On 24 July 2012, a press release from Merck announced that the company had signed licensing agreement for the development of two new nucleoside analogues and is about to launch a phase 2 study for its in house NNRTI.1
CMX157 is a nuceloside analogue in development at Chimerix that reported promising phase 1 results over four years ago and has been waiting for a financial backer since.2 The compound is a prodrug of tenofovir (tenofovir diphosphate as the active moiety), with an improved pharmacokinetic profile to tenofovir and initial results suggesting a potential for once-weekly dosing. The in vitro resistance profile includes sensitivity to K65R with some but not all thymidine analogue mutations. This was a compound that was expected to be picked up several years ago.
EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine) is a compound in development with the Japanese biotech division of the Yasama Corporation (who have a history that includes brewing soy sauce since the time of the English civil war) and which has been studied with amFAR and US NIH support. A poster presented at the 19th IAS conference in Washington this summer reported a significantly stronger in vitro resistance profile compared to tenofovir following multiple passaging with a mixture of 11 multinucleoside resistant viral mutations.
Merck also used the opportunity to announce its in-house NNRTI compound MK1439 is about to enroll treatment naive patients into a phase 2 dose-finding study (from 25 mg to 200 mg) using efavirenz as a comparitor and tenofovir/FTC as background nukes.
It is promising news that Merck is developing an active programme of research for new HIV drugs to in parallel to development of integrase inhibitors.
Although less well publicised, Merck is also one of the companies investing in cure research.
- Merck press release. Merck signs two deals for novel HIV drug candidates and initiates phase II clinical trial of MK-1439 for HIV. (24 July 2012). www.merck.com/newsroom/news-release-archive/research-and-development/2012_0724.html
- Lanier ER et al. Hexadecyloxpropyl tenofovir (CMX157) has enhanced potency in vitro against NRTI resistant HIV relative to tenofovir and a favorable preclinical profile. XVII IHDRW 2008, Sitges. Poster 4. http://i-base.info/htb/598
- Maeda K et al. Delayed emergence of HIV-1 variants resistant to 4'-ethnyl-2-fluoro-2'-deoxyadenosine (EFdA): comparative sequential passage study with tenofovir, emtricitabine and festinavir. 19th IAC, 22-25 July 2012, Washington. Poster abstract TUPE017. http://pag.aids2012.org/abstracts.aspx?aid=18620
- A dose-ranging study to compare MK-1439 plus Truvada versus efavirenz plus Truvada in human immunodeficiency virus (HIV)-1 infected participants (MK-1439-007 AM5). http://clinicaltrials.gov/ct2/show/NCT01632345