Rare dis­ease tri­als can't find enough pa­tients. It's forc­ing the FDA to re­think its ap­proach

When Han­nah Sames was 4 years old, she was di­ag­nosed with an ul­tra-rare ge­net­ic con­di­tion called gi­ant ax­on­al neu­ropa­thy. She’s 18 now, and her doc­tors ex­pect­ed long ago that she would be quad­ri­pleg­ic, and con­signed to an ear­ly death.

In­stead, she can stand, al­beit with help. “Even with her phys­i­cal chal­lenges, she’s hap­py. She’s a typ­i­cal teenag­er who is so­cial and loves mu­sic,” said her moth­er, Lori Sames.

Han­nah was, in 2016, one of the first pa­tients to re­ceive an ex­per­i­men­tal gene ther­a­py that has since shown promis­ing re­sults in more pa­tients. It ap­pears to have strength­ened some of her mus­cles and slowed the pro­gres­sion of her dis­ease.

But it’s un­clear whether the ther­a­py will move be­yond clin­i­cal tri­als. An es­ti­mat­ed 5,000 peo­ple in the world have her dis­ease, ac­cord­ing to the com­pa­ny that li­censed the ther­a­py, Taysha Gene Ther­a­pies. And the NIH has found on­ly 50 fam­i­lies that have re­port­ed cas­es. Ei­ther way, there are not enough pa­tients to run an ad­di­tion­al study that the FDA has asked for, Taysha says.

Sci­en­tif­ic ad­vance­ments have re­sult­ed in a flood of com­pa­nies and pa­tient ad­vo­ca­cy groups tar­get­ing ul­tra-rare dis­eases like Han­nah’s. Yet it can be dif­fi­cult to prove these ther­a­pies work. The agency has tried to walk a fine line — push­ing for more ev­i­dence to sup­port break­through treat­ments where the sci­ence is new, the pa­tients are des­per­ate, and the fi­nan­cial in­cen­tives can be mar­gin­al at best.

The small pools of pa­tients, many of them with fa­tal dis­eases, have forced com­pa­nies to lean on bi­o­log­i­cal sig­nals or pa­tient da­ta col­lect­ed over time, rather than large, place­bo-con­trolled tri­als that have long been the gold stan­dard of drug de­vel­op­ment.

“It’s a ter­ri­ble co­nun­drum,” said Su­san El­len­berg, a for­mer FDA of­fi­cial and a pro­fes­sor emer­i­tus of bio­sta­tis­tics at the Uni­ver­si­ty of Penn­syl­va­nia. “But what you al­so don’t want is to put some­thing on the mar­ket that’s go­ing to cost a huge amount of mon­ey, doesn’t work and is giv­ing peo­ple false hope.”

Taysha was op­ti­mistic that its ther­a­py for gi­ant ax­on­al neu­ropa­thy would land the com­pa­ny its first ap­proved med­i­cine fol­low­ing a cash crunch that led the com­pa­ny to pause much of its pipeline. Then the ther­a­py’s fu­ture came in­to ques­tion in De­cem­ber when the FDA rec­om­mend­ed dos­ing more pa­tients in a ran­dom­ized, place­bo-con­trolled tri­al.

In an in­vestor call in late Jan­u­ary, the com­pa­ny’s man­age­ment said that the FDA’s rec­om­men­da­tion would be un­work­able be­cause of the small pa­tient pop­u­la­tion and even small­er pool of pa­tients el­i­gi­ble for a study.

“We don’t think that par­tic­u­lar de­sign is fea­si­ble,” Taysha CEO Sean Nolan said dur­ing the con­fer­ence call. Fol­low­ing the call, some an­a­lysts down­grad­ed their out­look on the com­pa­ny, and Taysha’s stock has hov­ered around $1 a share.

Reg­u­la­to­ry flex­i­bil­i­ty

Even as Taysha and com­pa­nies like it have strug­gled, there are more re­cent signs of flex­i­bil­i­ty with­in the FDA. On Feb. 28, the agency ap­proved a drug from Rea­ta Phar­ma­ceu­ti­cals to treat Friedre­ich’s atax­ia, a rare dis­ease that dam­ages the spinal cord and short­ens lifes­pans.

