A new medication by Vertex Pharmaceuticals has proven to be effective for post-surgical pain as the efficacy was exhibited in two small phase II clinical trials, according to a study published in The New England Journal of Medicine in early August.
Mark Wallace, a physician at UC San Diego’s division of pain medicine, said that these trials act as an early foray into an exciting new class of drugs in a difficult field with modest effects. The medication is now ready to undergo two phase III trials with 1,000 participants each, plus an open-label study with 250 participants.
With increasing cases of deaths associated with opioid overdose, The U.S. Department of Health and Human Services (HHS) officially declared opioid abuse as a public health emergency in 2017. With no effective and safe alternative to opioids, the result of the phase II trials has given better hope to the situation. The opioid epidemic continues to ravage the United States with about 50,000 people dying each year from overdose, and 10 million abusing the highly addictive medications annually.
“There is an immense unmet need for new pain medications, even without the opioid epidemic,” Stephen Waxman, a Yale neuroscientist, wrote an editorial supporting the recent NEJM study.
With a similar goal, Vertex, another key player, is also pursuing the same motive of providing a better cure for pain management associated with overdose of opioids due to chronic diseases such as cancer, while others are exploring different pain-blocking approaches. “There hasn’t been a new class of pain medicine in more than 20 years,” Vertex spokesperson Heather Nichols. He also said, “We believe we could redefine the treatment of pain with the first new mechanism of action in decades.” Meanwhile, other companies are trying to increase the safety factor of opioids themselves by removing their addictive aspects.
The research was performed by Vertex researchers on two distinct, repeatable sources of pain including bunionectomy (a type of foot surgery) and abdominoplasty (tummy tuck).
Both conditions require analgesic medication for acute, post-operative pain. The design allows for a patient pool, where a certain pain was activated by the same injury.
A bunionectomy trial was conducted, in which a total of 274 participants were enrolled, and 303 participants in the abdominoplasty trial. Participants rated their pain at 19 time points on a scale of zero (no pain) to 10 (the worst pain one can imagine). This led to an overall score known as sum of the pain-intensity difference, or SPID, a measurement the FDA recommends as a primary endpoint in acute pain trials.
However, a higher dose of VX-548 significantly exhibited improvement in comparison to a moderate dosage at 48 48-hour timestamp. Additionally, the high dose acted rapidly within the first hour of treatment. A minimum 30% reduction was recorded in patients in the score on the pain rating scale than the placebo, offered by the high dose of VX-548. Mild and temporary side effects were encountered in the patients, such as nausea, headaches, or constipation.
The new molecule is the result of decades of research into peripheral voltage-gated sodium channels, often referred to as NaV channels. These channels are found in sensory neurons outside the brain and are responsible for detecting painful or noxious stimuli. There are nine different types of voltage-gated sodium channels in the body (NaV1.1 to NaV1.9). Vertex’s new medication targets NaV1.8, which is expressed exclusively in sensory neurons of the peripheral nervous system and not the brain.
Moreover, there have been substantial concerns raised by researchers about the results associated with the length of trials and testing only small doses of acetaminophen/oxycodone.
“It wasn’t necessarily a home run, but it showed that blocking peripheral gated sodium channels does reduce pain, without central nervous system side effects and without addictive potential,” pointed Waxman. Waxman additionally exhibited his hopes for the gradual expansion of these findings toward effective treatments for chronic pain as well. Vertex is already conducting a Phase II trial on diabetic neuropathy, with a study completion date in the spring of 2024.
More key players in the market are now trying to innovate new treatments and therapies in pain management. “It’s been a race for the holy grail. In 2006, we established very clearly that NaV1.8 is a major controller of the repetitive firing of pain signaling in neurons and if you could block it, you would reduce pain,” commented Waxman.
Finland-based Orion Pharmaceuticals is trying to develop a non-opioid pain therapy, dubbed JMKX000623, that also blocks the NaV1.8 sodium channel. This therapy is in Phase I trials currently.
Virpax Pharmaceuticals' latest analgesics is a liposomal, long-acting, injectable formulation of bupivacaine, a potent local anesthetic, like lidocaine, which is meant to be used for pain management after a surgical procedure. Virpax is developing the formulation in collaboration with the U.S. Army, which is studying its potential in battlefield wounds. The company is also planning Phase I safety trials on two intranasal sprays, targeting pain centers in the brain, enkephalin, and a pharmaceutical grade cannabidiol.
Ensysce Biosciences, which is a biotech startup, has developed a novel chemistry that modifies how opioids are released when taken to make them safer.
The platform, called TAAP (trypsin-activated abuse protection), uses the body’s own digestive enzyme, trypsin, to trigger the release of the opioid. Recreational abuse would not result in effective outcomes such as crushing pills to be snorted or injected. The opioid is supposed to be activated in the presence of trypsin in the stomach only.
In addition, a tiny amount of trypsin inhibitor to every dose has been added for enhanced overdose protection. “If you take the prescribed amount, the amount of trypsin inhibitor is negligible, so nothing happens,” explained chemist Lynn Kirkpatrick, CEO at Ensysce Biosciences. “But if you take more than you should, there is enough inhibitor to shut down the activation.”
The company’s molecule is called PF614 and is currently in Phase II clinical trials and fast-tracked by the FDA. It is a prodrug of oxycodone, with a safety profile like other traditional opioids, but a 12-hour half-life once ingested, which is longer-acting than current opioids.
“We are talking to the FDA about Phase III plans,” stated Kirkpatrick. She also shared the possibility of submitting an NDA to the agency by 2025, if things go as planned.
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