New painkiller could benefit millions of patients without risk of addiction

Samantha Mash

Author: Duan Yuechu and Huang Yanhong

In today's society, pain problems plague many people, especially chronic pain, which brings great pain and inconvenience to patients' lives. However, with the continuous advancement of medical research, the emergence of a new type of painkiller has brought new hope to pain patients.

Recently, Scientific American magazine published an article titled "New painkiller expected to benefit millions of patients without risk of addiction", which attracted widespread attention. The author of this article is Marla Broadfoot, a senior writer focusing on the science field. She has a doctorate in genetics and molecular biology, which enables her to explain complex medical research results in a simple way so that ordinary readers can understand the mysteries.

The new painkiller mentioned in the article was originally called VX-548. Its development stems from scientists' in-depth research on the mechanism of pain. There are a large number of pain signal nerve cells in our body. They are like a sophisticated alarm system, always monitoring external stimuli. When the body is threatened by high temperature, sharp objects or harmful chemicals, these nerve cells will quickly generate electrical pulses, transmit pain signals along nerve fibers to the dorsal root ganglia next to the spinal cord, and then transmit them to the brain, so that we feel pain. In this process of pain transmission, sodium channels play a key role. It is like a "gate" on the cell membrane of nerve cells, controlling the entry and exit of sodium ions, thereby generating nerve impulses.

As early as about 20 years ago, scientists discovered the close connection between sodium channels and pain diseases. For example, in a family in China, researchers discovered a rare disease called erythromelalgia (commonly known as "man in fire" syndrome), the cause of which is a mutation in the SCN9A gene. The NaV1.7 sodium channel encoded by this gene is abnormal, causing pain signal neurons to be overactive, and patients will suffer from severe pain like being burned by a blowtorch even when slightly heated. In a young fire walker in Pakistan, scientists found the opposite situation. A gene mutation in his body caused the NaV1.7 channel to be unable to transmit pain signals normally, allowing him to walk on burning charcoal without pain. These discoveries have allowed the pharmaceutical industry to see the direction of developing new painkillers. Many pharmaceutical companies have invested a lot of money and manpower to try to develop drugs that can accurately block NaV1.7 channels, but unfortunately, many compounds that seem promising in the laboratory have failed in clinical trials.

While many pharmaceutical companies are stuck in research and development, Vertex Pharmaceuticals has taken a different approach. They believe that the compounds tested previously were either not selective enough or could not attach to the sodium channel for a long time, so they decided to continue exploring in depth. In order to speed up this process, Vertex researchers have developed a technology system called E-VIPR (Electrically Stimulated Voltage Ion Probe Reader). The system uses a high-density array of cells, each of which expresses a specific type of sodium channel. These channels are stimulated by electric fields generated by tiny electrodes up to 100 times per second. When the channel opens, a voltage-sensitive dye changes from orange to blue, and this color change is captured by precision optical detection tools, allowing a large number of compounds to be quickly and accurately tested for their effects on sodium channels.

With this advanced technology, Vertex conducted extensive and in-depth testing of various sodium channels, and gradually focused on the NaV1.8 channel, while the entire industry was mainly focused on the NaV1.7 channel. After years of hard work, they finally developed VX-548, a NaV1.8 inhibitor. In January 2024, Vertex announced the positive results of two large-scale key clinical trials, which undoubtedly injected a shot in the arm for the field of pain treatment.

In both trials, researchers enrolled about 1,100 patients who were undergoing bunionectomy or abdominal plastic surgery, two common models for simulating acute pain. Patients were divided into three groups and received placebo, VX-548, or a combination of hydrocodone (an opioid) and acetaminophen (Vicodin). The results showed that VX-548 performed as well as Vicodin when assessing pain relief using a 0-10 pain scale, but without the risk of addiction. Specific data showed that both treatments reduced patients' pain scores from about 7 to about 4, and that VX-548's analgesic effect took effect faster in patients recovering from abdominal surgery. In addition, when assessed using another pain scale, VX-548 was slightly less effective than Vicodin in analgesic treatment for bunionectomy patients, but patients taking VX-548 reported significantly fewer side effects (such as nausea, constipation, headache, and dizziness) than those taking placebo, indicating that the drug is generally safe.

This research result also has important potential significance for patients with chronic pain. Although VX-548 has been tested mainly in patients with acute pain, scientists at Vertex believe that the underlying mechanisms of chronic pain and acute pain are similar, so the drug is expected to bring good news to patients with chronic pain. In fact, the company has achieved positive results in small-scale efficacy and safety trials for diabetic peripheral neuropathy (a common chronic pain caused by high blood sugar) and plans to conduct phase 3 clinical trials. In addition, they have also conducted separate studies on a chronic low back pain called lumbar radiculopathy, and have used their drug development platform to continuously optimize compounds to make them more potent and selective. For example, they have developed the next-generation NaV1.8 inhibitor VX-993 and are advancing to phase 2 clinical trials.

This research result has attracted widespread attention and discussion in the field of pain treatment, and many experts and scholars have given it high praise. Although Stephen Waxman, a neurologist at Yale University, did not participate in Vertex's clinical trials, he has been paying attention to the study of pain signals. He believes that although the current effect of VX-548 is relatively mild, its importance cannot be underestimated, and even calls it a "game changer." He pointed out that this achievement will change the entire landscape of pain research, just like the development of statins. Although the initial statins were not perfect, they laid the foundation for the subsequent development of more effective drugs, and VX-548 is also expected to pave the way for the development of more efficient and safer analgesics in the future.