The agency said in 2020 that the com­pa­ny’s sin­gle clin­i­cal tri­al didn’t gen­er­ate enough ev­i­dence. But af­ter Rea­ta sub­mit­ted pa­tient da­ta col­lect­ed over decades, the FDA re­lent­ed and cleared the drug for use — more than three years af­ter the com­pa­ny first sought ap­proval.

The ac­tion has been read as greater FDA open­ness to so-called nat­ur­al his­to­ry stud­ies as a re­place­ment for larg­er con­fir­ma­to­ry stud­ies.

But it was an ex­cep­tion, and as drug de­vel­op­ment sci­ence has rapid­ly pro­gressed, so has the num­ber of treat­ments in de­vel­op­ment. That’s left the agency in some cas­es over­whelmed, and not al­ways able to help com­pa­nies work through unique cir­cum­stances.

“I do think you have in­con­sis­tent an­swers with dif­fer­ent peo­ple in dif­fer­ent di­vi­sions in the FDA, and I think that this is very chill­ing for ul­tra-rare drug de­vel­op­ment,” Ree­nie Mc­Carthy, the CEO of Stealth Bio­Ther­a­peu­tics, told the ad­vo­ca­cy group Glob­al Genes in Jan­u­ary. The com­pa­ny did not re­spond to a re­quest for com­ment.

Stealth is try­ing to nav­i­gate a way for­ward for its treat­ment tar­get­ing Barth syn­drome, a dis­ease known to af­fect few­er than 130 pa­tients that caus­es an en­larged heart and mus­cle is­sues. The FDA in 2021 stat­ed the com­pa­ny’s drug ap­pli­ca­tion did not have enough pa­tient da­ta to sup­port a re­view. In­stead, the agency sought an ad­di­tion­al place­bo-con­trolled tri­al, which Stealth has char­ac­ter­ized as an un­wel­come shift from ear­li­er guid­ance say­ing such a tri­al would not be re­quired.

Oth­ers say the FDA has not made enough use of bio­mark­ers that can pre­dict how a drug per­forms, nor ac­cel­er­at­ed ap­provals for ul­tra-rare drugs.

A rare dis­ease, by de­f­i­n­i­tion, af­fects few­er than 200,000 peo­ple in the US at a giv­en time. Dis­eases at the up­per end of that thresh­old have a much eas­i­er time find­ing enough pa­tients to tease out sta­tis­ti­cal sig­nif­i­cance in clin­i­cal tri­als, and the FDA in draft guid­ance eased test­ing re­quire­ments for an­ti­sense med­i­cines — though not gene ther­a­pies — aimed at on­ly one or two pa­tients.

“While the agency does not have guid­ance ex­plic­it­ly ad­dress­ing the num­ber of pa­tients be­tween more than 3 pa­tients and less than 200,000 pa­tients, we are com­mit­ted to work­ing with spon­sors to fa­cil­i­tate the de­vel­op­ment of prod­ucts for rare dis­eases,” said the FDA in a state­ment to End­points News.

Look­ing for more ev­i­dence

Taysha says it plans to sub­mit ad­di­tion­al nerve and vi­su­al acu­ity da­ta to the FDA, in hopes the agency backs off on the place­bo-con­trolled rec­om­men­da­tion. “We look for­ward to work­ing close­ly with the FDA to as­sem­ble the most ro­bust da­ta pack­age pos­si­ble,” said the com­pa­ny in a state­ment.

Last year, Taysha in a small clin­i­cal tri­al re­port­ed that the gene ther­a­py at vary­ing dos­es slowed dis­ease pro­gres­sion based on a mo­tor con­trol test that has been used for oth­er drug ap­provals.

Nicole Paulk, as­sis­tant pro­fes­sor of gene ther­a­py at the Uni­ver­si­ty of Cal­i­for­nia, San Fran­cis­co, said the FDA is like­ly look­ing for more ev­i­dence be­cause Taysha’s study da­ta look pos­i­tive but not stel­lar.

“Taysha may be able to get ap­proval based on the to­tal­i­ty of da­ta,” Paulk said, re­fer­ring to the ad­di­tion­al da­ta the com­pa­ny plans to sub­mit.

