Piv­otal myas­the­nia gravis da­ta from ar­genx au­gur well for FcRn in­hibitors in de­vel­op­ment

Lead­ing the pack of biotechs vy­ing for a piece of the gen­er­al­ized myas­the­nia gravis (gMG) mar­ket with an FcRn in­hibitor, ar­genx on Tues­day un­veiled keen­ly an­tic­i­pat­ed pos­i­tive late-stage da­ta on its lead as­set, bring­ing it one step clos­er to reg­u­la­to­ry ap­proval and lift­ing its stock by more than a third.

De­spite steroids, im­muno­sup­pres­sants, acetyl­cholinesterase in­hibitors, and Alex­ion’s Soliris, pa­tients with the rare, chron­ic neu­ro­mus­cu­lar dis­or­der (more than 100,000 in the Unit­ed States and Eu­rope) don’t nec­es­sar­i­ly ben­e­fit from these ex­ist­ing op­tions, leav­ing room for the crop of FcRn in­hibitors in de­vel­op­ment.

Bel­gium-based ar­genx’s ex­per­i­men­tal drug, ef­gar­tigi­mod, was test­ed against a place­bo over 26 weeks in 167 adults with gen­er­al­ized myas­the­nia gravis (gMG) who were on back­ground gMG ther­a­py in the late-stage study chris­tened ADAPT.

In the study, 67.7% of acetyl­choline re­cep­tor-an­ti­body pos­i­tive pa­tients treat­ed with ef­gar­tigi­mod achieved the pri­ma­ry end­point — the per­cent­age of re­spon­ders (a re­spon­der was de­fined as ≥2 point im­prove­ment for at least 4 con­sec­u­tive weeks, dur­ing the first 8-week pe­ri­od) on a dai­ly liv­ing with MG scale — com­pared with 29.7% on place­bo (p<0.0001).

On the sec­ondary goal, 63.1% of those pa­tients re­spond­ed to ef­gar­tigi­mod com­pared with 14.1% on place­bo on an­oth­er scale called Quan­ti­ta­tive Myas­the­nia Gravis (QMG) (p<0.0001). Oth­er sec­ondary end­points, in­clud­ing time on tri­al in clin­i­cal­ly mean­ing­ful im­prove­ment and fast on­set of re­sponse, were al­so found to be sta­tis­ti­cal­ly sig­nif­i­cant, al­though the time to qual­i­fy for re­treat­ment end­point was not met.

“While re­spon­der cri­te­ria in ar­genx’s ADAPT tri­al are slight­ly dif­fer­ent than those uti­lized in the piv­otal tri­als of Alex­ion’s Soliris, we broad­ly view ar­genx’s top-line da­ta as strong in com­par­i­son to the piv­otal da­ta from Soliris, and be­lieve this da­ta could po­si­tion FcRN in­hi­bi­tion as hav­ing a sig­nif­i­cant role …” Baird’s Bri­an Sko­r­ney wrote in a note.

Mean­while, there were no red flags on the safe­ty side. “Over­all, we think the like­ly speed of on­set and def­i­nite­ly the safe­ty of ef­gar­tigi­mod com­pares ex­treme­ly well to stan­dard of care ther­a­pies, such as IVIG and PLEX, which have rapid on­set but are no­to­ri­ous for their safe­ty is­sues,” Stifel an­a­lysts wrote in a note.

Shares of the com­pa­ny $ARGX shot up near­ly 33% to $210 on the Nas­daq in Tues­day morn­ing trad­ing.

With these re­sults, ar­genx plans to sub­mit a mar­ket­ing ap­pli­ca­tion for the IV for­mu­la­tion (60 min in­fu­sion) by the end of 2020. If ap­proved, like­ly by 2021, this ver­sion of the prod­uct should pave the way for the com­pa­ny’s sub­cu­ta­neous for­mu­la­tion (pack­aged as a sin­gle ~5 mL in­jec­tion) to boost com­mer­cial prospects. Stifel an­a­lysts fore­cast ~$1.7 bil­lion in peak sales for both ef­gar­tigi­mod for­mu­la­tions for use in MG pa­tients.

