‘This is not a sci­ence prob­lem any­more': Paths emerge for scal­ing up rare dis­ease med­i­cine

In 2014, the Na­tion­al In­sti­tutes of Health post­ed an es­ti­mate that at the cur­rent pace of drug de­vel­op­ment and ap­proval, it would take 1,000 years to get treat­ments for the 7,000 known rare dis­eases.

A pa­per at the time sug­gest­ed speed­ing up that work by group­ing to­geth­er sim­i­lar dis­eases, and then treat­ing these pa­tients with the same ther­a­py in a sin­gle clin­i­cal tri­al.

A sim­i­lar idea — and oth­er ways to go faster — are now get­ting clos­er to re­al­i­ty, pushed for­ward by new tech­ni­cal, eco­nom­ic and reg­u­la­to­ry ap­proach­es. The frame­work is be­ing cre­at­ed by com­pa­nies like Mod­er­na, by sci­en­tists who de­vel­oped cus­tom ther­a­pies that have the po­ten­tial to ben­e­fit a larg­er pop­u­la­tion, and by a moth­er who knows the pain when a med­i­cine doesn’t ar­rive in time.

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Since 2014, the FDA has cleared 180 ther­a­pies for rare con­di­tions. But the sci­ence has been es­pe­cial­ly slow to reach the rarest of rare con­di­tions, where drug­mak­ers strug­gle to eke out prof­its. Nine­ty-five per­cent of rare dis­eases still lack a treat­ment, a num­ber that may be even high­er amid ge­net­ic test­ing point­ing to pre­vi­ous­ly un­known rare con­di­tions.

A sys­tem de­signed for some­thing dif­fer­ent

The 2014 pa­per on scal­ing was based on small-mol­e­cule drugs. But ad­vances in gene edit­ing and oth­er plug-and-play tech­nolo­gies could pro­vide an even quick­er path.

“Our whole sys­tem is set up around de­vel­op­ing one treat­ment for one dis­ease. The idea of ther­a­peu­tic plat­forms is one that’s com­ing along,” said PJ Brooks, act­ing di­rec­tor of the di­vi­sion of rare dis­eases re­search in­no­va­tion at the Na­tion­al Cen­ter for Ad­vanc­ing Trans­la­tion­al Sci­ences.

Brooks, one of the au­thors of the pa­per, is al­so in­volved in a $42 mil­lion NIH pro­gram call­ing for pro­pos­als to sup­port gene edit­ing mul­ti­ple dis­eases in a sin­gle clin­i­cal tri­al.

Those mul­ti-dis­ease tri­als would change the se­quence of the guide RNA — which shut­tles CRISPR to the right spot in the genome — but keep every­thing else the same, in­clud­ing the gene ed­i­tor and the route of ad­min­is­tra­tion.

In­tel­lia Ther­a­peu­tics is in­ter­est­ed in the ap­proach.

In March, the FDA ap­proved In­tel­lia test­ing its ex­per­i­men­tal CRISPR med­i­cine for a rare dis­or­der called hered­i­tary an­gioede­ma, show­ing that the agency is in­creas­ing­ly will­ing to al­low tri­als for ther­a­pies that ed­it genes in the body. And al­though that ther­a­py is de­signed for a sin­gle dis­ease, In­tel­lia is hope­ful that it’s a step to­ward quick­ly re­jig­ger­ing its gene edit­ing plat­form for oth­er dis­eases.

“We have these mod­u­lar com­po­nents that now reg­u­la­to­ry agen­cies have seen,” In­tel­lia chief fi­nan­cial of­fi­cer Glenn God­dard said.

An­oth­er push to scale rare dis­ease med­i­cines can be traced to Ju­lia Vitarel­lo’s plea to help her daugh­ter, Mi­la. In 2017, it re­sult­ed in a land­mark for the field: a treat­ment tai­lored to one per­son’s unique ge­net­ic mu­ta­tion, de­vel­oped in just un­der a year.

Mi­la’s drug halt­ed her rapid­ly pro­gress­ing con­di­tion, an ul­tra-rare form of Bat­ten dis­ease, and im­proved her qual­i­ty of life over three years. Still, it was too late for the ad­vanced-stage dis­ease, and in 2021 Mi­la died at 10 years old.