William Blair an­a­lysts said they’re “per­plexed” by the FDA’s feed­back giv­en that the agency had ear­li­er called for po­ten­tial ex­pe­dit­ed re­view of gene ther­a­pies tar­get­ing well-stud­ied brain dis­or­ders. The an­a­lysts added it’s not “lo­gis­ti­cal­ly, fi­nan­cial­ly or sta­tis­ti­cal­ly” pos­si­ble for the com­pa­ny to con­duct a ran­dom­ized and place­bo-con­trolled tri­al.

The FDA, which does not dis­close in­for­ma­tion on drug pro­grams un­der re­view, said in a state­ment that it’s “com­mit­ted to de­vel­op­ing a reg­u­la­to­ry par­a­digm that can fa­cil­i­tate the de­vel­op­ment of safe and ef­fec­tive gene ther­a­pies, par­tic­u­lar­ly for rare dis­eases where there is un­met need.”

“The de­vel­op­ment of in­no­v­a­tive in­ves­ti­ga­tion­al prod­ucts can in­tro­duce unique chal­lenges due to un­known safe­ty pro­files, com­plex man­u­fac­tur­ing tech­nolo­gies and is­sues, in­cor­po­ra­tion of in­no­v­a­tive man­u­fac­tur­ing equip­ment, and the use of cut­ting-edge test­ing method­olo­gies,” the agency said.

A wider de­bate

For Taysha, the FDA feed­back comes as yet an­oth­er set­back.

The com­pa­ny’s founder and for­mer CEO, RA Ses­sion II, re­signed in De­cem­ber, af­ter the com­pa­ny laid off 35% of its staff and paused all but two of its more than 20 drug pro­grams. Taysha has al­so faced in­tense crit­i­cism for re­fus­ing to trans­fer in­tel­lec­tu­al prop­er­ty to fam­i­lies that hatched the stalled ther­a­pies.

“We are ac­tive­ly work­ing with pa­tient ad­vo­ca­cy groups on po­ten­tial op­tions. As you can imag­ine, there are com­plex­i­ties, and we are work­ing through these to find so­lu­tions that ben­e­fit these groups,” said the com­pa­ny state­ment.

While Han­nah al­ready re­ceived the ther­a­py in the clin­i­cal tri­al, Sames be­lieves oth­er pa­tients could ben­e­fit from FDA ap­proval and a wider pa­tient roll­out. “There’s a wider com­mu­ni­ty,” Sames said.

The de­bate about the ther­a­py Han­nah re­ceived is a mi­cro­cosm of the wider ar­gu­ments around treat­ments for a small num­ber of pa­tients. The ther­a­pies of­ten cost hun­dreds of thou­sands of dol­lars and with­out reg­u­la­to­ry rig­or stand to give des­per­ate fam­i­lies mis­placed hope.

“It’s not un­eth­i­cal to use a place­bo con­trol when you re­al­ly are un­sure whether the in­ter­ven­tion is go­ing to be ben­e­fi­cial and you need to an­swer that ques­tion,” said Hol­ly Fer­nan­dez Lynch, an as­sis­tant pro­fes­sor of med­ical ethics and health pol­i­cy at the Uni­ver­si­ty of Pen­nys­lva­nia.

But Craig Ben­son, the founder and chair­man of Be­yond Bat­ten Dis­ease Foun­da­tion, said the FDA is too quick to re­sort to place­bo tri­als for ul­tra-rare con­di­tions.

The pa­tient ad­vo­ca­cy group — which was start­ed by Ben­son and his wife af­ter their daugh­ter was di­ag­nosed with ju­ve­nile Bat­ten dis­ease — is spon­sor­ing a Phase III clin­i­cal tri­al test­ing a re­pur­posed drug for the con­di­tion that caus­es seizures, vi­sion loss and ear­ly death. Ben­son is frus­trat­ed that, based on FDA feed­back, there will like­ly be a study place­bo arm.

It will be chal­leng­ing to find a suf­fi­cient num­ber of pa­tients to pow­er the study, and as­sum­ing the drug works, it means pa­tients in the place­bo group will fur­ther de­gen­er­ate.

“Many would say it’s un­eth­i­cal to re­quire a place­bo tri­al for a fa­tal child­hood dis­ease,” Ben­son said, “par­tic­u­lar­ly when there are no al­ter­na­tives.”