Oth­er play­ers with FcRn in­hibitors in the pipeline for MG in­clude UCB’s rozano­lix­izum­ab (~30 min sub­cu­ta­neous in­fu­sion), Mo­men­ta Phar­ma­ceu­ti­cals’ nipocal­imab (~7.5-15 min IV in­fu­sion, with a sub­cu­ta­neous for­mu­la­tion in de­vel­op­ment), Im­muno­vant’s IMVT-1401 (two sub­cu­ta­neous in­jec­tions of 2 mL each per dose) and Alex­ion’s ALXN1830 (a sub­cu­ta­neous in­fu­sion that will be test­ed in a Phase II tri­al planned for the sec­ond half of 202o). Apart from ef­fi­ca­cy, the con­ve­nience of dos­ing and du­ra­tion will play a key role in the adop­tion of these FcRn ther­a­pies, an­a­lysts said.

Ar­genx’s re­sults fur­ther val­i­date the an­ti-FcRn mech­a­nism in MG and bode well for the mid-stage nipocal­imab read­out ex­pect­ed in the com­ing weeks, Stifel an­a­lysts added on Tues­day.

MG oc­curs when IgG an­ti­bod­ies dis­rupt com­mu­ni­ca­tion be­tween nerves and mus­cles, caus­ing po­ten­tial­ly life-threat­en­ing mus­cle weak­ness. More than 85% of pa­tients progress to gen­er­al­ized MG (gMG) with­in 18 months, where mus­cles through­out the body may be af­fect­ed, re­sult­ing in ex­treme fa­tigue and dif­fi­cul­ties with fa­cial ex­pres­sion, speech, swal­low­ing and mo­bil­i­ty.

The need for new treat­ment op­tions is ap­par­ent — giv­en the tox­i­c­i­ty of steroids and im­muno­sup­pres­sants and Soliris’ pro­hib­i­tive costs. While in­tra­venous im­munoglob­u­lin (IVIg) is used as a stop-gap, high costs, long in­fu­sions ac­com­pa­nied by headaches and sup­ply con­straints lim­it its broad­er ap­peal.

“FcRn an­tag­o­nists’ broad­ly ap­plic­a­ble mech­a­nism of ac­tion and safe and ef­fi­ca­cious clin­i­cal pro­file should sup­port their com­pet­i­tive edge and sup­port use in ear­li­er lines of ther­a­py. Giv­en ef­gar­tigi­mod’s lead to mar­ket and like­ly avail­abil­i­ty as both IV and SQ, we an­tic­i­pate that it will cap­ture the li­on’s share of the mar­ket,” Cowen an­a­lyst Yaron Wer­ber wrote in an April note.

The neona­tal Fc re­cep­tor (FcRn) plays a key role in pre­vent­ing the degra­da­tion of IgG an­ti­bod­ies. FcRn re­cy­cles IgG an­ti­bod­ies by shut­tling them away from lyso­so­mal degra­da­tion, there­by pre­serv­ing path­o­gen­ic an­ti­body lev­els in IgG-me­di­at­ed dis­eases such as myas­the­nia gravis (a long-term con­di­tion). Drugs de­signed to in­hib­it FcRn, there­fore, are de­signed to de­crease to­tal IgG — cru­cial­ly path­o­gen­ic IgG — to treat pa­tients.

So­cial im­age: ar­genx

Health­care Dis­par­i­ties and Sick­le Cell Dis­ease

In the complicated U.S. healthcare system, navigating a serious illness such as cancer or heart disease can be remarkably challenging for patients and caregivers. When that illness is classified as a rare disease, those challenges can become even more acute. And when that rare disease occurs in a population that experiences health disparities, such as people with sickle cell disease (SCD) who are primarily Black and Latino, challenges can become almost insurmountable.

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David Meek, new Mirati CEO (Marlene Awaad/Bloomberg via Getty Images)

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