Al­ny­lam shores up en­thu­si­asm for givosir­an with ear­ly dataset ahead of cru­cial PhI­II read­out

In the run-up to top-line re­sults from a cru­cial Phase III for its sec­ond RNAi drug, Al­ny­lam has so­lid­i­fied an ear­ly set of safe­ty and ef­fi­ca­cy num­bers for givosir­an’s da­ta pack­age — part of a rolling sub­mis­sion at the FDA.

Re­sults from the Phase I, which we first heard about last April, sug­gest that month­ly in­jec­tions of givosir­an re­duced the num­ber of at­tacks in pa­tients with acute he­pat­ic por­phyr­ia by up to 79%, ac­cord­ing to a new pa­per in the New Eng­land Jour­nal of Med­i­cine. The us­age of hemin, an in­fu­sion cur­rent­ly used to treat these at­tacks, al­so dropped by 83% com­pared to place­bo, the com­pa­ny added.

Source: NE­JM

Click on the im­age to see the full-sized ver­sion


The key tar­get here is the ALAS1 mes­sen­ger RNA, or delta aminole­vulin­ic acid syn­thase 1, which leads to ac­cu­mu­la­tion of the tox­ic metabo­lites aminole­vulin­ic acid (ALA) — be­lieved to be the pri­ma­ry dis­ease trig­ger — and por­pho­bilino­gen (PBG). That leads to “acute de­bil­i­tat­ing neu­ro­vis­cer­al at­tacks and, in some pa­tients, dis­abling chron­ic symp­toms.”

Givosir­an brought all of them to nor­mal lev­els and kept it there, with a mean max­i­mum re­duc­tion of over 90%.

While promis­ing, these re­sults will have to be borne out by the on­go­ing PhI/II open-la­bel ex­ten­sion and Phase III stud­ies, es­pe­cial­ly con­sid­er­ing that the at­tack re­duc­tion da­ta are based on 6 pa­tients as­signed to givosir­an in one of three parts of this 40-pa­tient study.

Part C of the tri­al al­so ze­roed in on acute in­ter­mit­tent por­phyr­ia, “the most com­mon sub­type of AHP where pa­tients ex­pe­ri­ence re­cur­rent, in­ca­pac­i­tat­ing, neu­ro­vis­cer­al at­tacks re­quir­ing hos­pi­tal­iza­tion or ur­gent med­ical at­ten­tion,” ac­cord­ing to Eliane Sardh of the Karolin­s­ka In­sti­tutet, the lead au­thor of the NE­JM pa­per.

In terms of safe­ty — a his­toric con­cern for Al­ny­lam’s RNAi drugs — in­ves­ti­ga­tors doc­u­ment­ed se­ri­ous ad­verse events in 6 pa­tients who re­ceived givosir­an through­out the tri­al, in­clud­ing a fa­tal case of he­m­or­rhag­ic pan­cre­ati­tis con­sid­ered un­like­ly re­lat­ed to the drug. Oth­er com­mon ad­verse ef­fects in­clude na­sopharyn­gi­tis, ab­dom­i­nal pain and di­ar­rhea.

“There was no clear dif­fer­ence in the pro­por­tion of pa­tients who re­port­ed ad­verse events and se­vere ad­verse events be­tween the place­bo group and the givosir­an group, and there was no clear re­la­tion­ship be­tween givosir­an dose and the in­ci­dence of ad­verse events,” the NE­JM pa­per not­ed.

As­sum­ing pos­i­tive re­sults in the Phase III, Al­ny­lam aims to sub­mit full clin­i­cal sec­tions in mid-2019 for its rolling NDA af­ter drop­ping ear­li­er plans for an ac­cel­er­at­ed ap­proval.

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Sanofi brings in 4 new ex­ec­u­tives in con­tin­ued shake-up, as vac­cines and con­sumer health chief head out the door

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The company also said today that Alan Main, the head of their consumer healthcare unit, is out, and they named 4 executives to fill new or newly vacated positions, 3 of whom come from both outside both Sanofi and from Pharma.

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Roger Perlmutter, Merck R&D chief (YouTube)

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Pablo Legorreta, founder and CEO of Royalty Pharma AG, speaks at the annual Milken Institute Global Conference in Beverly Hills, California (Patrick T. Fallon/Bloomberg via Getty Images)

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As­traZeneca’s $7B ADC suc­ceeds where Roche failed, im­prov­ing sur­vival in gas­tric can­cer

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Dan O'Day, Gilead CEO (Andrew Harnik, AP Images)

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