Eas­ing con­cerns, Fi­bro­Gen, As­traZeneca se­cure FDA date for their ane­mia drug in broad chron­ic kid­ney dis­ease pop­u­la­tion

Armed with a new chief fol­low­ing the un­ex­pect­ed pass­ing of long­time CEO Thomas Neff last year, Fi­bro­Gen is off to the races with its con­tro­ver­sial As­traZeneca-part­nered ane­mia drug. The FDA has ac­cept­ed the com­pa­ny’s ap­pli­ca­tion to mar­ket the oral ther­a­py — which is po­si­tioned to re­place the stan­dard of care — in pa­tients with chron­ic kid­ney dis­ease re­gard­less of dial­y­sis sta­tus.

The drug, rox­adu­s­tat, which is de­signed to stim­u­late the pro­duc­tion of red blood cells by mim­ic­k­ing the ef­fect of high al­ti­tude in hu­mans was ap­proved in Chi­na last year — mark­ing per­haps the first in­stance of a multi­na­tion­al phar­ma­ceu­ti­cal com­pa­ny As­traZeneca paving the way for the sale of a med­i­cine in Chi­na, be­fore the Unit­ed States or Eu­rope.

Fi­bro­Gen and As­traZeneca are locked in a race with Ake­bia, whose ex­per­i­men­tal drug vadadu­s­tat has a sim­i­lar mech­a­nism of ac­tion. But piv­otal vadadu­s­tat da­ta are not ex­pect­ed un­til lat­er in 2020. The dom­i­nant drugs for ane­mia in the Unit­ed States are red-blood-cell boost­ing ery­thro­poiesis-stim­u­lat­ing agents (ESA) from Am­gen. The stan­dard-of-care does, how­ev­er, come with high car­dio risks — but giv­en the steep over­all mor­tal­i­ty rate for this pa­tient pop­u­la­tion, it is a risk reg­u­la­tors con­sid­er ac­cept­able.

Healthy kid­neys pro­duce a hor­mone called ery­thro­poi­etin (EPO), which prompts the bone mar­row to make red blood cells that car­ry oxy­gen through­out the body. If dis­eased or dam­aged, kid­neys are un­able to make enough EPO, re­sult­ing in few­er blood cells, and even­tu­al­ly ane­mia.

Fi­bro­Gen, which orig­i­nal­ly de­vel­oped the drug, has part­nered with As­traZeneca since 2013. On Tues­day, the com­pa­ny — which brought on Lil­ly vet En­rique Con­ter­no to take over the reins last month — said the FDA was ex­pect­ed to make its de­ci­sion by De­cem­ber 20 — trig­ger­ing a $50 mil­lion mile­stone pay­ment from As­traZeneca.

“(R)eas­sur­ing­ly, the FDA si­mul­ta­ne­ous­ly ac­cept­ed the NDA fil­ing for both DD (dial­y­sis-de­pen­dent) and NDD (non-dial­y­sis de­pen­dent) in­di­ca­tions, which should par­tial­ly re­move some of the neg­a­tive over­hang on FGEN’s stock as­so­ci­at­ed with lin­ger­ing skep­ti­cism sur­round­ing the prospects for a suc­cess­ful fil­ing and ap­proval in the more con­tro­ver­sial NDD in­di­ca­tion,” SVB Leerink’s Ge­of­frey Porges wrote in a note.

“Al­though a pri­or­i­ty re­view now ap­pears to be off the ta­ble, the PDU­FA date time­line re­mains con­sis­tent with our ex­pec­ta­tions for an Ad­Com to oc­cur some­time in Q3 2020.”

While rox­adu­s­tat did meet the main goal of en­hanc­ing he­mo­glo­bin lev­els in a pair of piv­otal stud­ies, the drug has a check­ered past.

Last spring, Fi­bro­Gen came un­der fire for mask­ing some un­sa­vory safe­ty da­ta in­di­cat­ing the drug could un­der­whelm in key mar­ket seg­ments — in the top-line mes­sag­ing of ‘pos­i­tive’ pooled safe­ty da­ta on the drug from two sets of re­sults on ma­jor car­dio events (MACE and MACE+) re­quired by US and Eu­ro­pean reg­u­la­tors. The mes­sag­ing in­spired a short at­tack bet­ting that rox­adu­s­tat would come up short when re­searchers un­veil the hard num­bers on the piv­otal safe­ty da­ta on ma­jor car­dio events com­pared to place­bo and EPO.

Then, in No­vem­ber, some con­cerns were as­suaged when As­traZeneca broke out the pooled haz­ard ra­tios on rox­adu­s­tat safe­ty. In­ves­ti­ga­tors as­sessed the drug against place­bo for non-dial­y­sis de­pen­dent CKD pa­tients, and against EPO in dial­y­sis pa­tients, in­clud­ing a pop­u­la­tion of pa­tients new-to-dial­y­sis, or in­ci­dent dial­y­sis. But even at its worst haz­ard ra­tio on the MACE end­point, re­searchers showed rox­adu­s­tat’s safe­ty pro­file was com­pa­ra­ble to EPO — which damp­ened the block­buster ex­pec­ta­tions that would have come with achiev­ing su­pe­ri­or­i­ty.

Mean­while, some crit­ics panned the analy­sis be­cause the com­pa­nies looked at the full in­tent-to-treat pop­u­la­tion. As place­bo pa­tients were switched to EPO, they were more like­ly to ex­pe­ri­ence CV events, swing­ing the pen­du­lum in rox­adu­s­tat’s fa­vor.

“Ma­jor de­bates re­volve around whether it’s go­ing to ac­tu­al­ly be ap­proved and if it’s a broad la­bel in DD and NDD and if they get a black box (we as­sume yes be­cause FDA is su­per con­ser­v­a­tive – and we think Street un­der­stands that’s prob­a­ble so we like the up­side if they do not get a black box),” Jef­feries’ an­a­lyst Michael Yee wrote in a note.

“We think FDA is on board with the sta­tis­tics and da­ta (per FGEN’s FDA meet­ing min­utes, dis­cus­sions, and di­a­log), and part­ners AZN and Astel­las have been pos­i­tive (vo­cal­ly) on the re­sults. AZN wouldn’t have helped file and paid a large $50M mile­stone if they didn’t be­lieve in the drug.”

Ri­val Ake­bia’s da­ta is now in fo­cus.

Yee said he ex­pect­ed the com­pa­ny’s drug, vadadu­s­tat, to hit the end­points of on ef­fi­ca­cy and “non-in­fe­ri­or­i­ty” on CVOT safe­ty ver­sus EPO, like Fi­bro­Gen $FGEN. “But we will look to see if they can hit on “su­pe­ri­or­i­ty” to EPO on in­ci­dent dial­y­sis since this is where FGEN had “su­pe­ri­or” MACE CV da­ta of +30% ben­e­fit in a pooled analy­sis.”

So­cial im­age: Fi­bro­gen

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