Novel analgesics with potential for treating a broad spectrum of painful conditions.
There is large commercial opportunity for a novel analgesic that is both effective and safe, as current treatment options leave many patients in ongoing pain or experiencing dose-limiting side effects such as nausea, vomiting, somnolence, gastrointestinal bleeding and cardiovascular complications.
To develop a novel analgesic to address this significant unmet medical need, we have applied our clinical genetic approach to discover essential pain signaling pathways in humans by studying the genetics of the opposite phenotype “absence of pain.” Knowing what genes are involved in human pain perception represents a key entry point into designing novel drugs to treat pain. Using our worldwide clinical network, we identified rare individuals with a congenital form of human analgesia known as Congenital Insensitivity to Pain (CIP). CIP is characterized by the total absence of the ability to perceive and/or understand any kind of noxious stimulus as painful. We discovered CIP patients have mutations in the SCN9A gene resulting in absence of the NaV1.7 sodium channel, thereby validating this drug target as essential for human pain sensation. Remarkably, CIP patients are otherwise healthy, underpinning NaV1.7’s specific role in mediating pain in humans. For example, all sensory modalities such as touch, temperature and proprioception are unaffected as are other physiological functions. Our clinical genetic studies underscore that in humans, NaV1.7 inhibition should be a highly effective and safe mechanism to treat a broad spectrum of painful conditions.
We have advanced several NaV1.7 inhibitors into clinical studies. Oral XEN402 has successively concluded two proof-of-concept trials as a prelude to its development as a topical product. In the acute inflammatory pain setting of third molar dental extraction multiple endpoints supported efficacy including significant increase in the proportion of responders. To further explore NaV1.7 target engagement by XEN402, we have conducted a study in patients with inherited erythromelalgia. This disorder of spontaneous or easily provoked severe pain is caused by mutations that activate the NaV1.7 channel and represents the opposite of the absence of pain observed in CIP caused by NaV1.7 deficiency. We have demonstrated efficacy in these patients and as such we have shown that XEN402 can engage and block NaV1.7 mediated pain in humans. One of the erythromelalgia patients while dosed with XEN402 took a hot shower for the first time in his life; previously this was too painful for him to do. The Food and Drug Administration (FDA) has granted XEN402 orphan drug designation for the treatment of erythromelalgia. These proof of concept studies have helped support the development of the topical product for these and other painful conditions.
A Phase 2 study to evaluate the effectiveness in alleviating the pain of post herpetic neuralgia by topical XEN402 has been concluded. The proportion of patients reporting clinically meaningful reductions in pain was significantly greater for topical XEN402 than for placebo (p=0.049 for >30% and p=0.0078 for >50%). In this trial, the product also showed favorable trends in other co-morbidities commonly associated with PHN, including improvements in sleep. Importantly, dose limiting side effects were not observed in the trial, potentially differentiating topical XEN402 from the currently available oral treatments. By treating pain locally at its source through block of NaV1.7, topical XEN402 could be an effective and safe treatment option both as a mono-therapy and an adjuvant to oral therapies.