Ver­sus Ver­tex, Pro­teosta­sis' triplet CF da­ta fall short, wilt­ing stock

It’s too lit­tle, too late for lit­tle Pro­teosta­sis Ther­a­peu­tics.

The Boston drug de­vel­op­er that is look­ing to take on Ver­tex Phar­ma­ceu­ti­cals — and the com­pa­ny’s en­trenched slate of cys­tic fi­bro­sis med­i­cines — re­port­ed da­ta from a mid-stage study test­ing its own CF triplet on Tues­day. The re­sults failed to im­press, sink­ing the stock $PTI more than 42% to $2.51 in pre­mar­ket trad­ing.

The tri­al test­ed Pro­teosta­sis’ diro­caftor (or PTI-808), and posen­caftor (or PTI-801) with or with­out neso­li­caftor (or PTI-428) against a place­bo in a four-week Phase II study in CF pa­tients. Over­all, 28 F508del ho­mozy­gous and 40 F508del het­erozy­gous sub­jects were en­rolled in the dou­blet, triplet or place­bo arms. CF is caused by a de­fec­tive and/or miss­ing CFTR pro­tein re­sult­ing from cer­tain mu­ta­tions in the CFTR gene — the F508del mu­ta­tion is one of the most com­mon.

The ho­mozy­gous pa­tients that got the triplet com­bo saw a mean ab­solute im­prove­ment in ppFEV1 of 8 per­cent­age points over pooled place­bo at day 28.  The per­cent pre­dict­ed forced ex­pi­ra­to­ry vol­ume in one sec­ond, or ppFEV1,  is an es­tab­lished mark­er of cys­tic fi­bro­sis lung dis­ease pro­gres­sion.

In peo­ple with CF, there is a prob­lem in mov­ing chlo­ride across cell mem­branes, which means high­er con­cen­tra­tions of chlo­ride (as salt) in sweat. In Pro­teosta­sis’ tri­al, sweat chlo­ride con­cen­tra­tion in ho­mozy­gous sub­jects re­ceiv­ing the triplet demon­strat­ed a mean im­prove­ment of -29 mmol/L at day 28, com­pared to pooled place­bo.

On both mea­sures, the triplet in­duced sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ments — the dou­blet da­ta was pos­i­tive, but not sta­tis­ti­cal­ly sig­nif­i­cant, the com­pa­ny said.

The da­ta ap­pears less com­pet­i­tive than Ver­tex’s Trikaf­ta, Jef­feries’ Michael Yee wrote in a note, es­ti­mat­ing that Pro­teosta­sis’ 8% ppFEV1 ben­e­fit over place­bo is about 40% low­er than Trikaf­ta’s ben­e­fit of 13-14%.

Pro­teosta­sis must achieve +10% ben­e­fit in ppFEV1 and 20mmol de­cline in sweat chlo­ride with its triplet at 14-28 days to stay com­pet­i­tive as a sec­ond en­trant, Can­tor Fitzger­ald’s El­e­mer Piros wrote in a note in March. Days lat­er, the com­pa­ny un­der­whelmed in­vestors when its pro­pri­etary triplet da­ta showed a ppFEV1 ben­e­fit of 5%-8%, de­pend­ing on the pa­tient group on day 14.

Mean­while, in the het­erozy­gous pop­u­la­tion of Pro­teosta­sis’ Phase II tri­al, mean changes in ppFEV1 were not deemed sta­tis­ti­cal­ly sig­nif­i­cant, al­though the im­prove­ment in sweat chlo­ride con­cen­tra­tion was.

(T)he PTI com­bos did not work at all in the het­erozy­gous group, which in our view rais­es a ques­tion about the over­all ef­fect and mech­a­nism of PTI’s drugs (which nec­es­sar­i­ly doesn’t make sense),” Yee said, adding that the re­sults were on very small num­bers of pa­tients and that Pro­teosta­sis’ Phase II en­rolled CF pa­tients with high dis­ease bur­den or those who had failed pri­or ther­a­pies rep­re­sent a very niche pop­u­la­tion, giv­en that 85-90% of the CF mar­ket can be treat­able (in the­o­ry) by a more ro­bust CF VRTX reg­i­men.

Still, with pos­i­tive da­ta in the ho­mozy­gous pop­u­la­tion, Pro­teosta­sis will mo­tor on. On Tues­day, the com­pa­ny said it would grad­u­ate to a Phase III tri­al, un­veil­ing plans to launch a late-stage study in CF pa­tients with the com­mon F508del ho­mozy­gous mu­ta­tion in 2020.

The cys­tic fi­bro­sis drugs made by Ver­tex are the first treat­ments that ad­dress the un­der­ly­ing ge­net­ic caus­es of CF, which is char­ac­ter­ized by thick sticky mu­cus in the lungs, di­ges­tive sys­tem and oth­er or­gans that re­duces life ex­pectan­cy. Ver­tex’s med­i­cines tar­get the cys­tic fi­bro­sis trans­mem­brane con­duc­tance reg­u­la­tor (CFTR) gene and are en­gi­neered to de­signed to cor­rect the mal­func­tion­ing pro­tein it makes. The com­pa­ny’s triplet, Trikaf­ta, was ap­proved ear­li­er this year and is en­gi­neered to ad­dress 90% of the CF pop­u­la­tion.

Pro­teosta­sis drug, neso­li­caftor is meant to boost lev­els of the CFTR pro­tein. The ther­a­py is an add-on treat­ment for pa­tients with the F508del mu­ta­tion in the CFTR gene who are al­ready tak­ing an ap­proved CFTR mod­u­la­tor or as part of Pro­teosta­sis’ triple com­bo reg­i­men that in­cludes diro­caftor, a po­ten­tia­tor, and posen­caftor, a cor­rec­tor. Pro­teosta­sis is al­so in­ves­ti­gat­ing the use of its drugs in com­bi­na­tion with Ver­tex’s CF ther­a­pies.

Last year was tu­mul­tuous for Pro­teosta­sis, marked by a vi­cious short at­tack, a yanked stock of­fer­ing — but the biotech was giv­en the en­dorse­ment of mighty Roche, which seized the rights to po­ten­tial small mol­e­cule mod­u­la­tors with undis­closed tar­gets from the com­pa­ny.

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