Vitarel­lo works from Mi­la’s old room — the sheets and fairy cur­tains still the same — on the com­pa­ny she co-found­ed, Every­ONE Med­i­cines. Every­ONE is try­ing to make this type of drug de­vel­op­ment sus­tain­able — or what she calls “Mi­la to mil­lions.” The com­pa­ny has back­ing from ven­ture cap­i­tal firms like Khosla Ven­tures.

“This is not a sci­ence prob­lem any­more. We have the tech­nol­o­gy to find the un­der­ly­ing dis­ease cause and cre­ate a drug for it,” Vitarel­lo said.

By tech­nol­o­gy, she’s re­fer­ring to an­ti­sense oligonu­cleotides, which in­sert snip­pets of ge­net­ic code to patch ge­net­ic mu­ta­tions. The ge­net­ic se­quence can be eas­i­ly changed — mak­ing the sys­tem pro­gram­ma­ble for tar­get­ing var­i­ous dis­eases — and de­signed in such a way to reach a wider pop­u­la­tion.

The doc­tor who led the cre­ation of Mi­la’s drug, Tim­o­thy Yu, showed in a re­cent pa­per that an­ti­sense drugs could treat up to 15% of pa­tients with atax­ia-telang­iec­ta­sia, a rare con­di­tion made up of many mu­ta­tions. And im­por­tant­ly, he es­ti­mat­ed that not every in­di­vid­ual would need their own cus­tom-made ther­a­py. Ex­perts be­lieve the find­ings could be a road map for more quick­ly de­vel­op­ing treat­ments in oth­er rare con­di­tions.

In yet an­oth­er ap­proach, Mod­er­na — which brings deep ex­pe­ri­ence with reg­u­la­tors and sci­en­tif­ic ca­chet — has aimed its mR­NA tech­nol­o­gy to­ward rare con­di­tions, in­clud­ing es­pe­cial­ly rare con­di­tions like Crigler-Na­j­jar syn­drome type 1. It oc­curs when the liv­er can­not break down a sub­stance cre­at­ed by red blood cells, caus­ing chil­dren to die young.

“We’re go­ing full steam in rare dis­ease,” CEO Stéphane Ban­cel told End­points News in an ex­clu­sive in­ter­view last month.

All these tech­nolo­gies look to play a role amid a great need: One in 10 peo­ple have a rare dis­ease.

Not just a fi­nance chal­lenge

Mov­ing those sorts of treat­ments from the lab to pa­tients will re­quire dif­fer­ent reg­u­la­to­ry ap­proach­es. In draft guid­ance, the FDA re­laxed test­ing re­quire­ments for an­ti­sense med­i­cines aimed at on­ly one or two pa­tients. But rare dis­ease ad­vo­cates say much more could be done.

Vitarel­lo’s com­pa­ny, Every­ONE, is pitch­ing Eu­ro­pean reg­u­la­tors on a pro­gram where trust­ed ac­tors check far few­er box­es be­fore de­liv­er­ing treat­ments to pa­tients. The plan would cre­ate in­fra­struc­ture for scal­ing.

“Cer­tain Eu­ro­pean coun­tries’ reg­u­la­tors are very will­ing to think about this dif­fer­ent­ly,” Vitarel­lo said. “The tech­nol­o­gy is be­com­ing more fa­mil­iar.”

But reg­u­la­tors have to bal­ance un­met pa­tient needs with very re­al safe­ty con­cerns, in­clud­ing with cer­tain gene ther­a­pies. Ac­cord­ing to a pa­per re­leased this spring, an au­top­sy cleared CRISPR of blame in a pa­tient’s death, though the pa­tient was found to have died from an im­mune re­ac­tion caused by a high dose of the vi­ral vec­tor that de­liv­ered the ther­a­py to his cells. The case has fu­eled a search for new­er de­liv­ery ve­hi­cles.

