Merck hits the brakes on development program as safety fears trigger alarm

In a sur­prise set­back, Mer­ck has slammed the brakes on the de­vel­op­ment of an ex­per­i­men­tal HIV drug — in­clud­ing a Phase II tri­al — af­ter in­ves­ti­ga­tors flagged a drop in im­mune cell counts that an ex­ter­nal com­mit­tee de­ter­mined was re­lat­ed to treat­ment.

The Phase II study that first sound­ed the alarm, dubbed IMAG­INE-DR, was test­ing the once-week­ly com­bi­na­tion of MK-8507 (a non-nu­cle­o­side re­verse tran­scrip­tase in­hibitor) and is­la­travir, or ISL, a nu­cle­o­side re­verse tran­scrip­tase translo­ca­tion in­hibitor.

Where­as Mer­ck is paus­ing all pro­grams in­volv­ing MK-8507, the com­pa­ny says it ‘re­mains con­fi­dent in is­la­travir’s over­all pro­file’ and will car­ry on with it.

For Mizuho an­a­lyst Mara Gold­stein, that of­fers a glass half full sit­u­a­tion.

‘MRK’s lead an­ti-HIV can­di­date is is­la­travir (ISL), which we see as undis­turbed at this point,’ she wrote. ‘Based on a larg­er body of clin­i­cal da­ta for ISL’s an­ti-HIV ef­fi­ca­cy in­clud­ing the re­cent pos­i­tive top-line up­date (see NOTE), we are not fore­cast­ing changes in the broad­er ISL-based HIV stud­ies, and our mod­el re­mains the same.’

Is­la­travir is al­so one of the two cen­ter­pieces of Mer­ck and Gilead’s joint ef­fort to de­vel­op a long-act­ing HIV ther­a­py, along­side Gilead’s cap­sid in­hibitor lenaca­pavir. Joan But­ter­ton, VP of in­fec­tious dis­eases glob­al clin­i­cal de­vel­op­ment at Mer­ck Re­search Lab­o­ra­to­ries, not­ed Mer­ck re­mains ‘res­olute’ in its pledge to help end the HIV pan­dem­ic and high­light­ed that all clin­i­cal stud­ies pro­vide im­por­tant ‘learn­ings.’

In IMAG­INE-DR, study par­tic­i­pants ran­dom­ized to re­ceive ISL+MK-8507 saw a de­crease in to­tal lym­pho­cyte and CD4+ T cell counts. The great­est drops were ob­served in the arms of the study re­ceiv­ing the high­est dos­es of MK-8507, name­ly 200 mg and 400 mg.

The ex­ter­nal da­ta mon­i­tor­ing com­mit­tee con­clud­ed that the ad­verse ef­fect had to do with the treat­ment and rec­om­mend­ed stop­ping the tri­al. Mer­ck oblig­ed, and re­viewed all of its tri­als in­volv­ing ISL with a spe­cial eye to those met­rics.

Here’s what they found:

The on­go­ing Phase II tri­al (MK-8591-016) is eval­u­at­ing month­ly ISL for PrEP in par­tic­i­pants with low risk of HIV-1 in­fec­tion. Among this un­in­fect­ed group, there was a dose-de­pen­dent de­crease in lym­pho­cyte counts but mean de­creas­es were in the nor­mal range, and there was no in­crease in clin­i­cal ad­verse events re­lat­ed to in­fec­tion.

IL­LU­MI­NATE SWITCH A and IL­LU­MI­NATE SWITCH B (MK-8591A-017 and MK-8591A-018) are two Phase III tri­als eval­u­at­ing do­ravirine in com­bi­na­tion with ISL dai­ly (DOR/ISL) in HIV-1 vi­ro­log­i­cal­ly sup­pressed par­tic­i­pants. Here, Mer­ck found a small, treat­ment re­lat­ed mean de­crease in CD4+ T cell counts through week 48, but no in­creased in­ci­dence of AEs re­lat­ed to in­fec­tion.

Mer­ck re­cent­ly re­port­ed pos­i­tive da­ta from the IL­LU­MI­NATE stud­ies, sug­gest­ing the DOR/ISL com­bo has com­pa­ra­ble ef­fi­ca­cy as ex­ist­ing an­ti­retro­vi­ral ther­a­pies.

‘In­ves­ti­ga­tors for these tri­als have been in­formed and the tri­als are con­tin­u­ing,’ the com­pa­ny wrote.

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Douglas Fambrough, Dicerna CEO (Dicerna via YouTube)

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Mathai Mammen, head of R&D for J&J’s Janssen unit (Rob Tannenbaum)

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Jay Luly, Enanta CEO (via YouTube)

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Michel Vounatsos (Biogen via YouTube)

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