Illustration credit: Molly Ferguson

Fam­i­lies raised mil­lions and hand­ed rare dis­ease ther­a­pies off to biotechs. But com­pa­nies have backed out

When Ju­lia Tar­avel­la’s two sons were di­ag­nosed with an ul­tra-rare dis­ease, she did some­thing ex­tra­or­di­nary but not un­com­mon among par­ents like her: She formed a group that raised $1.2 mil­lion to try and find a treat­ment.

“With­out a ther­a­py, my sons will die,” Tar­avel­la said.

The mon­ey helped launch work on a po­ten­tial gene ther­a­py at the Uni­ver­si­ty of North Car­oli­na, which was then hand­ed off to a New York-based com­pa­ny called Neu­ro­gene.

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But what sounds like a vic­to­ry pro­pelled by a par­ent’s per­se­ver­ance is be­ing over­shad­owed by a less­er-known but in­creas­ing­ly com­mon trend: Drug­mak­ers are shelv­ing many of those fam­i­ly-fund­ed ther­a­pies.

In 2022, al­most four years af­ter Neu­ro­gene took over, the com­pa­ny stopped the work. The pro­gram is back with the Uni­ver­si­ty of North Car­oli­na, and Tar­avel­la and oth­er par­ents are try­ing to raise an­oth­er $2.3 mil­lion for a clin­i­cal tri­al.

In the last 16 months, drug­mak­ers have can­celed or paused de­vel­op­ment on 26 rare dis­ease pro­grams that were fi­nan­cial­ly sup­port­ed by pa­tient groups, based on an End­points News re­view of pub­lic fil­ings and news re­ports, which was cross-ref­er­enced with pa­tient groups.

The shelved ther­a­pies tar­get every­thing from seizures to in­tel­lec­tu­al dis­abil­i­ty to brain dis­eases that rob chil­dren of their abil­i­ties and then kill them at a young age. The list, while ex­ten­sive, is lim­it­ed by what com­pa­nies dis­close. Non-pub­lic com­pa­nies can say lit­tle, and oth­er drug de­vel­op­ers of­ten don’t talk about pre-clin­i­cal work that’s been cut.

It was not al­ways clear why pro­grams were shelved. But the cut pro­grams were large­ly dis­con­tin­ued as part of com­pa­ny re­struc­tur­ings, amid an on­go­ing in­dus­try down­turn that took hold in ear­ly 2022. The pull­back was pre­dom­i­nant­ly in treat­ments for ul­tra-rare dis­eases that face reg­u­la­to­ry chal­lenges and mar­gin­al mon­e­tary in­cen­tives.

“It’s clear that many pro­grams are be­ing dropped for fi­nan­cial rea­sons,” said James Ger­aghty, the au­thor of “In­side the Or­phan Drug Rev­o­lu­tion: The Promise of Pa­tient-Cen­tered Biotech­nol­o­gy,” and who sits on biotech boards.

In 2019, Neu­ro­gene said that Tar­avel­la’s pro­gram gen­er­at­ed en­cour­ag­ing da­ta that sup­port­ed a clin­i­cal tri­al, and the next year, the com­pa­ny raised $115 mil­lion in a pri­vate fi­nanc­ing round to ad­vance its pipeline.

In li­cens­ing Tar­avel­la’s pro­gram, the com­pa­ny agreed to take on de­vel­op­ment costs. In ex­change, it stood to prof­it if the pro­gram was suc­cess­ful.

In re­sponse to a re­quest to com­ment, Neu­ro­gene for­ward­ed its 2022 let­ter to fam­i­lies that cit­ed strug­gles in find­ing enough US pa­tients for a clin­i­cal tri­al and its own “fi­nite re­sources.” The com­pa­ny al­so de­ter­mined it would have to change how the gene ther­a­py is de­liv­ered to the brain.

Neu­ro­gene de­clined to com­ment on whether the com­pa­ny shelved ad­di­tion­al pro­grams.

