A ra­dioac­tive prostate can­cer ther­a­py is a last life­line for pa­tients. No­var­tis can't make enough of it

Al­fre­do Na­já Domin­gos’ prostate can­cer was spread­ing. The ma­lig­nant cells per­me­at­ed his bones, kid­ney, lungs and liv­er, and in De­cem­ber, his on­col­o­gist told him there was no point in con­tin­u­ing chemother­a­py treat­ment.

But there was a new treat­ment he could try: a tar­get­ed ra­dio­ther­a­py called Plu­vic­to — if he could get it in time. Both Mof­fitt Can­cer Cen­ter and Mayo Clin­ic in Flori­da, not too far from Domin­gos and his fam­i­ly, said he would have to wait be­tween three and a half and four months to get the treat­ment. His wife, No­ra Flor, said she and her sis­ter made calls to at least 30 cen­ters across the US look­ing for the drug.

“I was in a state of des­per­a­tion,” Domin­gos said.

Pa­tients like Domin­gos have faced months-long waits for Plu­vic­to, de­lay­ing or elim­i­nat­ing a last life­line, ac­cord­ing to doc­tors. The sup­ply crunch has be­come so acute that No­var­tis on Sun­day sus­pend­ed new pa­tient starts for the drug, a spokesper­son con­firmed to End­points News yes­ter­day. It’s the lat­est twist in the on­go­ing short­age that has left pa­tients and doc­tors grap­pling with what to do next.

Go­ing main­stream

Last March, the FDA ap­proved Plu­vic­to for pa­tients with late-stage prostate can­cer who’ve al­ready tried both chemother­a­py and hor­mone block­ers. But as No­var­tis was ramp­ing up Plu­vic­to’s launch, the drug­mak­er ran in­to man­u­fac­tur­ing is­sues that have de­layed dis­tri­b­u­tion and re­sult­ed in on-again, off-again sup­ply.

The on­go­ing short­age high­lights the tall or­der of sup­ply­ing a drug with a ra­dioac­tive iso­tope that gives it a shelf life of mere days, mak­ing it im­pos­si­ble to stock­pile.

Plu­vic­to is an ear­ly test case in the bid to main­stream tar­get­ed ra­dio­ther­a­pies that di­rect ra­di­a­tion at can­cer cells, while spar­ing the sur­round­ing tis­sue from side ef­fects. Ra­dio­ther­a­pies have been stud­ied since the 1980s, and sev­er­al have won ap­proval but reached lim­it­ed pa­tient pop­u­la­tions. No­var­tis be­lieves that Plu­vic­to could fi­nal­ly gain wider use, and that the drug could reach at least $2 bil­lion in peak sales, which would make it the first block­buster tar­get­ed ra­dio­ther­a­py.

Tar­get­ed ra­dio­ther­a­pies, al­so known as ra­di­oli­gand ther­a­pies, at­tach a ra­dioac­tive iso­tope to a hom­ing drug which seeks out a spe­cif­ic can­cer cell mark­er, send­ing ra­di­a­tion di­rect­ly to tu­mor cells. In Plu­vic­to’s case, that mark­er is an anti­gen known as PS­MA, which over 80% of prostate can­cers have.

For Plu­vic­to, pa­tients have had to wait sev­er­al weeks to a few months to start the drug — though the time­frame fluc­tu­ates of­ten and un­pre­dictably, doc­tors said, de­pend­ing on when No­var­tis re­leas­es new dos­es of the drug. And now, new pa­tients won’t be able to get the drug as No­var­tis con­tin­ues to grap­ple with its Plu­vic­to short­age. “Pa­tients who are cur­rent­ly in our sched­ul­ing sys­tem and await­ing their first dos­es will need to be resched­uled,” said the com­pa­ny in a state­ment.

At the Mayo Clin­ic in Rochester, MN, for in­stance, which is a ma­jor treat­ment cen­ter for Plu­vic­to, 30 new pa­tients will be im­pact­ed.

Ge­off John­son

“In the last five weeks there has been a sig­nif­i­cant in­crease in the fre­quen­cy of sup­ply dis­rup­tions and now a more se­vere short­age,” Mayo Clin­ic’s nu­clear med­i­cine chair Ge­off John­son said. He not­ed that more than 100 pa­tients at Mayo Clin­ic have had their dos­es de­layed in that time­frame.

