Topical NaV1.7 channel blocker failed in postherpetic Neuralgia (PHN): lessons to learn

Abstract

Xenon Pharmaceuticals and Teva Pharmaceuticals both worked on the development of TV-45070, previously known as XEN402, characterized by Teva as a potent Nav1.7 inhibitor [1,3]. Inherited erythromelalgia (IEM) is a rare disorder, based on a range of gain-of-function mutations, located in domains I to IV of NaV1.7. TV-45070 orally administered was reported to decrease pain in a first pilot study in IEM patients [2]. For the further development, TEVA decided to also develop a topical formulation based on an ointment, and its physicochemical and pharmaceutical properties were not further specified. The rationale for this new development was given as: "To maximize inhibition of Navs locally in skin and subcutaneous tissue and minimize systemic adverse events, topical TV-45070 was developed to depot in the skin and underlying tissue while maintaining low plasma concentrations (pp310-311) [3]." Results of a new proof of principle study in postherpetic neuralgia (PHN) was reported last year (2017), based on an elegant cross-over design in 70 patients, randomized to receive twice daily active or placebo ointment. Patients with mean daily pain scores equal or greater than 4 (using an 11-point Numerical Rating Scale) for at least 4 days during the initial placebo 7-day run-in period were randomized. The dose administered was dependent on the area treated, and varied between 60 and 240 mg. The concentration of TV-45070 in the ointment was 4% and 8%, as mentioned by TEVA at its website [4]. Due to drop-outs during the study in both arms and during both cross-over periods, the efficacy analysis was based on 57 patients only. There was no difference between analgesia as measured via the primary outcome variable in both treatment groups, and the reduction compared to baseline was only around 0,95 points on the NRS. Plasma concentrations detected were reported to be low in comparison to plasma levels earlier measured after oral dosing. After oral dosing plasma levels were higher and were related to the induction of some adverse events. However, the base ointment selected, frequently induced local skin reactions in both arms, although reported to be mild in 66%, they were occasional moderate in 28%, suggesting a suboptimal vehicle. Now there may be various reasons why topical TV-45070 did not reach significance in this study, as measured via the first outcome variable. One possible reason was that the mean duration of pain in this cohort was much longer than normal (longer than 5 years), and thus the cohort might be more treatment refractory than normal. In the explored population 8 patients were heterozygous carriers of the Nav1.7 R1150W polymorphism, and in this small subpopulation the carriers of the mutation responded better compared to the placebo-response. The authors also conducted a 50% responder analysis, where TV-45070 did significantly better compared to placebo. In the discussion they pointed out that this positive responder rate: "suggests that a subpopulation of PHN patients exists that is more likely to have an analgesic effect and, further suggests the possibility exists that this response to topical TV-45070 could be mechanism based (p.317 [3]". This is a very important remark, because recent data support their suggestion, and although there is uniformity in etiology, currently at least 3 different pathogenetic and symptomatic subgroups defined in PHN, that are differentiated from each other [5].