Em­maus re­scinds EU mar­ket­ing ap­pli­ca­tion, fol­low­ing neg­a­tive re­view

Two years ago, Em­maus Life Sci­ences se­cured FDA ap­proval for its sick­le cell dis­ease (SCD) ther­a­py — mark­ing the first new ap­proval for pa­tients af­fect­ed by the group of in­her­it­ed red blood cell dis­or­ders that typ­i­cal­ly af­flict those of African an­ces­try in two decades. But the Eu­ro­pean reg­u­la­tor was not sat­is­fied with the dataset sup­port­ing the ther­a­py  — prompt­ing its mak­er on Thurs­day to re­scind its ap­pli­ca­tion.

En­dari is a high­ly pu­ri­fied (phar­ma­ceu­ti­cal grade) ver­sion of the amino acid L-glu­t­a­mine and was ap­proved in Ju­ly 2017 to re­duce the se­vere com­pli­ca­tions that come with SCD. (Non-med­ical grade L-glu­t­a­mine is avail­able as a sup­ple­ment over the counter).

The US ap­proval was based large­ly on a 230-pa­tient place­bo-con­trolled study that ran for 48 weeks. Da­ta showed pa­tients on En­dari ex­pe­ri­enced 25% few­er sick­le cell crises, as well as a 33% drop in hos­pi­tal­iza­tions, com­pared to place­bo. Ad­di­tion­al­ly, pa­tients on En­dari spent few­er cu­mu­la­tive days in the hos­pi­tal and ex­pe­ri­enced a low­er in­ci­dence of acute chest syn­drome.

In its as­sess­ment, the Eu­ro­pean reg­u­la­tor took is­sue with the num­ber of dropouts in the study. The EMA’s Com­mit­tee for Med­i­c­i­nal Prod­ucts for Hu­man Use (CHMP) said the main study on the ther­a­py — chris­tened Xyn­dari in Eu­rope — did not show it was ef­fec­tive at re­duc­ing the num­ber of sick­le cell crises or hos­pi­tal vis­its, due to the high­er num­ber of dropouts in the drug arm.

“(I)nfor­ma­tion on how the med­i­cine worked for those pa­tients (who dropped out) was not avail­able. The CHMP con­sid­ered that the way da­ta from these pa­tients were dealt with was not ap­pro­pri­ate,” the agency said ear­li­er this year.

A to­tal of 156 pa­tients com­plet­ed the tri­al — 97 of 152 pa­tients (63.8%) in the L-glu­t­a­mine group and 59 of 78 pa­tients (75.6%) in the place­bo group, ac­cord­ing to da­ta pub­lished by Em­maus. “The rea­sons for dis­con­tin­u­a­tion were sim­i­lar in the two tri­al groups; the most com­mon rea­sons were with­draw­al of con­sent, ‘oth­er’ rea­sons, and non­ad­her­ence,” the com­pa­ny wrote.

The EMA went on to flag con­cern about a small study used to sup­port the ap­pli­ca­tion for the drug. Once again, many pa­tients in this study dropped out ear­ly, the reg­u­la­tor un­der­scored. “(I)n this study more of the pa­tients tak­ing Xyn­dari had re­ceived a med­i­cine for sick­le cell dis­ease called hy­drox­yurea than pa­tients tak­ing place­bo. This could have in­flu­enced the re­sults.”

Af­ter its ini­tial neg­a­tive rec­om­men­da­tion in May, Em­maus asked the EMA to re­view its da­ta again in June, but the reg­u­la­tor stood by its orig­i­nal stance.

On Thurs­day, Em­maus — which was delist­ed from the Nas­daq ear­li­er this month — dis­closed it was with­draw­ing its Eu­ro­pean mar­ket­ing ap­pli­ca­tion.

Yu­ta­ka Ni­ihara Busi­ness Wire

“Be­cause we have demon­strat­ed the ef­fi­ca­cy of Xyn­dari, as sup­port­ed by the da­ta from the tri­als con­duct­ed, we are dis­ap­point­ed in the CHMP’s po­si­tion,” chief Yu­ta­ka Ni­ihara said in a state­ment.

How­ev­er, Xyn­dari is cur­rent­ly sup­plied through ear­ly ac­cess pro­grams based on named pa­tient use in a num­ber of EU mem­ber states, Turkey and the Mid­dle East.

Mean­while, Em­maus’ ri­vals in the Unit­ed States are scram­bling to get their SCD prod­ucts on the mar­ket.

Glob­al Blood Ther­a­peu­tics $GBT un­veiled pos­i­tive piv­otal da­ta on its sick­le cell dis­ease drug in June — the once-dai­ly pill vox­elo­tor is de­signed to work by in­creas­ing he­mo­glo­bin’s affin­i­ty for oxy­gen. No­var­tis’ $NVS ther­a­py for the blood dis­or­der was grant­ed a speedy re­view by the FDA in Ju­ly — the mon­o­clon­al an­ti­body, called crizan­l­izum­ab,  is ad­min­is­tered in­tra­venous­ly and en­gi­neered to bind to a mol­e­cule called P-se­lectin, one of the ma­jor dri­vers of the va­so-oc­clu­sive process. Oth­er drug­mak­ers, in­clud­ing Blue­bird Bio, Imara, and part­ners CRISPR Ther­a­peu­tics and Ver­tex, are al­so work­ing on their own drugs.

Sick­le cell dis­ease pa­tients have atyp­i­cal he­mo­glo­bin mol­e­cules, which can dis­tort red blood cells in­to a sick­le, or cres­cent, shape. Symp­toms such as ane­mia, re­peat­ed in­fec­tions and pe­ri­od­ic episodes of pain called va­so-oc­clu­sive crises (VOC) when sick­le-shaped red blood cells get stuck in­side blood ves­sels be­gin to ap­pear in ear­ly child­hood. These episodes de­prive the body of oxy­gen-rich blood, which can cul­mi­nate in wide­spread tis­sue and or­gan dam­age — par­tic­u­lar­ly in the lungs, kid­neys, spleen, heart, and brain — and dras­ti­cal­ly di­min­ish life ex­pectan­cy.

For now, bone mar­row trans­plants of­fer the on­ly po­ten­tial cure for sick­le cell ane­mia — but the pro­ce­dure is not safe enough for pa­tients old­er than 16 — be­sides se­cur­ing a healthy donor is dif­fi­cult and the risks can be life-threat­en­ing. There­fore, treat­ment is typ­i­cal­ly lim­it­ed to avoid­ing crises, re­liev­ing symp­toms and pre­vent­ing com­pli­ca­tions. Hy­drox­yurea, a drug be­lieved to stim­u­late the pro­duc­tion of fe­tal he­mo­glo­bin, is of­ten giv­en dai­ly to re­duce the fre­quen­cy of painful crises — but it in­creas­es the risk of in­fec­tion, and the risks as­so­ci­at­ed with long-term use are un­clear.

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Alice Shaw, Lung Cancer Foundation of America

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Sean Parker, AP

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Hal Barron, GSK's president of R&D and CSO, speaks to Endpoints News founder and editor John Carroll in London at Endpoints' #UKBIO19 summit on October 8, 2019

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Flu Virus (Source: CDC)

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