Such shut­downs rep­re­sent a cru­el eco­nom­ic re­al­i­ty for some fam­i­lies. When a com­pa­ny backs out, it can mean there’s no path for­ward. Years of work and hope evap­o­rate.

Tar­avel­la’s ef­fort to save her sons has al­ready been long and dif­fi­cult. Doc­tors ini­tial­ly di­ag­nosed them with autism. She sus­pect­ed some­thing else, en­rolled in com­put­er pro­gram­ming class­es, and an­a­lyzed her fam­i­ly’s ge­net­ic in­for­ma­tion. Tar­avel­la un­cov­ered a ge­net­ic ab­nor­mal­i­ty that showed as­partyl­glu­cosamin­uria, or AGU.

On­ly 300 peo­ple have been di­ag­nosed with the dis­ease, char­ac­ter­ized by in­tel­lec­tu­al dis­abil­i­ty and peo­ple dy­ing be­fore their 40s.

Ju­lia Tar­avel­la’s sons Alexan­der (left) and Daniel (Cour­tesy pho­to)

Click on the im­age to see the full-sized ver­sion

A re­pur­posed drug slowed its pro­gres­sion in Tar­avel­la’s sons — Daniel, 28, and Alexan­der 23 — but a gene ther­a­py is an at­tempt to more di­rect­ly tar­get the dis­ease and ex­tend their lives.

Tar­avel­la wants, for as long as pos­si­ble, for the two to con­tin­ue do­ing what they love: work­ing out, read­ing and lend­ing a hand in their New Or­leans neigh­bor­hood.

“They’re just so gen­tle. Every­one around here knows them be­cause they’re out there and ea­ger to help,” she said.

The clin­i­cal tri­al — spon­sored by the or­ga­ni­za­tion Tar­avel­la start­ed, Rare Trait Hope Fund, and a yet-to-be-an­nounced uni­ver­si­ty — is slat­ed for Sep­tem­ber if and when the mon­ey can be raised. The study is en­rolling pa­tients in the US and be­yond in hopes of at­tract­ing a wider pool. In re­sponse to Neu­ro­gene’s con­cern over how the drug is de­liv­ered to the brain, Tar­avel­la’s or­ga­ni­za­tion fund­ed a study that’s ex­am­in­ing the orig­i­nal route of ad­min­is­ter­ing the drug and an al­ter­na­tive.

Giv­en the high cost of drug de­vel­op­ment, she’s hop­ing the clin­i­cal tri­al gen­er­ates pos­i­tive da­ta and en­tices an­oth­er com­pa­ny to step in, though she would seek ex­tra as­sur­ances.

Di­vide be­tween par­ents and the FDA

There are about 10,800 rare dis­eases, and half of all rare-dis­ease pa­tients are chil­dren. Many don’t sur­vive in­to adult­hood. Even get­ting a di­ag­no­sis is a chal­lenge, and it’s of­ten just the start of a jour­ney — 95% of these con­di­tions lack a treat­ment.

With a dearth of pri­vate and pub­lic fund­ing for ul­tra-rare dis­eases, there are dozens, if not hun­dreds, of pa­tient groups ded­i­cat­ed to cre­at­ing ther­a­pies.

The pub­lic knows these “rare par­ents” through bake sales, lemon­ade stands and Go­FundMe cam­paigns. More and more, they’re al­so mak­ing their case di­rect­ly to the FDA to ease the path for treat­ments.

In a meet­ing last month, par­ents warned FDA Com­mis­sion­er Robert Califf and oth­er top FDA of­fi­cials that fur­ther cuts to drug pipelines are com­ing if the agency doesn’t show more flex­i­bil­i­ty over what lev­el of ev­i­dence is need­ed to ap­prove treat­ments.

Pa­tient ad­vo­cates and the FDA of­ten dif­fer over what con­sti­tutes suf­fi­cient ev­i­dence that a ther­a­py works – and how to bal­ance risk ver­sus ben­e­fit.

