Advancing Therapeutic Development for Pain and Opioid Use Disorders Through Public-Private Partnerships Proceedings of a Workshop (2018) / Chapter Skim
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4 Clinical Development of Non-Addictive Pain Medications
4 Clinical Development of Non-Addictive Pain Medications
Pages 29-44
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From page 29... ...
. • Biomarkers can facilitate drug development by confirming a ther apeutic hypothesis, demonstrating target engagement, enabling stratification of potential clinical trial participants, and predicting response to treatment (Ahn, Volkow)
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From page 30... ...
Despite intense efforts by the pharmaceutical and biotech industries, translating the preclinical identification of new targets into new medicines that will benefit patients and address the opioid crisis has been largely unsuccessful, said John Dunlop, vice president of neuroscience research at Amgen. Preclinical models may fail to predict clinical efficacy for many reasons.
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From page 31... ...
Biomarkers can offer an opportunity to reach across that divide, he said, noting that partnerships are essential in this area given that pharmaceutical companies may not have all the expertise needed to identify mechanisms, connect them to a disorder, and develop tools and assays to move from a mechanistic hypothesis to "druggable" targets and eventually, novel compounds. Many workshop participants noted that objective markers are needed to demonstrate clinical efficacy of pain medications in development.
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From page 32... ...
Setting the optimal dose to test in clinical trials of these monoclonal antibody therapeutics has been facilitated in part by the availability of a biomarker of peripheral target engagement, which involves injecting into the skin a small amount of capsaicin and then measuring to what extent the investigational drug blocks an increase in dermal blood flow (Sinclair et al., 2010)
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From page 33... ...
to characterize pain circuitry and drug actions. He and his colleagues identified an fMRI-based neurological pain signature that captures the neurobiological correlates of evoked pain, starting with heat-induced pain, but then generalizing to other pain conditions (Wager et al., 2013)
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From page 34... ...
research network.1 A recent publication from MAPP compiled clinical data as well as structural and fMRI data from more than a thousand patients at seven sites, including patients with urological chronic pelvic pain (localized and widespread) (Kutch et al., 2017)
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From page 35... ...
She noted that the stability of exosomes in serum makes retrospective studies possible and suggested using serum and plasma samples from failed clinical trials, where the therapeutic outcome is known, to search for miRNA signatures that could be used for patient stratification. For biomarker discovery, she advocated obtaining miRNA profiles beginning in Phase I studies, which may enable later stage trials to be conducted in defined patient subgroups.
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From page 36... ...
Dawson elaborated that no safety profile is fully elucidated by the clinical trials, as uncommon and rare events will be missed; however, the risk–benefit profile that supports therapeutic development should not be the same as for a treatment focused on an illness or disorder that is not as serious or severe. With this approach, the full population of persons with the disorder will have an opportunity to take the therapy, rather than just those who meet the inclusion and exclusion
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From page 37... ...
If a network of physicians skilled in doing clinical investigational work was available, this pathway might be traversed fairly quickly, he said. In addition, Verburg cited the need for more exploratory work developing new clinical trial study paradigms.
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From page 38... ...
Important questions he raised that emerge from this model include whether targeting these mechanisms will reverse the transition, returning someone to a pain-free or normal acute pain state, and whether treatments currently being used impact the transition or conversion to chronic pain. Preclinical Perspective Price suggested that preclinical models can provide insight into the acute-to-chronic pain transition and possibly illuminate ways to stop, reverse, or prevent it from occurring.
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From page 39... ...
Moreover, Price stated that priming models are useful to predict efficacy of various analgesics for the treatment of chronic pain, as well as to predict whether an acute pain treatment can prevent priming and the transition to chronic pain. He added that a better understanding of the mechanisms underlying the acute-to-chronic pain transition may suggest therapeutic approaches to reverse the transition and treat chronic pain.
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From page 40... ...
clinical trials to test putative preventive interventions. Some of the risk factors are well established, he said.
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From page 41... ...
He also mentioned that while three clinical trials of vitamin C for prevention of CRPS have produced conflicting results, this low-risk intervention should be tested further. Ultimately, he said that preventing the acute-to-chronic pain transition will likely require multimodal intervention, including pharmacological and non-pharmacological treatments, such as physical therapy and psychological treatment.
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From page 42... ...
Past and current history of smoking increases the risk for developing chronic pain conditions like temporomandibular disorders, said Maixner. Price said the preclinical data also support this idea -- giving a μ-opioid agonist at the time of injury seems to promote neuronal plasticity, while inverse agonists4 precipitate a more transient pain state (e.g., Kandasamy and Price, 2015)
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From page 43... ...
He added that a surrogate endpoint is "very problematic," and will require validation that it is reasonably likely to predict clinical benefit. The FDA generally restricts the use of surrogate endpoints to serious conditions for which the event rate (e.g., death)
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