J&J has tak­en an­oth­er big step for­ward in its quest to bring home a block­buster ap­proval for its nasal spray for­mu­la­tion of ke­t­a­mine as a new rem­e­dy for ma­jor de­pres­sion.

Just weeks af­ter the phar­ma gi­ant re­port­ed that es­ke­t­a­mine had es­sen­tial­ly aced short-term piv­otal stud­ies, re­searchers are back with ev­i­dence of its long-term ef­fi­ca­cy. But they will like­ly face care­ful scruti­ny over the sub­stan­tial side ef­fects spurred by the ther­a­py, in­clud­ing a set of se­ri­ous ad­verse events re­port­ed in the lengthy safe­ty study.

The ef­fi­ca­cy study fo­cused on 705 treat­ment-re­sis­tant pa­tients re­cruit­ed out of its Phase III pro­gram who were sta­ble af­ter 16 weeks of ther­a­py with es­ke­t­a­mine and an oral an­ti-de­pres­sant. Fol­low­ing an­oth­er stretch of treat­ment, the es­ke­t­a­mine com­bo proved sig­nif­i­cant­ly more ef­fec­tive in pre­vent­ing a re­lapse than a place­bo spray plus oral de­pres­sion drug.

About one in four (26.7%) of the sta­ble re­mit­ters in the es­ke­t­a­mine arm ex­pe­ri­enced a re­lapse com­pared to 45.3% of the place­bo group (p=0.003) — a strong­ly pos­i­tive out­come. It’s par­tic­u­lar­ly sig­nif­i­cant that the re­searchers were able to track longterm re­spons­es for a drug known for its ephemer­al im­pact.

The safe­ty da­ta are a lit­tle more com­plex. As seen ear­li­er, and com­plete­ly ex­pect­ed, there was a high rate of dis­so­ci­a­tion — 22.4%. That un­der­scores why J&J plans to have the drug in­fused in a clin­ic, with an ob­ser­va­tion pe­ri­od to make sure pa­tients were be­hav­ing nor­mal­ly be­fore they leave.

Es­ke­t­a­mine is a low dose of ke­t­a­mine, a par­ty drug and horse tran­quil­iz­er that’s of­ten abused. J&J here is try­ing to nav­i­gate its way through Phase III with an ac­cept­able for­mu­la­tion for a tough pa­tient pop­u­la­tion in a field known for wide­spread fail­ure.

The safe­ty study was open la­bel, with pa­tients aware they were get­ting the drug. Re­searchers re­port­ed:

Fifty-five (6.9%) pa­tients ex­pe­ri­enced 68 se­ri­ous treat­ment-emer­gent ad­verse events. Of these, five se­ri­ous treat­ment-emer­gent ad­verse events from four sub­jects were as­sessed by the in­ves­ti­ga­tor as es­ke­t­a­mine nasal spray-re­lat­ed. There were two deaths which the in­ves­ti­ga­tor de­ter­mined to be un­re­lat­ed to es­ke­t­a­mine nasal spray or oral an­ti­de­pres­sant use. Lab­o­ra­to­ry tests, phys­i­cal ex­am­i­na­tion, and nasal tol­er­a­bil­i­ty re­vealed no trends of clin­i­cal con­cern in pa­tients treat­ed with es­ke­t­a­mine nasal spray for up to 52 weeks. No clin­i­cal­ly mean­ing­ful changes in cog­ni­tion were found. No cas­es of in­ter­sti­tial or ul­cer­a­tive cys­ti­tis were re­port­ed.

I asked a com­pa­ny rep what the five se­ri­ous ad­verse events were, as it could be rel­e­vant to a reg­u­la­to­ry re­view. Her re­sponse: de­pres­sion, delir­i­um, anx­i­ety and delu­sion, sui­ci­dal ideation and sui­cide at­tempt.

J&J has list­ed es­ke­t­a­mine as one of its top late-stage de­vel­op­ment pro­grams, prep­ping ap­pli­ca­tions for both sides of the At­lantic. They’re not home free yet, but in de­pres­sion uni­form safe­ty and ef­fi­ca­cy is un­heard of, with reg­u­la­tors will­ing to bal­ance the risks with the ben­e­fits for a tough group to treat.

On that score, J&J is well ahead of the game.