Pain in the brain? Trigemina seeking to break the barrier

Bioworld Today – No matter what the cause – cluster headaches, migraines, cancer, nerve damage, temporomandibular joint disorder, trigeminal neuralgia or another disorder – chronic head pain remains among the most vexing of medical conditions for patients and the most daunting of challenges for scientists. Over-the-counter remedies that may help acute conditions often are ineffective for chronic pain, and opioids that can relieve pain come with serious downsides.

Trigemina Inc. is seeking to resolve chronic head pain while sidestepping the dependency of opioid drugs by administering a new application of oxytocin to the nasal mucosa, where the drug migrates along cranial nerves and is delivered directly to the central nervous system.

The Moraga, Calif.-based company was founded in 2006
by David Yeomans, director of pain research and associate professor of anesthesia at Stanford University School
of Medicine, and the company’s chief scientist. Some
months earlier, Yeomans had struck up a conversation at a conference with William Frey, founder and co-director of the Alzheimer’s Research Center at Regions Hospital, professor of pharmaceutics and a faculty member in neurology, oral biology and neuroscience at the University of Minnesota. Frey had discovered a non-invasive, intranasal method for bypassing the blood-brain barrier to rapidly deliver and target therapeutic agents to the brain along the olfactory and trigeminal neural pathways – thus, the company’s name. Yeomans thought the method could prove an ingenious route for delivering large molecules to the brain to provide an analgesic effect.

The two began running experiments, which showed impressive results using oxytocin, according to Charles Yeomans, David’s brother, who now serves as Trigemina’s CEO. The scientists filed patents based on David Yeomans’ work at Stanford and continued to conduct preclinical and early clinical experiments. In the lab, they showed the application of oxytocin, using Frey’s delivery method, halted the effect of calcitonin gene-related peptide, or CGRP, the neurotransmitter for pain. The process worked even to tamp down migraine, with its constellation of symptoms.

In 2007, the company conducted a phase II trial in Australia, administering a single dose in acute migraine patients as soon as possible after the onset of symptoms. The mechanism of action was not well understood at the time, however, according to Charles Yeomans, who explained that a certain amount of time was needed following the onset of migraine to up-regulate the receptor and induce inflammation, providing a target for the drug to do its job. Too, it was critical for patients to avoid the use of any substance that might potentially prevent that up-regulation process. Long story short, the initial efficacy trial fell flat.

The scientists went back to the drawing board and, in 2009, conducted a smaller trial in 40 patients with chronic migraine, “who were more likely to be up-regulating all the time,” Charles Yeomans said. This time, the oxytocin delivery method worked better, but the company ran out of money before it could repeat the experiments and study the long-term effects of the drug.

Charles Yeomans, who had a background in banking and private equity investment and was an early investor in Trigemina, offered to step in so his brother could keep the research team together. The new CEO attracted venture funding from Chilean-based investor Aurus, through its Aurus Bios Fund, supplemented by additional funding from high net worth individuals. In late 2011, Trigemina was “reconstituted,” Yeomans said.

‘WE DON’T WANT TO HAND THIS OFF AND WALK AWAY’

Work on the intranasal oxytocin candidate, TI-001, has progressed rapidly ever since. In May 2013, the company began a randomized, double-blind, placebo-controlled, withdrawal- and enrollment-enriched phase II safety and efficacy study using the nasal spray formulation. The study is expected to enroll 240 chronic migraine patients in Chile and Australia.

The primary outcome measure is mean reduction in migraine headache days from baseline – the 28-day screening period before enrollment in the study, according to Thomson
Reuters Cortellis Clinical Trials Intelligence (CTI). Secondary measures include frequency of migraine episodes; change in migraine pain scores; frequency and severity of adverse events; frequency of nausea, phonophobia and photophobia; time to discontinuation due to any cause; and interleukin-6 levels as a marker of response, according to Cortellis CTI. The study also is assessing several doses, from 15 to 60 IU, to determine the best dose for a phase III study.

In June 2013, Trigemina completed a $4.5 million series A financing, led by Aurus and supplemented by a grant from the government of Chile, to fund the phase II study to completion. The company expects to report data late in the third quarter.

“If the early trends hold, we will have a very strong candidate to help chronic migrainers,” Yeomans said. “We think this will be a candidate to move into phase III pretty fast.”

Migraine is a large but challenging space dominated by Botox (onabotulinumtoxinA, Allergan Inc.). In January 2013, Allergan moved to secure its position in migraine treatment by purchasing MAP Pharmaceuticals Inc. in a cash deal, acquiring the company’s shares at $25 each. (See BioWorld Today, Jan. 24, 2013.)

In December 2013, Depomed Inc. added some interest to the space and boosted its pain portfolio with the purchase
of Nautilus Neurosciences Inc.’s migraine drug, Cambia (diclofenac potassium for oral solution) – the only single agent nonsteroidal anti-inflammatory specifically indicated for migraine. (See BioWorld Today, Dec. 19, 2013.)

But chronic migraine remains unchartered territory, though a growing number of companies is seeking to fill the void, with CGRP receptor antagonists among the leading mechanisms of action. Once the TI-001 phase II is complete, Trigemina likely will seek another financing round to move post haste into phase III, Yeomans said.

Trigemina has a second molecule, TI-002, a polypeptide also delivered via the nasal-cerebral pathway that is designed to target a broad range of pain throughout the body, including neuropathic pain.

With multiple assets, the company’s long-term business strategy will depend on the circumstances.

“If we complete our trial, we could look for a partner that would be supportive and help us to get this into the market,” Yeomans said. “But with the expertise we’ve developed internally, we don’t want to hand this off and walk away. We have a lot of passion for this drug, and we want to see it get to people whom it could help.”

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