Novel Peptide Drugs Offer Extended Pain Relief

October 19, 2021

By Deborah Borfitz

October 19, 2021 | University at Buffalo (UB) researchers plan to commercialize a platform for site-of-injury pain relief that targets nerve endings, the starting point of pain signaling, using lipidated peptides (peptides modified with lipid molecules) that prevent overexcitement of pain neurons. “Our peptides will never cross the blood-brain barrier, so addiction is never going to be a problem,” says Arin Bhattacharjee, Ph.D., associate professor of pharmacology and toxicology and cofounder of the startup Channavix focused on bringing non-opioid drugs to market.

Peptides are generally thought to be poor drug candidates because of their tendency to rapidly metabolize in the body, he says. But lipidated peptides, once inside the nerve endings, are remarkably stable, providing long-lasting pain relief after a single administration—up to three weeks of analgesia for arthritic pain.

In an article recently published in Nature Communications (DOI:  10.1038/s41467-021-26100-6), where the novel therapeutic approach was demonstrated on both a chronic pain model and a postoperative pain model, acute and chronic pain-like behaviors were significantly reduced for up to six days. At that point in these models, pain is generally self-resolving, Bhattacharjee notes.

The lipidated peptides achieve pain relief by blocking endocytosis, the process in which substances are brought inside the cell, he explains. So, while prostaglandins produced at the injury site are sending out signals to the pain-sensing neurons, those nociceptors can’t change their electrical activity to report the injury to the brain.

An endocytosis subunit called AP2α2, which is found exclusively in calcitonin-gene related peptide (CGRP) pain neurons, is what gives the local treatment approach its specificity, continues Bhattacharjee. “We only affect those neurons.”

Specific potassium channels become endocytosed in these CGRP nociceptors, blocking their endocytosis and thereby their activity. These CGRP nociceptors are responsible for inflammation-induced ongoing pain.

CGRP neurons are found throughout the body and are responsible for chronic migraine headaches—another target of the lipidated peptide platform, Bhattacharjee says.

Clinical Need

An alternative to opioids is desperately needed. According to the Centers for Disease Control and Prevention, overdose deaths involving opioids increased more than sixfold since 1999. In 2019, overdoses involving opioids killed nearly 50,000 people. The central problem is that opioids get into the brain and “hijack” the reward pathway to create addiction and, frequently, subsequent death from major respiratory depression, says Bhattacharjee.

The advantage of locally applied anesthetics, such as Novocaine, is that they have few adverse effects, including the potential for addiction. But, in addition to lacking specificity, this therapeutic approach has a short duration of action. “When the anesthetic wears off, you need pain relief and dentists sometimes have to give narcotic prescriptions, [contributing to] the opioid crisis,” Bhattacharjee says.

Opioids are now dispensed more sparingly by physicians, who might instead recommend patients first try taking alternatives such as ibuprofen. While ibuprofen is a good pain killer, he says, it can’t be taken over the long term or patients run the risk of developing a bleeding ulcer. Ibuprofen works by preventing the production of prostaglandin, which keeps damaged tissue from talking to pain-sensing nerves but also leaves the stomach vulnerable to excess acid production.

Oral drugs used for chronic pain relief can be dangerous because they impact the entire body. Patients who suffer from prolonged pain will in any case do whatever it takes to ease their suffering, says Bhattacharjee.

Current clinical practices include injecting steroids into arthritis joints, which can have detrimental side effects with extended use, he notes. Among people with osteoarthritic knees, repeated steroid injections over two years appears to speed the loss of the cartilage that cushions the knee joint, according to a 2017 study published in JAMA (DOI: 10.1001/jama.2017.5283).

Bhattacharjee believes peptide injections could one day replace, or at least be additive, to steroids for arthritic pain relief. They could also become an alternative to injections of Botox or CGRP-targeting drugs to address migraine pain.

Commercialization Plans

Channavix launched in 2018 by Bhattacharjee and Elsa Daurignac, a UB neuroscientist in the department of psychiatry, to commercialize the lipidated peptide platform and meet the criteria for small business grants from the National Institutes of Health (NIH). The company is in the process of raising venture capital to conduct toxicology and formulation studies to enable a new Investigational Drug Application (IND) from the Food and Drug Administration (FDA) for human testing.

The university is the patent holder, but the company is working on licensing the AP2α2-targeting peptide, he says. Channavix was already granted the license for another peptide targeting sodium channels. A third target has recently been identified.

Peptides serve as a “decoy” that can potentially block a whole host of pain-signaling processes, Bhattacharjee says. The possibilities are immense—as is the market for such products.

The target U.S. annual estimated market potential is $69.18 billion, he reports. Arthritic pain alone is predicted to affect up to 80 million people by 2025. With another 80 million surgeries being conducted annually, postoperative analgesics likewise account for a large share of the commercial demand for such products.

Clinical Trials

Clinical trials with the lipidated peptides will be relatively easy since pain is typically assessed on a 1-to-10 pain rating scale using emojis, says Bhattacharjee. The clinical centers needed to do studies are also ubiquitous because pain is the primary reason people see their doctor.

If all goes well, the company’s first FDA-approved product could be in clinical use in as soon as four years, Bhattacharjee says.

Local delivery of the peptides at pain nerve endings reduces the risk of side effects, which is a key reason new drugs fail to get FDA approval, Bhattacharjee says. Adding a lipid on a peptide increases its half-life, and free-floating peptides that get into the blood quickly disappear.

The same concept applies to mRNA COVID-19 vaccines—only a bit of RNA gets in the muscle to produce a spike protein for immune response and the rest of the RNA rapidly degrades, he points out. Side effects are generally a result of how people respond to the spike protein.

Sex-Specific Responses

The widely prescribed diabetes medications Trulicity and Ozempic are both lipidated peptide drugs that need to be administered through daily to weekly injections, says Bhattacharjee. Early indications are that lipidated peptides under development by the UB team could provide pain relief for at least three weeks. 

Differences in how males and females experience pain has also been seen. With chronic established pain, female rats tend to have a delayed response to treatment relative to their male counterparts, he says.

When it comes to postoperative pain, females respond much better to treatment than males provided researchers “nipped it in the bud,” he says, drawing a comparison with women who preemptively treat their menstrual pain starting the day before their period. Opioids also don’t work as well in managing postoperative pain in females, highlighting the importance of prophylactic pain relief prior to surgery.

“The key reason we have not been able to develop a really good pain drug is for years scientists only studied male [rodents],” says Bhattacharjee. As he and his UB colleagues have underscored, understanding how both sexes respond to pain treatment is a critical consideration in analgesic development.

Channavix hopes to partner with several contract research organizations (CROs), such as Charles River Laboratories, for the IND-enabling studies, Bhattacharjee shares. CRO assistance will also be sought for manufacturing of the peptides and ensuring adherence to good laboratory practices, with expected support from the NIH HEAL Initiative.