John Maraganore, Alnylam CEO (Scott Eisen/Bloomberg via Getty Images)

With lumasir­an on the FDA's doorstep, Al­ny­lam reads out new PhI­II da­ta in PH1

Just over a month away from its De­cem­ber PDU­FA date, Al­ny­lam flaunt­ed new da­ta from two Phase III stud­ies to back lumasir­an in pri­ma­ry hy­per­ox­aluria type 1 (PH1), a rare liv­er con­di­tion.

The Cam­bridge, MA-based biotech snagged a pri­or­i­ty re­view for the can­di­date back in June, and got pos­i­tive feed­back from the EMA’s Com­mit­tee for Med­i­c­i­nal Prod­ucts for Hu­man Use just last week. Lumasir­an us­es RNA in­ter­fer­ence (RNAi) to si­lence the gene for gly­co­late ox­i­dase, an en­zyme used in the pro­duc­tion of ox­alate.

On Thurs­day at this year’s ASN Kid­ney Week, Al­ny­lam read out 6-month re­sults from a study in chil­dren be­tween 3 months and 6 years old, and 12-month re­sults from a tri­al in pa­tients old­er than 6 years.

In the lat­ter study, dubbed IL­LU­MI­NATE-A, pa­tients ini­tial­ly placed in the treat­ment arm were shown to main­tain a re­duc­tion in 24-hour ox­alate ex­cre­tion, with a 64% mean re­duc­tion rel­a­tive to base­line. Of this group, 88% achieved nor­mal or near-nor­mal uri­nary ox­alate lev­els, ac­cord­ing to Al­ny­lam. Pa­tients with PH1 tend to over­pro­duce uri­nary ox­alate, which po­ten­tial­ly leads to kid­ney stones, or in some cas­es kid­ney fail­ure at a young age.

Those who were ini­tial­ly in the place­bo arm but crossed over to lumasir­an showed a 57% mean re­duc­tion in 24-hour uri­nary ox­alate ex­cre­tion af­ter 6 months of treat­ment, the com­pa­ny an­nounced. About 77% of these pa­tients reached nor­mal or near-nor­mal uri­nary oxy­late lev­els.

Al­ny­lam says there were no deaths, se­ri­ous ad­verse events (SAEs), treat­ment in­ter­rup­tions or dis­con­tin­u­a­tions linked to the drug. One pa­tient ex­pe­ri­enced urosep­sis, but the biotech said it was un­re­lat­ed to the ex­per­i­men­tal can­di­date. Some pa­tients ex­pe­ri­enced mild in­jec­tion site re­ac­tions, in­clud­ing ery­the­ma, pain, pru­ri­tus, or swelling.

As for the pe­di­atric study, IL­LU­MI­NATE-B, those in the treat­ment arm showed a 72% mean re­duc­tion in spot uri­nary ox­alate to cre­a­ti­nine ra­tio from base­line, av­er­aged across months 3 to 6, ac­cord­ing to the biotech. Half of pa­tients ex­pe­ri­enced nor­mal or near-nor­mal uri­nary ox­alate lev­els.

A pre­lim­i­nary analy­sis al­so showed that 8 of 18 pa­tients — about 44% — had im­prove­ments in nephro­cal­ci­nosis. At base­line, 14 pa­tients ex­pe­ri­enced the dis­or­der, char­ac­ter­ized by too much cal­ci­um de­po­si­tion in the kid­neys. At the 6-month mark, no pa­tients wors­ened, 10 re­mained sta­ble, and 8 showed bi­lat­er­al or uni­lat­er­al im­prove­ments, Al­ny­lam said.

The biotech re­port­ed no deaths, SAEs, dis­con­tin­u­a­tions of treat­ment or with­drawals from the study. The ef­fi­ca­cy and safe­ty re­sults, it said, were sim­i­lar to those ob­served in IL­LU­MI­NATE-A. Like that study, one pa­tient ex­pe­ri­enced an SAE that the biotech said wasn’t linked to the drug (in this case, a vi­ral in­fec­tion).

In an on­go­ing Phase II open-la­bel ex­ten­sion study, re­searchers ob­served sus­tained re­duc­tions in uri­nary ox­alate ex­cre­tion and an “ac­cept­able safe­ty pro­file,” ac­cord­ing to Al­ny­lam. They al­so found that af­ter long-term treat­ment, few­er pa­tients had re­nal stones. Pri­or to the study, 6 of 20 pa­tients re­port­ed re­nal stones. In the Phase I/II Part B study, 4 of 20 pa­tients re­port­ed them. And dur­ing Phase II (with up to 22 months of treat­ment), no pa­tients re­port­ed them, Al­ny­lam said.

“Based on longer term fol­low-up from the IL­LU­MI­NATE-A and Phase 2 open-la­bel ex­ten­sion stud­ies, in­ves­ti­ga­tors pre­sent­ed da­ta show­ing en­dur­ing re­duc­tions of uri­nary ox­alate – the dis­ease-caus­ing metabo­lite in PH1. More­over, we be­lieve that new­ly pre­sent­ed re­sults of ex­plorato­ry end­points pro­vide pre­lim­i­nary ev­i­dence that re­duc­tions in uri­nary ox­alate may lead to re­duced rates of re­nal stone events and im­prove nephro­cal­ci­nosis in some pa­tients,” Pritesh Gand­hi, VP and gen­er­al man­ag­er of the lumasir­an pro­gram, sum­ma­rized in a state­ment.

Around 2011, ma­jor com­pa­nies like Pfiz­er and Ab­bott bailed from the RNAi field, eat­ing heavy loss­es. But Al­ny­lam CEO John Maraganore re­mained stead­fast, pledg­ing to bring 5 RNAi drugs in­to late-stage de­vel­op­ment by 2015.

If ap­proved, lumasir­an would be Al­ny­lam’s third ap­proved drug in the last three years. The biotech has two oth­er RNAi drugs in late-stage de­vel­op­ment, in­clud­ing in­clisir­an (now part­nered with No­var­tis), plus a la­bel ex­pan­sion for patisir­an in the works. Sev­en oth­er can­di­dates are in ear­ly-stage de­vel­op­ment, in­clud­ing one for Covid-19.

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