Em­blem­at­ic of the di­vide is San­fil­ip­po syn­drome. Chil­dren with the con­di­tion can­not pro­duce a crit­i­cal en­zyme, lead­ing to neu­rode­gen­er­a­tion, and an ag­gres­sive form of the dis­ease kills pa­tients in their ear­ly teens.

Like many oth­er ul­tra-rare dis­eases, work on a gene ther­a­py has been dri­ven by par­ents who have like­wise run in­to chal­lenges from the reg­u­la­tions set by the agency.

“While there may be long-term plans at the FDA for pos­i­tive change, those may not be things that hap­pen in time to save these crit­i­cal pro­grams,” Cara O’Neill, co-founder of the Cure San­fil­ip­po Foun­da­tion, said in an in­ter­view. She was among the par­ents who at­tend­ed the FDA meet­ing.

The foun­da­tion pro­vid­ed $1.2 mil­lion in seed fund­ing for a gene ther­a­py that O’Neill’s daugh­ter, Eliza, re­ceived in 2016. By then, she was 6 years old, and she could no longer speak and need­ed con­stant care.

Eliza and her mom, Cara O’Neill (Cred­it: Car­mo­ny Cor­ley Pho­tog­ra­phy)

Click on the im­age to see the full-sized ver­sion

But the gene ther­a­py boost­ed Eliza’s qual­i­ty of life and bought her time, her par­ents said. The re­sults were more pos­i­tive in a small group of younger pa­tients who re­ceived a high­er dose of the ther­a­py. It pre­served cog­ni­tive de­vel­op­ment and im­proved dis­ease bio­mark­ers.

The FDA wants more proof. The agency ex­pressed a pref­er­ence for the gold stan­dard in test­ing: a ran­dom­ized, place­bo-con­trolled clin­i­cal tri­al. Find­ing enough San­fil­ip­po pa­tients for such a study would be daunt­ing, if not im­pos­si­ble. By the time most pa­tients are di­ag­nosed, the dis­ease has al­ready ir­re­versibly pro­gressed.

The agency — which does not com­ment on spe­cif­ic ther­a­pies un­der re­view — in a lengthy state­ment list­ed in­ter­nal pro­grams and grants to boost nov­el ways of col­lect­ing da­ta for clin­i­cal tri­als, and not­ed its reg­u­la­to­ry guid­ance could evolve.

“As we con­tin­ue to de­vel­op an ev­i­dence-based frame­work for these prod­ucts, the FDA un­der­stands that we may need to re-eval­u­ate and mod­ern­ize our ap­proach to the unique chal­lenges of these prod­ucts while al­so en­sur­ing the re­sult­ing ther­a­pies are both safe and ef­fec­tive,” said the agency.

The San­fil­ip­po ther­a­py is be­ing com­mer­cial­ized by Ul­tragenyx, a Cal­i­for­nia com­pa­ny that spe­cial­izes in rare dis­eases. The com­pa­ny a year ago ac­quired the rights to the po­ten­tial San­fil­ip­po ther­a­py af­ter Abeona Ther­a­peu­tics paused de­vel­op­ment fol­low­ing a repri­or­i­ti­za­tion of re­search and spend­ing.

Ul­tragenyx be­lieves bio­mark­ers — a sur­ro­gate mea­sure of ef­fi­ca­cy that doesn’t re­quire pa­tients to get a place­bo — are a sound way to mea­sure ef­fec­tive­ness. But the FDA has pushed back on that plan, ac­cord­ing to CEO Emil Kakkis, who al­so at­tend­ed the meet­ing.

“Our pitch to them was: What is your lega­cy as an FDA of­fi­cial?” he said. “Is it to watch gene ther­a­py ther­a­pies dis­ap­pear or treat 10 to 20 dis­eases that have nev­er been treat­ed be­fore?”

