Neb­u­liz­er fails PhII COPD study, but Verona plans to march on

Billed as the first new class of bron­chodila­tor in more than four decades, Verona Phar­ma’s $VR­NA ex­per­i­men­tal neb­u­liz­er did not con­fer sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment on a mea­sure of lung func­tion in Phase II study in­volv­ing pa­tients with chron­ic ob­struc­tive pul­monary dis­ease (COPD) who were al­ready on in­haled long-act­ing bron­chodila­tors.

Verona has tout­ed the drug, known as en­sifen­trine or RPL554, as the first po­ten­tial ther­a­py for res­pi­ra­to­ry dis­eases that acts as both a bron­chodila­tor and an­ti-in­flam­ma­to­ry agent in a soli­tary com­pound. Two dos­es of the drug in a neb­u­lized for­mu­la­tion were be­ing test­ed in the three-day, place­bo-con­trolled tri­al as a main­te­nance treat­ment for 79 COPD pa­tients, who were al­ready on com­mon­ly used LAMA/LA­BA treat­ments.

Pa­tients re­ceived three days of treat­ment with each of two dose strengths (1.5 mg or 6 mg) of neb­u­lized en­sifen­trine or place­bo twice dai­ly. The pri­ma­ry end­point was im­prove­ment in lung func­tion with en­sifen­trine, as mea­sured by FEV1 (forced ex­pi­ra­to­ry vol­ume in one sec­ond), a stan­dard mea­sure of res­pi­ra­to­ry func­tion, four hours post-dose af­ter the morn­ing dose on day three.

Jan-An­ders Karls­son

The pri­ma­ry end­point of FEV1 was not found to be sta­tis­ti­cal­ly sig­nif­i­cant af­ter the morn­ing dose, al­though the small­er en­sifen­trine dose im­proved peak FEV1, the com­pa­ny said, adding that the im­prove­ment was main­tained through­out the 24-hour pe­ri­od on day 3. The com­pa­ny’s shares slumped about 36% in mid­day trad­ing.

How­ev­er, da­ta on sec­ondary end­points in­clud­ing peak FEV1 over time and re­duc­tions in resid­ual vol­ume were en­cour­ag­ing: Peak FEV1 af­ter evening dose on day 3 showed sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment with both dos­es, and sta­tis­ti­cal­ly sig­nif­i­cant re­duc­tions in mean resid­ual vol­ume were ob­served 15 min­utes fol­low­ing the evening dose on day 3, the Lon­don-based com­pa­ny said.

Over­all, the high­er dose did not re­sult in greater im­prove­ment in lung func­tion as com­pared with the 1.5 mg dose.

But Verona struck an up­beat tone. “Hav­ing demon­strat­ed in pre­vi­ous stud­ies the po­ten­tial of en­sifen­trine to de­liv­er ben­e­fits to pa­tients on no or sin­gle bron­chodila­tor ther­a­py, we be­lieve that this short study con­tin­ues to sup­port our view that en­sifen­trine may al­so be of ben­e­fit to more se­vere COPD pa­tients on dual and triple ther­a­py, for whom there are few oth­er treat­ment op­tions,” said Verona chief Jan-An­ders Karls­son in a state­ment.

“While we are dis­ap­point­ed that this ex­plorato­ry Phase 2 study did not achieve sta­tis­ti­cal sig­nif­i­cance for its pri­ma­ry end­point, these da­ta give us clar­i­ty on the de­sign…for fu­ture long-term stud­ies.”

Sun­Trust Robin­son Humphrey’s Ed­ward Nash ap­peared to agree with the com­pa­ny’s as­sess­ment, say­ing that the tri­al’s main goal was not met due to an un­ex­pect­ed­ly high­er place­bo ef­fect – oth­er­wise the drug did show im­proved FEV1 on top of dual/triple ther­a­py in a very chal­leng­ing COPD pa­tient pop­u­la­tion.

“We be­lieve the FDA would wel­come the low­er dose from a safe­ty stand­point and be­lieve to­tal­i­ty of da­ta which in­cludes ~104mL and 127mL im­prove­ment on top of monother­a­py (tiotropi­um) back­ground and 40mL to 50mL FEV1 im­prove­ments seen in dual/triple back­ground ther­a­py re­port­ed to­day pro­vides a pos­i­tive clin­i­cal and com­mer­cial pro­file for en­sifen­trine.”

Of the pa­tients treat­ed with dual bron­chodila­tor (LAMA/LA­BA) and triple ther­a­py (LAMA/LA­BA/ICS), re­search sug­gests that up to 40% (ap­prox­i­mate­ly 800,000 pa­tients in the US alone) are un­con­trolled, re­main­ing symp­to­matic and at an in­creased risk of ex­ac­er­ba­tions, ac­cord­ing to Verona.

Da­ta have sug­gest­ed that en­sifen­trine is an ef­fec­tive ad­di­tion to sin­gle bron­chodila­tors. The com­pa­ny is cur­rent­ly con­duct­ing a Phase II tri­al to eval­u­ate a dry pow­der in­haler for­mu­la­tion of en­sifen­trine for the same pa­tient pop­u­la­tion, and plans to test en­sifen­trine in a me­tered-dose in­haler for­mu­la­tion in pa­tients with COPD. In ad­di­tion, the drug is al­so be­ing test­ed for use in cys­tic fi­bro­sis and asth­ma.

Secretary of health and human services Alex Azar speaking in the Rose Garden at the White House (Photo: AFP)

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