Up­dat­ed: In sur­prise turn, FDA ad­comm votes in fa­vor of Arde­lyx CKD drug de­spite agency ques­tions

Af­ter the FDA re­ject­ed and ques­tioned Arde­lyx’s po­ten­tial drug for the con­trol of serum phos­pho­rus lev­els in adults with chron­ic kid­ney dis­ease on dial­y­sis, the FDA’s Car­dio­vas­cu­lar and Re­nal Drugs ad­vi­so­ry com­mit­tee on Wednes­day vot­ed 9-4 in fa­vor of the drug as a monother­a­py, and 10-2 (with one ab­sten­tion) in fa­vor of the drug when ad­min­is­tered in com­bo with phos­phate binder treat­ment.

Ad­comm com­mit­tee chair Ju­lia Lewis of Van­der­bilt Med­ical Cen­ter said the drug, known as tena­panor, of­fers small­er pills, and al­though it may see less ef­fi­ca­cy than the cur­rent stan­dard of care, there’s a small sub­set of CKD pa­tients who will re­spond to monother­a­py and “let’s make that avail­able to them.”

Pan­elist Ed­ward Kasper, pro­fes­sor in car­di­ol­o­gy at Johns Hop­kins, al­so vot­ed in fa­vor of it as a monother­a­py, call­ing the safe­ty ques­tions around se­vere di­ar­rhea ac­cept­able giv­en how close­ly this pop­u­la­tion will be mon­i­tored, and he said there’s clear­ly a role for this drug. Oth­ers who vot­ed against tena­panor as a monother­a­py raised ques­tions about the mag­ni­tude of the ef­fect of the drug.

In af­ter-hours trad­ing yes­ter­day evening, Arde­lyx’s stock price rose by as much as 75%. The FDA’s Of­fice of New Drugs is ex­pect­ed to pro­vide a re­sponse to Arde­lyx’s ap­peal to its ear­li­er CRL with­in 30 days, the com­pa­ny said.

“To­day’s vote by the CR­DAC is a promis­ing de­vel­op­ment for the chron­ic kid­ney dis­ease com­mu­ni­ty, as pa­tients con­tin­ue to strug­gle to con­trol serum phos­pho­rus lev­els de­spite use of cur­rent­ly avail­able ther­a­pies, which are all lim­it­ed to the phos­phate binder class,” Mike Raab, pres­i­dent and CEO of Arde­lyx, said in a state­ment. “We are con­fi­dent that the da­ta from three Phase 3 clin­i­cal tri­als in­volv­ing more than 1,200 pa­tients sup­port the ap­proval of XPHOZAH in the U.S. for the con­trol of serum phos­pho­rus in adult pa­tients with CKD on dial­y­sis.”

De­bate dur­ing the morn­ing Wednes­day cen­tered on FDA’s ques­tions around the mag­ni­tude of ben­e­fit of the drug in the piv­otal tri­als.

But Arde­lyx made the case that tena­panor, which is al­ready ap­proved for ir­ri­ta­ble bow­el syn­drome with con­sti­pa­tion in adults, can help what is a sig­nif­i­cant un­met need for new op­tions to con­trol serum phos­pho­rus lev­els. Even the FDA’s ini­tial re­jec­tion let­ter in 2021 said that the sub­mit­ted da­ta “pro­vide sub­stan­tial ev­i­dence that tena­panor is ef­fec­tive in re­duc­ing serum phos­pho­rus in CKD pa­tients on dial­y­sis,” Arde­lyx’s pre­sen­ta­tion said.

FDA, how­ev­er, point­ed to a mean treat­ment ef­fect for tena­panor in this pop­u­la­tion of −0.7 mg/dL in both monother­a­py stud­ies, which “ap­peared to be less than that ob­served with ap­proved agents (~1.5 to 2.2 mg/dL).” And for tena­panor use in com­bi­na­tion with phos­phate binder treat­ment, the FDA said the mag­ni­tude of the treat­ment ef­fect was sim­i­lar to that ob­served in the monother­a­py tri­als.

Even still, in the com­mit­tee’s dis­cus­sion, pan­elists re­it­er­at­ed that there would be a sub­set of pa­tients who will ben­e­fit from Arde­lyx’s pill, par­tic­u­lar­ly those who can’t tol­er­ate phos­phate binders that are large and dif­fi­cult to swal­low (al­though pill bur­den wasn’t tab­u­lat­ed) and have to be tak­en mid-meal, ac­cord­ing to some of the pub­lic com­ments.

Ad­comm pan­elist Su­san Mend­ley of the NIH’s Di­vi­sion of Kid­ney, Uro­log­ic and Hema­to­log­ic Dis­eases, who vot­ed in fa­vor of tena­panor as monother­a­py, not­ed that while oral phos­phate binders have shown a larg­er ef­fect size, many pa­tients don’t tol­er­ate them, and they’re not pleas­ant to take. As a monother­a­py in the right pa­tient, “I think they have met their out­come,” she said.

But pan­elist Christo­pher O’Con­nor of Vir­ginia’s In­o­va Heart and Vas­cu­lar In­sti­tute, who vot­ed against tena­panor, ques­tioned whether 0.7 mg/dL “is enough when you’re talk­ing about a sur­ro­gate end­point that has not been val­i­dat­ed. We have to talk about the clin­i­cal mean­ing­ful­ness we have, and I’m con­cerned it may not be there.” FDA brief­ing doc­u­ments raised sim­i­lar ques­tions about the mag­ni­tude of the treat­ment ef­fect.

Ad­comm mem­ber Lin­da Fried of the Uni­ver­si­ty of Pitts­burgh, who vot­ed in fa­vor of the drug’s risk-ben­e­fit pro­file, said she doesn’t see tena­panor much as a monother­a­py ex­cept in those who don’t tol­er­ate the phos­phate binders.

Safe­ty con­cerns from FDA honed in on both­er­some and some­times se­vere di­ar­rhea, with the ma­jor­i­ty of cas­es last­ing more than 30 days, and with se­vere mean­ing the tri­al par­tic­i­pant was un­able to work or con­duct usu­al ac­tiv­i­ties. Al­most half of the tena­panor arm in one of the piv­otal tri­als re­quired a change of dose or dis­con­tin­ued be­cause of di­ar­rhea, FDA’s safe­ty an­a­lyst Se­le­na De­Con­ti told the com­mit­tee.

Ed­i­tor’s note: Ar­ti­cle up­dat­ed with com­ment from Arde­lyx and the change in stock price.

Has the mo­ment fi­nal­ly ar­rived for val­ue-based health­care?

RBC Capital Markets’ Healthcare Technology Analyst, Sean Dodge, spotlights a new breed of tech-enabled providers who are rapidly transforming the way clinicians deliver healthcare, and explores the key question: can this accelerating revolution overturn the US healthcare system?

Key points

Tech-enabled healthcare providers are poised to help the US transition to value, not volume, as the basis for reward.
The move to value-based care has policy momentum, but is risky and complex for clinicians.
Outsourced tech specialists are emerging to provide the required expertise, while healthcare and tech are also converging through M&A.
Value-based care remains in its early stages, but the transition is accelerating and represents a huge addressable market.

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