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New weapon against opioid abuse?

May 4, 2017

What if local anesthesia didn’t wear off after surgery? Or at least not for three or four days. That’s a concept Heron Therapeutics is moving into Phase 3 trials this year, with its long-acting and potentially opioid-sparing formulation.

Based in San Diego, California, Heron’s journey started back in the 1990s with a chemistry company called Advanced Polymer Sciences. The company worked on a range of polymers and applications, explained CEO Barry Quart in a recent phone interview.

“Then at some point, they came across a very interesting polymer that could be used to deliver drugs at a defined rate,” Quart said. “So you could take a short-acting drug and turn it into a long-acting drug, and deliver it over a day or several days, or even longer.”

The company pivoted to focus on the application of this so-called ‘Biochronomer’ technology in drug development, rebranding as AP Pharma in the late 1990s.

Sustol soon emerged as its lead candidate. The therapy was a sustained release version of Granisetron, which is widely used to treat nausea and vomiting associated with chemotherapy. The downside with the existing drug was that the effects wore off after the first day. By incorporating it into the Biochronomer polymer matrix, doctors could treat patients for the full five days that side effects usually persist, Quart said.

AP Pharma advanced the drug, rebranding as Heron Therapeutics in August 2013. After several false starts, Sustol was eventually approved by the FDA and launched in October 2016.

As the drug neared the FDA finish line, Heron’s team turned their attention and resources to other therapeutic candidates. Where else could the Biochronomer technology succeed?

“The first place we looked was putting a local anesthetic into the polymer matrix so that you could put the product into a surgical incision and have the polymer release the local anesthetic for three, four days, resulting in a reduction in the amount of pain the patient would experience after surgery.”

That program became HTX-011, a longer-acting version of the generic painkiller bupivacaine. Before long, Heron hit a roadblock. The problem, Quart explained, was that the environment around surgical wounds becomes acidic as part of the healing process. That acidity interfered with the drug. Inflammation can also prevent the drug from penetrating the local nerves.

“So even though it’s there and getting released, the anesthetic isn’t working,” he said.

After some trial and error, the team arrived at a workable solution. Meloxicam, a common nonsteroidal anti-inflammatory drug (NSAID), was added to the mix to dampen the inflammation and subsequent acidity. Extensive testing was performed in animal models and then in clinical trials to confirm that the healing process wasn’t impacted. In terms of pain, Quart said the two drugs provide synergistic benefits.

Heron’s Phase 2 clinical trial focused on bunion and hernia surgeries. For the latter, Quarts said there are one million operations performed each year. On average, a patient is sent home with a prescription for 30 opioid pills. Based on the Phase 2 trial, HTX-011 appears to significantly reduce the need for opioidsby 30-50 percent. Patients could be sent home with perhaps five pills, he said, as a backup pain relief option.

“Just imagine that multiplied by 30 million procedures a year where patients have a lot of pain and receive opioids,” Quart said. “That works out to, shockingly, approximately 900 million opioid pills that are dispensed annually for those surgical procedures. And that’s a low estimate. There’s an opportunity for a dramatic reduction in the number of opioid pills in society.”

Of note, patients who received HTX-011 were able to control their pain much better than those taking a placebo and self-medicating with opioid pills. There’s a common misconception that opioids completely remove the pain, Quart said, which isn’t true. Part of the problem is that it’s treating pain in the brain, not at the site of the injury where the nerves are being impacted.

If it reaches the market, HTX-011 will go head-to-head with Pacira Pharmaceuticals’ Exparel, a bupivacaine liposome injectable suspension. In other words, it’s a long-lasting form of bupivacaine, similar to what Heron is trying to achieve. However, Quart believes that the product is limited without the addition of an anti-inflammatory drug.

“It shows activity in reducing pain and opioid use but that activity is really concentrated in the first 12-24 hours. What we’ve found is that in order to get significant benefits on the second or third day, even the fourth day, you have to deal with the inflammation as well,” Quart said.

Depending on the type of surgery and the individual, HTX-011 shows efficacy for approximately 96 hours.

A drawback for both bupivacaine formulations is that the body eventually absorbs the drugs. When it enters the bloodstream it can have side effects at high doses. While that limits the dose that can be given locally, Quart said the reliability of the Biochronomer technology allows the team to tightly control the levels to strike the right balance between benefit and risk.

In terms of timeline, Heron is looking ahead to an end-of-Phase 2 meeting with the FDA. From that, the team will initiate a pivotal Phase 3 trials, in the hopes of submitting an NDA in 2018.

“I think it’s been made very clear by both the previous commissioner, Califf, and the incoming commissioner that dealing with the opioid epidemic is their number one priority at the FDA. We’re hopeful that because this is such a high-profile issue and because we have a product that can reduce opioid use by 30-50 percent, that we will, in fact, be on an easier, faster path,” Quart said, though he noted that they are only now moving into Phase 3 trials, which is when those kinds of decisions are typically made.

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