As ri­vals march on, No­var­tis se­cures pri­or­i­ty FDA re­view for sick­le cell dis­ease ther­a­py

About a month af­ter ri­val Glob­al Blood Ther­a­peu­tics $GBT un­veiled pos­i­tive piv­otal da­ta on its sick­le cell dis­ease drug, No­var­tis’ $NVS ther­a­py for the blood dis­or­der has been grant­ed a speedy re­view by the FDA.

Vas Narasimhan

Tout­ed by No­var­tis chief Vas Narasimhan as a po­ten­tial block­buster, the Swiss drug­mak­er’s drug, crizan­l­izum­ab, in Jan­u­ary se­cured the FDA’s break­through ther­a­py des­ig­na­tion for its abil­i­ty to pre­vent de­bil­i­tat­ing­ly painful va­so-oc­clu­sive cri­sis (VOCs) for pa­tients af­fect­ed by the group of in­her­it­ed red blood cell dis­or­ders that typ­i­cal­ly af­flict those of African an­ces­try.

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.

No­var­tis’ mon­o­clon­al an­ti­body, called crizan­l­izum­ab or SEG101, is ad­min­is­tered in­tra­venous­ly and en­gi­neered to bind to a mol­e­cule called P-se­lectin, one of the ma­jor dri­vers of the va­so-oc­clu­sive process. No­var­tis gained ac­cess to the drug in 2016 via an ac­qui­si­tion of Se­lexys Phar­ma­ceu­ti­cals in a deal val­ued at up to $665 mil­lion.

The drug has shown to re­duce the me­di­an an­nu­al rate of VOCs lead­ing to health care vis­its, and an analy­sis of Phase II da­ta pre­sent­ed at the ASH con­fer­ence last year al­so showed that 35.8% of those giv­en the ex­per­i­men­tal treat­ment did not ex­pe­ri­ence a VOC, ver­sus 16.9% on the place­bo arm in pa­tients with a his­to­ry of 2-10 VOCs in the pre­ced­ing year. Af­ter ini­tial­ly sug­gest­ing a mar­ket­ing ap­pli­ca­tion would be sub­mit­ted in 2018, No­var­tis said it would make its case for the drug in 2019.

Last month, Glob­al Blood Ther­a­peu­tics said it was poised to sub­mit an ap­pli­ca­tion for ac­cel­er­at­ed ap­proval for its once-dai­ly pill vox­elo­tor — which is de­signed to work by in­creas­ing he­mo­glo­bin’s affin­i­ty for oxy­gen — in the sec­ond half of this year. Da­ta pre­sent­ed showed the drug con­ferred a sus­tained im­prove­ment in oxy­gen-rich he­mo­glo­bin lev­els, and was al­so as­so­ci­at­ed with few­er VOCs — a key sec­ondary end­point — but the dif­fer­ence wasn’t sta­tis­ti­cal­ly sig­nif­i­cant.

“While No­var­tis por­trays an ad­van­tage of po­ten­tial­ly hav­ing crizan­l­izum­ab ap­proved ahead of vox­elo­tor, we be­lieve vox­elo­tor has an edge on con­ve­nience. Ul­ti­mate­ly, we don’t view the drugs as di­rect com­peti­tors, but rather com­ple­men­tary treat­ments, giv­en both drugs show ben­e­fi­cial re­sults in dif­fer­ent mea­sures, and work through dif­fer­ent mech­a­nism of ac­tions,” Can­tor Fitzger­ald an­a­lyst El­e­mer Piros wrote in a note.

In 2017, Em­maus Life Sci­ences se­cured SCD ap­proval from the FDA for En­dari — a phar­ma­ceu­ti­cal ver­sion of L-glu­t­a­mine, a drug sold over-the-counter as a nu­tri­tion­al sup­ple­ment. EU reg­u­la­tors in con­trast re­cent­ly rec­om­mend­ed the drug not be ap­proved on the ba­sis that the da­ta from the main tri­al did not show it was ef­fec­tive at re­duc­ing the num­ber of sick­le cell crises or hos­pi­tal vis­its, and a high drop-out rate in the study.

GBT last Au­gust li­censed a P-se­lectin an­tag­o­nist, in­clacum­ab, from Roche. Oth­er drug­mak­ers, in­clud­ing blue­bird Bio $BLUE, Imara, and part­ners CRISPR Ther­a­peu­tics and Ver­tex $VRTX, are al­so work­ing on their own ther­a­pies. Pfiz­er $PFE and Gly­coMimet­ics $GLYC are test­ing their SCD drug, riv­ipansel, in an on­go­ing Phase III study.

In a note pub­lished in late June with com­men­tary from a key opin­ion leader, Cowen an­a­lysts laid out the po­ten­tial land­scape of SCD ther­a­pies.

“BLUE’s Lenti­Glo­bin showed im­pres­sive da­ta and has a po­ten­tial to be cu­ra­tive…GBT’s Vox­elo­tor needs more mean­ing­ful da­ta to prove re­al-world ef­fi­ca­cy and safe­ty. NVS’s crizan has com­pelling da­ta like­ly to gar­ner ap­proval in 18+ yo and PFE/GLYC’s Riv­ipansel Ph3 study de­sign has some el­e­ments that raise con­cerns, but might still be ap­prov­able.”

So­cial im­age: No­var­tis, AP Im­ages

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Anthony Fauci (AP Images)

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