008, following the establishment of Vivozon, the team spent approximately six months developing an electrophysiological screening method. Collaborating with Professors Lee Eun and Lee Chul-beom from Seoul National University’s Department of Chemistry, they synthesized compounds targeting glycine transporter 2 and initiated screening processes. When activating glycine transporter 2 alone proved insufficient to achieve the desired efficacy, the team continued synthesizing compounds to identify the most promising therapeutic candidates. Within a year, they successfully developed opiranserin, a compound targeting both glycine transporter 2 and the 5-HT2A receptor. While neither compound demonstrated pain-relief effects individually, animal studies revealed a highly potent analgesic effect when the two were combined. This breakthrough ultimately led to the decision to advance the development of opiranserin.”
Was there government support for the project?
”Yes, there was. In 2011, we were selected for the Ministry of Health and Welfare’s new drug development support program, specifically for the non-clinical division, which facilitated the initial stages of non-clinical development. By 2013, we were also chosen for the clinical Phase 1 division, enabling us to seamlessly advance to Phase 1 clinical trials. Later, in 2016, we were selected for the global Phase 2 clinical trials program, paving the way for clinical development in the U.S. Overall, we received approximately 78 billion won ($5.33 million) in government funding.”
How much funding was required from development to approval?
”Altogether, around 780 billion won ($53.29 million) was invested, including government support. Approximately 80% of this amount was dedicated to global development initiatives. Up to the Phase 2 clinical trial stage, roughly 200 billion won was spent. For clinical development in the U.S., the investment amounted to around 500 billion won. However, progress in the U.S. was significantly disrupted by the COVID-19 pandemic, which began in early 2020. To address these delays, we expedited Phase 3 trials in South Korea, initiating them in July 2021. These trials were conducted under an exclusive implementation license granted to Vivozon, requiring an additional 80 billion won investment to date.”
What were the major challenges?
“Securing funding was one of the greatest challenges. When the company was founded, investing in biotechnology was virtually unheard of in the domestic market. During the first three to four years, financial pressures were immense, forcing us to make tough decisions, including letting go of researchers who had been with us from the start. The turning point came when we were consecutively selected for the Ministry of Health and Welfare’s new drug development support programs, which attracted private investors and allowed us to advance clinical development. By 2017, we had successfully raised 100 billion won ($68.32 million) through a shareholder allocation paid-in capital increase.
The COVID-19 pandemic presented another significant hurdle, with Phase 3 clinical trials in the U.S. being suspended twice, leading to considerable financial losses and delays. While we managed to conduct Phase 3 trials in South Korea, progress in the U.S. came to a standstill, further straining resources. Compounding the situation, the ongoing war in Ukraine has worsened global economic conditions, making it even more challenging to secure investments.”
Despite these challenges, the new drug has been commercialized. What are the plans for entering international markets, including the U.S.?
”In the U.S., Vivozon plans to secure funding before resuming clinical trials, a process that is expected to take at least three years. Meanwhile, outside the U.S., Vivozon is actively pursuing export opportunities and technology transfer agreements. With domestic marketing approval already in place, discussions on exports and technology transfers are expected to progress rapidly.”
There is also news about the development of a non-opioid painkiller in pill form. Could you elaborate?
”We are currently developing VVZ-2471 as an oral medication. Unlike Unafra, which is injectable, this oral formulation offers greater convenience for long-term use. VVZ-2471 is currently in Phase 2 clinical trials, with results expected later this year. Notably, the drug has demonstrated potential efficacy in treating substance abuse, including opioid addiction. We are collaborating with addiction specialists in the United States and have applied for research funding from the National Institute on Drug Abuse (NIDA), a division of the National Institutes of Health (NIH). The proposal received strong evaluations during the initial review, and we anticipate steady progress in its development as a treatment for opioid addiction.”
