Researchers convinced about the role of modulating tetrahydrobiopterin (BH4) synthesis in chronic pain may find solace in a new company after the first venture failed to take off.

Quartet Medicine Inc., of Cambridge, Mass., raised $17 million in a series A financing to push its BH4 program through proof-of-concept experiments. Similar work has been done by Solace Pharmaceuticals Inc., also of Cambridge, but the company retreated in early 2010 after its lead candidate – involving an entirely different approach – fizzled. (See BioWorld Today, Oct. 27, 2006, and May 1, 2007.)

Solace in 2009 launched a proof-of-concept trial of its orally administered glial cell modulator SLC022, licensed from Paris-based Sanofi SA, for pain in patients with post-herpetic neuralgia. At the same time, the firm was separately exploring BH4, though not so assiduously.

"The majority of their venture funding went into support what turned out to be a global phase II clinical study with the Sanofi asset, and unfortunately that did not show the desired effect," said Quartet CEO Kevin Pojasek. "When that data came out, they took the rest of the company down with it."

Quartet was co-founded in late 2013 by Pojasek while he was working as an entrepreneur-in-residence at Atlas. Joining him were Clifford Woolf of Harvard Medical School and Boston Children's Hospital, who also had been involved with Solace, and Swiss scientist Kai Johnsson of École Polytechnique Fédérale de Lausanne, who brought insights from both academic groups into BH4's role in chronic pain and inflammation.

The series A was led by Atlas Venture with Novartis Venture Funds, with Pfizer Venture Investment and Partners Innovation Fund joining as well.

In BH4, "what had been done [by Solace] is a little bit of target work around a couple of enzymes in the pathway, and a little bit of medicinal chemistry, but really a bare minimum," Pojasek told BioWorld Today. Post-Solace, "the remainder of the compounds and the know-how ended up with Woolf, and he's been working on this in his lab at Children's pretty much since then," he said.

Biomarker data suggest BH4's role in neuronal excitability as well as immune cell activity after nerve injury. Specifically, researchers have discovered that a haplotype in the gene encoding GTP cyclohydrolase I, a BH4 synthetic enzyme, is connected to lower risk of chronic pain after nerve injury or chronic disease. Further investigation turned up the finding that pharmacological modulation of either GTP cyclohydrolase I or sepiapterin reductase (another enzyme in the BH4 synthesis pathway) safely restores BH4 to normal levels, resulting in relief of pain symptoms in preclinical models.

Atlas wanted to "look at what's the cutting-edge biology at the interface of the peripheral nerve system and the immune system," Pojasek said. "How do these two areas of biology talk to each other and intersect? The BH4 story kept coming up."

Since the 1980s and 1990s, BH4 was known to be involved with T cells, macrophages, dendritic cells, mast cells. "It goes up in response to inflammation," Pojasek said, "but nobody has dissected with 21st century immunology – better assays, better models and better research tools – what it's doing there. We got pretty intrigued by this."

Johnsson determined that sulfasalazine, the anti-inflammatory agent approved by the FDA in 1950, is an inhibitor BH4 synthesis. "Nobody knew the mechanism before," Pojasek said, and Johnsson's finding further bolstered the scientific case for BH4. "I wouldn't say the existing drug clinically validates the target, but it certainly brings an additional depth of clinical relevance," especially now that Quartet can track the BH4 biomarker, Pojasek said.

SERAGON PARAGON?

If the animal-model outcomes translate to human efficacy – a big "if" – the resulting drug could grab some of the multi-billion dollar market held by New York-based Pfizer Inc.'s Lyrica (pregabalin), which is not effective for all patients and brings side effects that include dizziness, drowsiness, dry mouth, edema, blurred vision, weight gain and difficulty concentrating. Alternatives include opioids, which may work better but carry addiction risks.

"Animal models aren't any better than they used to be," Pojasek said. "Clinical trials are a little better than they used to be. But what we're really focused on is the BH4 biomarker. Our R&D strategy is really about finding the right drug, and showing that where BH4 is elevated in causing pain, we can bring it back down. We can use that biomarker again in phase I to make sure our drug is hitting the pathway of interest and modulating BH4."

The strategy "gives us a path forward from animals to people," Pojasek said. "We're eyes-wide-open about what the phase II commitment will look like here, because you're still doing patient-reported outcomes in a challenging group," when testing a pain drug. "You look in the label of Lyrica and it provides 50 percent pain relief to about a third of the people," Pojasek said. "It's just shocking that's state of the art in this field."

If Quartet can get significant target engagement in even a small trial, the consequences could be rewarding. "There are some very good comparables recently on companies being acquired on that kind of data for a lot of money," Pojasek said, pointing to Roche AG unit Genentech's buyout for $725 million in cash, plus contingent milestone-based payments of up to $1 billion, of San Diego-based Seragon Pharmaceuticals Inc. In the deal, Genentech gained a portfolio of oral selective estrogen receptor degraders designed to treat hormone receptor-positive breast cancer. (See BioWorld Today, July 3, 2014.)

"It's a different space, and there are a lot of caveats there, but the target engagement [in a 30-patient trial] is what really sold Genentech," Pojasek said.