Un­der­scor­ing that rare dis­ease ther­a­pies are front and cen­ter at the FDA right now, the FDA lat­er this month will de­cide whether to ap­prove Sarep­ta Ther­a­peu­tics’ ther­a­py for Duchenne mus­cu­lar dy­s­tro­phy, a rare con­di­tion that leaves boys in wheel­chairs and re­sults in ear­ly death. The de­ci­sion comes with far-reach­ing im­pli­ca­tions.

Sarep­ta is seek­ing ac­cel­er­at­ed ap­proval, mean­ing the drug­mak­er could sell the ther­a­py while con­duct­ing a fol­low-up study to con­firm the clin­i­cal ben­e­fit. Last week, an FDA ad­vi­so­ry com­mit­tee nar­row­ly backed the plan. If the FDA ul­ti­mate­ly grants ac­cel­er­at­ed ap­proval, it’s thought that the reg­u­la­to­ry path will be open to more rare dis­ease drug­mak­ers.

This comes against the back­drop of safe­ty con­cerns re­lat­ed to some gene ther­a­pies, in­clud­ing a pa­tient dy­ing in a clin­i­cal tri­al test­ing Pfiz­er’s Duchenne ther­a­py, re­sult­ing in a clin­i­cal tri­al hold that was lift­ed last sum­mer.

Lemon­ade stands fund­ing a drug pipeline

When com­pa­nies pause pro­grams, fam­i­lies can be left with no or few op­tions. Af­ter a cash crunch a year ago, the com­pa­ny Taysha Gene Ther­a­pies shelved all but two ther­a­pies in its pipeline. At the com­pa­ny’s peak in 2021, it was work­ing on more than 20 drugs for brain and ner­vous sys­tem dis­or­ders.

In some cas­es, pa­tient groups that sparked these pro­grams for their chil­dren sought a po­ten­tial­ly faster path by restart­ing the work else­where, End­points re­port­ed. But Taysha re­fused to hand over the in­tel­lec­tu­al prop­er­ty. In­stead, the com­pa­ny ar­gued fam­i­lies should kick in fund­ing to Taysha un­til the com­pa­ny has enough mon­ey to re­sume the pro­grams. In re­turn, fam­i­lies would get a small roy­al­ty should a ther­a­py win ap­proval.

“Taysha is seek­ing to fi­nance their R&D pipeline by re­ly­ing on lemon­ade stand dol­lars raised by pa­tient or­ga­ni­za­tions,” said Am­ber Freed, the founder of SLC6A1 Con­nect. “They’re re­al­ly hold­ing the most vul­ner­a­ble peo­ple, the pa­tients and their fam­i­lies, hostage.”

Freed’s group was named af­ter the gene mu­ta­tion be­hind her son’s de­bil­i­tat­ing form of epilep­sy. Taysha’s po­ten­tial ther­a­py for the con­di­tion has been on hold for more than a year.

In a state­ment, Taysha said it has re­viewed “po­ten­tial op­tions that may en­able fur­ther pro­gram de­vel­op­ment through out­side par­ties.”

But the sit­u­a­tion there is em­blem­at­ic of par­ents’ heart­break and frus­tra­tions.

In the void left by drug­mak­ers, new types of drug de­vel­op­ment op­er­a­tions are form­ing but face the chal­lenge of scal­ing. Elp­i­da Ther­a­peu­tics launched this month with $20 mil­lion to adopt aban­doned or paused drug pro­grams.

Oth­er fam­i­lies have sought to by­pass phar­ma­ceu­ti­cal com­pa­nies by form­ing their own com­pa­nies and joint ven­tures. The com­pa­ny Per­lara PBC part­ners with fam­i­lies to iden­ti­fy new and ex­ist­ing drugs to treat rare dis­eases.

“De­pen­den­cy on oth­er peo­ple’s labs and con­stant­ly mak­ing your­self pret­ty for biotech are not work­ing,” Per­lara’s CEO, Ethan Perl­stein, wrote on Twit­ter.