At Tu­lane Uni­ver­si­ty in New Or­leans, the wait was two to three months be­fore No­var­tis stopped new pa­tient starts on Sun­day. “That, to me, is an un­ac­cept­ably long de­lay, and it would be far more prefer­able to be able to start those treat­ments with­in one to two weeks, not two months,” said Tu­lane Can­cer Cen­ter’s med­ical di­rec­tor Oliv­er Sar­tor, who led the clin­i­cal tri­al that land­ed Plu­vic­to’s ap­proval.

Now, he says he doesn’t know how long new pa­tients will have to wait.

Clin­i­cal tri­als showed that Plu­vic­to ex­tend­ed the lives of late-stage prostate can­cer pa­tients by a me­di­an of 15 months — four months longer than stan­dard of care. For these pa­tients, a few months is pre­cious time.

Oliv­er Sar­tor

Sar­tor said that be­cause of long waits for Plu­vic­to, he gives some pa­tients a dif­fer­ent chemother­a­py or en­rolls them in clin­i­cal tri­als for oth­er tar­get­ed ra­dio­ther­a­pies, in­clud­ing an ear­ly-stage study of an ac­tini­um-225 an­ti­body de­vel­oped by John­son & John­son.

Like­wise, John­son said doc­tors at the Mayo Clin­ic will re­fer some pa­tients to oth­er treat­ments be­cause Plu­vic­to isn’t read­i­ly avail­able. The 30 pa­tients wait­ing at Mayo Clin­ic, he said, are those who re­al­ly have no oth­er op­tions.

In Domin­gos’ case, his on­col­o­gist said if he couldn’t get Plu­vic­to, he would have to start a dif­fer­ent chemother­a­py to at­tempt to stop his can­cer from spread­ing.

Prob­lems in New Jer­sey

In May, No­var­tis shut down its two man­u­fac­tur­ing plants be­cause of qual­i­ty is­sues. Two months lat­er, com­mer­cial Plu­vic­to pro­duc­tion was run­ning at its Ital­ian site, but the phar­ma com­pa­ny’s New Jer­sey site, which makes an­oth­er No­var­tis ra­dio­ther­a­py and Plu­vic­to for clin­i­cal tri­als and Cana­da, is still not ap­proved to make Plu­vic­to com­mer­cial­ly for the US.

In 2021, the New Jer­sey site was pre­vi­ous­ly cit­ed for qual­i­ty con­trol is­sues af­ter an FDA in­spec­tion.

No­var­tis, which has not pro­vid­ed de­tails on the man­u­fac­tur­ing is­sues that caused the plant clo­sure, filed for ac­cel­er­at­ed ap­proval for com­mer­cial pro­duc­tion at its New Jer­sey site. The com­pa­ny’s state­ment said that it’s wait­ing for more FDA clar­i­ty.

Plu­vic­to dos­es for US pa­tients have five days to be shipped from Italy, pass an FDA in­spec­tion, and then reach a can­cer cen­ter. Things like the weath­er can de­lay dos­es from be­ing shipped for one to two days, mak­ing them no longer us­able and re­sult­ing in pa­tients get­ting resched­uled.

Vas Narasimhan

No­var­tis is sup­ply­ing 200 of 500 pos­si­ble cen­ters in the US and hopes to fire up com­mer­cial pro­duc­tion at its New Jer­sey site by the mid­dle of this year, No­var­tis CEO Vas Narasimhan said dur­ing an in­vestor call in Feb­ru­ary.

“I think from a de­mand stand­point, I would say our ini­tial es­ti­mate of the vi­sion pop­u­la­tion has un­der­es­ti­mat­ed the po­ten­tial of this pop­u­la­tion, and the de­mand would sug­gest to us that there are a greater num­ber of pa­tients and providers in­ter­est­ed in this med­i­cine,” Narasimhan said dur­ing the call.

De­mand is on­ly ex­pect­ed to grow. Lat­er this year, No­var­tis plans to file for FDA ap­proval for use of Plu­vic­to in an ear­li­er line of treat­ment be­fore chemother­a­py. While No­var­tis has yet to re­lease the full da­ta from the tri­al, doc­tors and an­a­lysts said they gen­er­al­ly ex­pect the drug to get ap­proved in the ear­li­er set­ting, which could bring the num­ber of pa­tients el­i­gi­ble for the drug to 42,000, near­ly  dou­bling the cur­rent pa­tient pop­u­la­tion in the US, ac­cord­ing to No­var­tis’ es­ti­mate, though ex­perts said it could be more.

