Vertex Pharmaceuticals

New non-opioid pain reliever moves closer to approval

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In clinical trials, it significantly reduced patients’ pain after surgery.

Vertex Pharmaceuticals’ new painkiller significantly reduced moderate-to-severe pain in two phase 3 trials — suggesting it could be the new, non-addictive pain reliever we’ve been waiting for.

The challenge: Pain is the most common reason people seek out medical care, and while there are seemingly infinite causes of pain — from migraines and broken bones to infections and nerve disorders — we have very few options for treating it.

Over-the-counter meds, like ibuprofen and aspirin, are safe and easily accessible, but they are only effective for mild pain. Prescription opioids, like oxycodone and morphine, meanwhile, are highly effective, but they also cause a “high” that can be addictive and lead to misuse.

The new painkiller ​​led to a “clinically meaningful” reduction in pain in the 48 hours after the surgery.

Bocking pain’s pathway: A new painkiller that’s highly effective, but non-addictive is one of the holy grails of medicine, and the search for it has led Vertex Pharmaceuticals to a class of drugs called “sodium channel modulators.”

These medications act on a group of proteins that are involved in pain processing. Vertex is developing a drug, called VX-548, that it hopes will interfere with one of those proteins in a way that relieves pain, without any euphoric or addictive side effects.

What’s new? On January 30, Vertex shared the topline results of two phase 3 trials of its new painkiller as a treatment for moderate-to-severe acute pain (“acute” pain is usually defined as coming on suddenly, like from an injury or surgery, and lasting less than six months, while “chronic” pain develops gradually and lasts longer).

The trials involved a total of about 2,200 participants who were given either VX-548 or a placebo after undergoing abdominoplasty surgery (a “tummy tuck”) or surgery to remove a bunion from their foot. 

According to Vertex, the new painkiller ​​led to a “clinically meaningful” reduction in pain in the 48 hours after the surgery. It did not, however, meet its secondary endpoint: delivering more pain relief than a combination of the opioid drug hydrocodone (Vicodin) and acetaminophen (Tylenol).

Vertex also shared the results of a third phase 3 trial in which 256 people experiencing acute pain for a variety of reasons received VX-548 for up to 14 days. 

The drug was safe and well tolerated in that trial, leading to only mild-to-moderate adverse effects. About 83% of the participants rated the new painkiller as being “good,” “very good,” or “excellent” at treating their pain.

Looking ahead: There’s no word on when Vertex plans to publish the full trial results, but the company has said that it hopes to apply to the FDA by mid-2024 to get the medication approved to treat moderate-to-severe acute pain.

“For years, our goal has been to make a medicine with clinically meaningful pain relief for moderate-to-severe acute pain, with a safety and tolerability profile that’s better than an opioid,” David Altshuler, Vertex’s chief science officer, told BioPharma Drive. “We will file for approval with urgency.”

Vertex isn’t limiting itself to acute pain, though — an estimated one in five adult Americans lives with chronic pain, and a phase 3 trial of the new painkiller for long-lasting pain due to nerve damage from diabetes is ongoing.

Cell-suicide blocker holds promise as HIV therapy.

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NIBSC/Science Photo Library

Immune cells (green) infected with HIV (pink) undergo a cell-suicide process known as pyroptosis.

HIV infection causes a mass suicide of immune cells — a process that can be halted by an experimental drug that blocks cellular self-destruction, studies in cell cultures suggest. Researchers are now proposing a clinical trial of the drug in people with HIV.

Current HIV therapies act by targeting key proteins made by the virus. But findings from cell cultures, published today in Science1 and Nature2, suggest that targeting proteins in host cells might be an alternative approach to preserving the immune system in the face of an HIV infection.

The papers also address a decades-old mystery: why infection-fighting immune cells die off in people with HIV. A 2010 study3 showed that HIV does not directly kill most of these cells, called CD4 cells. Instead, the cells often self-destruct. “It’s much more a suicide than it is a murder,” says Warner Greene, a molecular virologist at the Gladstone Institute of Virology and Immunology in San Francisco, California, and a co-author of both the latest works.

Ring of fire

In the latest studies, Greene’s team investigated these ‘abortive’ infections. They identified a sensor that detects viral DNA in the cell and activates the suicide response1. And they found that most of the cellular suicide occurs via a process called pyroptosis, in which the dying cells unleash a ferocious inflammatory response2. A key protein involved in pyroptosis is caspase 1, and an experimental caspase-1 inhibitor made by Vertex Pharmaceuticals in Cambridge, Massachusetts, had already been tested in humans as a potential treatment for epilepsy. The drug, VX-765, failed to help epileptics, but six-week-long studies suggested that it was safe.

Greene and his colleagues tested VX-765 in HIV-infected cells cultured from human tonsils and spleens, and found that it blocked pyroptosis, prevented CD4 cell death, and suppressed inflammation. Greene hopes that the approach could one day provide an alternative or embellishment to the antiretroviral drugs currently used by 9.7 million people worldwide to manage HIV infection.

Because a caspase-1 inhibitor would target a host protein rather than the virus, HIV is less likely to become resistant to the therapy, says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. But any new HIV therapy will face steep competition from the more than 30 antiretroviral drugs currently available. “You’ve got to be pretty good to replace the antiretrovirals,” says Fauci.

Self-sacrifice

Understanding why HIV infection kills CD4 cells is an important step for researchers, says Gary Nabel, chief scientific officer at Sanofi, a pharmaceutical company headquartered in Paris. “We need to understand when a cell would rather die than let a virus infect it, and how the virus can evade that cellular suicide response to infection,” he says.

But Nabel also urges caution. He worries that some of the infections that Greene and his team consider abortive may progress if the immune cells survive. “Preventing cell death is a double-edged sword in the context of HIV,” he says. “Death can be protective if a T cell says ‘I’m going to die before I let this virus replicate and spread to other cells.’”

Greene counters that his team looked for evidence of progression to active infection, and found none. “Pyroptosis is not a strategy to protect the host from productive infection,” says Greene. “Instead, this is a pathway that actually promotes clinical progression to AIDS.”