Sean Harper, who once led research and development at biopharmaceutical giant Amgen, also praised Vertex's achievements. He recalled the difficult situation in 2017 when the White House declared the opioid crisis a public health emergency, when the entire pharmaceutical industry was almost stagnant in the development of new pain drugs, and Vertex's success gave people new hope. Inspired by this, he co-founded Latigo Biotherapeutics with other investors to develop sodium channel inhibitors. He believes that Vertex's research results will attract more companies to join the research and development in this field and promote the development of the entire industry.

Although only a few companies have publicly stated that they are developing pain treatment drugs targeting NaV1.8 or NaV1.7, it is foreseeable that with the success of Vertex, more companies will join in. For example, Merck's patent activity shows that it may be involved in this field, and some other companies may be encouraged to join this research and development race. These companies have adopted different research and development strategies. Some are committed to designing small molecules to block sodium channels or proteins near them, some try to modify natural toxins to block the transmission of pain signals, and some use gene therapy to reduce the generation of pain signals from the root.

Among the many R&D companies, Latigo Biotherapeutics is a rising star in this field. In February 2024, the company was established in California and received $135 million in funding. Its NaV1.8 inhibitor LTG-001 has entered Phase 1 clinical trials. Harper, the company's founder, said that at first they focused on both NaV1.7 and NaV1.8 targets, but after seeing that Vertex's drugs achieved positive results in both acute and chronic pain models, they decided to focus on NaV1.8 and prepare to test several other small molecule drugs. He believes that when a company like Vertex brings a brand new drug into the clinical trial stage, it often attracts many other companies to follow up, and the competition will become more intense.

In addition, Regulonix, a spin-off company of the University of Arizona, insists on targeting NaV1.7, but uses a different approach from the past. They try to remove NaV1.7 from the cell membrane, thereby reducing the number of sodium ions entering the cell and achieving an analgesic effect. Khanna, co-founder of the company and a professor at the University of Florida, said that their early versions of the compound have successfully affected NaV1.7 signaling in acute and chronic pain models in rats, mice, and pigs, but there is still a long way to go before human trials.

SiteOne, founded by Stanford University scientists, took another unique approach. They took sodium channel blockers that exist in nature (such as tetrodotoxin, which is deadly to pufferfish) and modified them so that they can precisely block sodium channels that are mainly present in pain-sensing neurons. In 2022, the company partnered with Vertex to develop therapeutic candidates for NaV1.7, and also received additional funding from the National Institutes of Health (NIH) to develop a NaV1.8 inhibitor called STC-004. The company's CEO Mulcahy said that in their experience, NaV1.7 inhibitors act like a "switch" for pain, while NaV1.8 drugs are more like a "dimmer" that can adjust pain more finely.

Navega, on the other hand, focuses on gene therapy, trying to reduce the formation of pain channels by reducing the activity of genes encoding sodium channels. While pursuing his doctorate at the University of California, San Diego, the company's founder, Moreno, developed a technology that uses CRISPR and its early gene editing technology zinc finger proteins to target genes that help build NaV1.7, achieving significant analgesic effects in rodent experiments. Since the company was founded, they have demonstrated that this approach is effective for many types of pain, including neuropathic pain, chemotherapy-induced pain, inflammatory pain, visceral pain, and arthritis pain, and are rapidly moving toward the first human trial. Moreno said that because their research results are long-lasting, they will focus on treating intractable pain, and plan to first test gene therapy in patients with rare diseases such as "man in fire" syndrome, whose pain is caused by known genetic mutations, and then consider more complex and large-scale clinical trials for chronic pain.

For chronic pain sufferers like Sara Gehrig of Wisconsin, the emergence of VX-548 is undoubtedly a new hope. Gehrig has long suffered from the severe pain of spinal stenosis. Over the years, she has tried various treatments, including physical therapy, anti-inflammatory injections and multiple surgeries, but none of them can effectively relieve the pain. Over-the-counter medications such as ibuprofen have little effect on her, and she is allergic to prescription opioids, which cause her to vomit violently. Her pain score is usually around 7 points, but sometimes it will soar to 9 or 10 points, which seriously affects her quality of life and even makes her have suicidal thoughts. Although Gehrig is cautious about trying new painkillers because she has suffered from the side effects of new drugs before, she is still full of hope that VX-548 can really relieve her pain without causing unbearable side effects.

However, we should also be aware that although VX-548 has shown great potential, it still has some limitations. For example, in clinical trials, some patients still feel obvious discomfort after using the drug, and current research is mainly focused on patients with acute pain. The therapeutic effect on chronic pain requires more clinical trials to verify. In addition, even if the drug is eventually approved for marketing, it does not mean that it can completely solve the problems of all pain patients. Pain treatment is still a complex and long process that requires comprehensive consideration of multiple factors, including individual differences in patients, the type and degree of pain, the side effects of the drug, and the patient's psychology and lifestyle.

In general, the successful development of VX-548 has brought new hope to the field of pain treatment. It has given us the possibility and hope of developing painkillers without the risk of addiction. But we also look forward to more research and clinical trials to further improve this drug. We also hope that other scientific research teams can make more breakthroughs in this field and bring truly effective treatments to millions of pain patients around the world, so that they can get rid of the pain and live a healthy and beautiful life again. This is not only the mission of medical research, but also a reflection of the care and responsibility of the entire society for pain patients.

In the future, with the continuous advancement of science and technology and the deepening of research, we have reason to believe that we will go further and more steadily on the road of pain treatment and make greater contributions to human health and well-being. Let us look forward to that day coming soon.

References:

New Painkiller Could Bring Relief to Millions—Without Addiction Risk｜Scientific American