In an in­ter­view Fri­day, No­var­tis’ US phar­ma chief Vic­tor Bul­to de­clined to com­ment on how many dos­es No­var­tis can cur­rent­ly pro­duce.

No­var­tis is build­ing a new man­u­fac­tur­ing fa­cil­i­ty in In­di­anapo­lis, which it hopes to open by the end of the year, and an­oth­er one in Spain to ex­pand ca­pac­i­ty in Eu­rope. With four fa­cil­i­ties, Narasimhan said No­var­tis hopes to de­liv­er over 250,000 dos­es a year by 2024. If No­var­tis can fol­low through, ex­perts say the amount would meet in­creased pa­tient de­mand and re­solve wait times.

Je­re­mie Calais

The whole­sale price of one dose is $42,500, but through in­sur­ance or Medicare cov­er­age, pa­tients can pay less.

Je­re­mie Calais, who di­rects UCLA’s ther­a­nos­tics clin­i­cal re­search, de­scribed the de­lays as a “be­gin­ner’s strug­gle,” and said he hopes that they won’t cause the drug to fol­low the same path as pre­vi­ous ra­dio­phar­ma­ceu­ti­cals like Bexxar, a lym­phoma drug which was dis­con­tin­ued by GSK in 2014 as it nev­er made it big com­mer­cial­ly.

“As I think of ram­i­fi­ca­tions for the field — if No­var­tis can have prob­lems, then so can you,” Sar­tor said. “And I think it is just a warn­ing that sup­ply chains need to be tak­en ex­treme­ly se­ri­ous­ly.”

Oth­er op­tions

An­oth­er route by which the sup­ply crunch could be fixed is com­pe­ti­tion, which could take a lit­tle while.

Di­ag­nos­tics com­pa­ny Lan­theus li­censed from Point Bio­phar­ma a sim­i­lar prostate can­cer ra­dio­ther­a­py that’s cur­rent­ly in Phase III stud­ies for the same pre-chemother­a­py pa­tient pop­u­la­tion as No­var­tis’ ex­pan­sion bid.

“It all comes down to the sup­ply chain,” Point’s CEO Joe Mc­Cann said of suc­ceed­ing in the field. If all goes as planned, Point’s drug could make it on­to the mar­ket by ear­ly 2025.

Ex­perts said hav­ing mul­ti­ple op­tions will pro­vide much-need­ed back­up in the sup­ply chain. Yet oth­er tar­get­ed ra­dio­ther­a­pies in de­vel­op­ment could be hard­er to scale be­cause they use iso­topes that are very rare or have even short­er half-lives. “An­oth­er way to put it is the sci­ence is get­ting ahead of the sup­ply chain,” Mayo Clin­ic’s John­son said.

The Mayo Clin­ic co-found­ed a com­pa­ny called Nu­cle­us Ra­dio­Phar­ma to im­prove the man­u­fac­tur­ing and sup­ply chain of ra­dio­phar­ma­ceu­ti­cals, and John­son serves as chief sci­en­tif­ic ad­vi­sor. Fix­es to the sup­ply chain, he said, start with cre­at­ing re­dun­dan­cies and fo­cus­ing more on the end user, such as hos­pi­tals and physi­cians treat­ing pa­tients.

In Jan­u­ary, Domin­gos’ on­col­o­gist fi­nal­ly found avail­able dos­es at a new ther­a­nos­tics cen­ter, which spe­cial­izes in these sorts of tar­get­ed ra­dio­ther­a­py treat­ments, in Jupiter, FL, about an hour away from where the fam­i­ly lives. The cen­ter, Flori­da Ther­a­nos­tics, had opened just be­fore Christ­mas.

“I was cry­ing. We were all cry­ing,” Domin­gos said. “[We were] emo­tion­al­ly so ex­cit­ed.”

Domin­gos got his first dose of Plu­vic­to lat­er that month, and then had to live in an AirBnB for three days, since he was “pret­ty much ra­dioac­tive” from the drug, he said. But for now, oth­er new pa­tients will have to wait.