The new reg­u­la­to­ry ap­proach­es are still large­ly in the the­o­ret­i­cal stage, in pi­lot pro­grams, or have yet to be wide­ly adopt­ed. And in the mean­time, many com­pa­nies that took up pro­grams for ul­tra-rare con­di­tions have aban­doned them af­ter mon­ey dried up, leav­ing fam­i­lies to try and shep­herd the drug pro­grams. There can be mar­gin­al mon­e­tary in­cen­tives to de­vel­op drugs for tiny pools of pa­tients.

Re­flect­ing the strug­gles, five-year ven­ture in­vest­ment in rare dis­ease peaked in 2020 at $3.3 bil­lion but in 2022 fell to $1.25 bil­lion, ac­cord­ing to Chris Doko­ma­ji­lar, the CEO of Deal­For­ma.

Phil­an­thropy or for-prof­it?

There have been a va­ri­ety of at­tempts to solve the fi­nanc­ing prob­lem, both with phil­an­thropy and for-prof­it ap­proach­es.

The n-Lorem Foun­da­tion, a not-for-prof­it that launched in 2020, is cre­at­ing ther­a­pies for more than 90 pa­tients with nano con­di­tions, who will re­ceive free med­i­cines for life. It has plans to reach more pa­tients.

“The pri­ma­ry goal and the ini­tial de­ci­sion to re­al­ly make us a non­prof­it has en­tire­ly to do with the in­abil­i­ty of these pa­tients to get ad­e­quate care,” n-Lorem’s chief op­er­at­ing of­fi­cer Sarah Glass said.

Be­cause mul­ti­ple com­pa­nies have left the space, the chal­leng­ing eco­nom­ics are the fo­cus for MIT pro­fes­sor An­drew Lo, whose ideas on fi­nanc­ing rare med­i­cines were put in­to prac­tice by the com­pa­ny Bridge­Bio.

Lo sees fund­ing ul­tra-rare con­di­tions as the next step. As one so­lu­tion, a com­pa­ny he co-found­ed, Quan­tile Health, has a sub­scrip­tion mod­el to re­im­burse drug­mak­ers.

Quan­tile pro­vides cov­er­age to self-in­sured em­ploy­ers for a pletho­ra of rare dis­eases by ne­go­ti­at­ing agree­ments with drug com­pa­nies, which get sub­scrip­tion fees. Lo said a sub­scrip­tion mod­el could pay not just for ap­proved drugs, but al­so for drug de­vel­op­ment.

“Be­cause of the spe­cial­ized na­ture of rare dis­eases and the chal­leng­ing eco­nom­ics of any giv­en sin­gle dis­ease, pa­tients of­ten don’t have any op­tions and are large­ly ig­nored by Big Phar­ma, so they have nowhere to turn,” Lo said.

Oth­er busi­ness mod­els are well un­der­way. Per­lara PBC has screened drugs for more com­mon con­di­tions to find a match for rare dis­eases. A Japan­ese drug to treat nerve dam­age is now un­der­go­ing a clin­i­cal tri­al for PMM2-CDG, po­ten­tial­ly fa­tal and rare mu­ta­tions that cause ab­nor­mal en­zyme ac­tiv­i­ty.

La Jol­la Labs is do­ing the op­po­site. It’s cre­at­ing per­son­al­ized med­i­cines that could, one day, reach a wider pop­u­la­tion. The com­pa­ny, for in­stance, is de­vel­op­ing a med­i­cine for Noo­nan syn­drome — a rare dis­ease that caus­es bleed­ing prob­lems and skele­tal ab­nor­mal­i­ties — in what could al­so have ap­pli­ca­tions for one of the larg­er can­cer-caus­ing mu­ta­tions.

It’s an idea with a good amount of prece­dent: In the 1960s, sci­en­tists in Texas stud­ied a rare dis­ease that caused a child’s high cho­les­terol lev­els. It led to statins, the cho­les­terol-low­er­ing drugs, and a No­bel Prize for the sci­en­tists.

“There’s lots of ways you can do this with bi­ol­o­gy,” La Jol­la Labs CEO Jeff Mil­ton said, “be­cause there are so many dif­fer­ent path­ways that in­ter­sect with each oth­er.”