A teenag­er faced con­stant seizures. Could a drug de­vel­oped just for him stop them?

SAN DIEGO — Con­nor Dal­by’s shrieks filled his play­room, and the rest of the house. The teenag­er hushed when his mom, Kel­ley, asked a long-com­ing ques­tion: “Are you ready for the big day to­mor­row?”

He typed “yes” on his wood­en let­ter­board, his on­ly means to put his thoughts in­to words. But then he re­sumed shriek­ing, the pre­lude to a pair of seizures that, lat­er that night, caused his toes to curl, his eyes to di­late and his body to spasm. It had been like this for 14 years.

“I’ve been fight­ing for my son his en­tire life with all the en­er­gy in me,” Kel­ley said. “He’s smart and tena­cious but trapped in a body that doesn’t co­op­er­ate.”

The next day, doc­tors in­ject­ed Con­nor with an ex­per­i­men­tal treat­ment that had been tai­lored just for him. Af­ter years of dead ends and de­lays, the hope was that the drug could patch over the ul­tra-rare ge­net­ic mu­ta­tion that caus­es Con­nor’s seizures, de­vel­op­ment de­lays and a move­ment dis­or­der.

Past and fu­ture

Last March, Con­nor be­came one of the first pa­tients to be treat­ed by the n-Lorem Foun­da­tion, a non­prof­it set up to de­vel­op med­i­cines for dis­eases af­fect­ing 30 or few­er pa­tients.

There’s lit­tle prof­it in mak­ing a med­i­cine for such a tiny pop­u­la­tion — an es­ti­mat­ed 95% of rare dis­eases lack a treat­ment, ac­cord­ing to the ad­vo­ca­cy group Glob­al Genes. And many chil­dren nev­er live long enough to be di­ag­nosed, as their par­ents be­come mired in di­ag­nos­tic odysseys.

Con­nor’s med­i­cine on­ly ar­rived be­cause Kel­ley ig­nored neu­rol­o­gists who viewed her son as a lost cause. She paid for ex­haus­tive ge­net­ic test­ing that re­vealed Con­nor’s ge­net­ic glitch. Even af­ter his dis­ease was found, ge­neti­cists told her it would be 100 years be­fore a treat­ment was de­vel­oped.

But Con­nor, af­ter long sym­bol­iz­ing per­son­al­ized med­i­cine’s fail­ures, has come to rep­re­sent its promise. Kel­ley’s plea to help her son in­spired a for­mer biotech ex­ec­u­tive to start n-Lorem. It fund­ed and cre­at­ed Con­nor’s med­i­cine, and the non­prof­it even­tu­al­ly wants to do the same for thou­sands of pa­tients. If n-Lorem suc­ceeds, it will show a path for­ward for the many oth­er pa­tients like Con­nor. If it fails, it’s a ma­jor set­back in the quest to stan­dard­ize tai­lored treat­ments.

Con­nor’s fam­i­ly al­lowed End­points News ac­cess to his life as the n-Lorem Foun­da­tion de­vel­oped his med­i­cine. This sto­ry is a prod­uct of in­ter­views that spanned more than three years.

The low­est of lows

N-Lorem’s roots go back to 2017, when Kel­ley and an­oth­er par­ent asked Stan­ley Crooke, then the CEO of Io­n­is Phar­ma­ceu­ti­cals, to de­vel­op a med­i­cine for the cul­prit be­hind their chil­dren’s seizures: a mu­ta­tion in the gene SCN2A that plays a key role in trans­mit­ting elec­tri­cal sig­nals in the brain.

In re­sponse, Crooke said the known preva­lence of SCN2A pa­tients was too small to be pur­sued com­mer­cial­ly. (Io­n­is lat­er sup­port­ed drug dis­cov­ery ef­forts.) But the con­ver­sa­tion got him think­ing about a bet­ter way to cre­ate drugs for ul­tra-rare dis­eases.

Io­n­is had spent decades hon­ing an­ti­sense oligonu­cleotides that in­ter­rupt dis­ease-caus­ing pro­teins. Its first an­ti­sense break­through ar­rived in 2016 with the ap­proval of Spin­raza, which trans­formed treat­ment for spinal mus­cu­lar at­ro­phy, once a death sen­tence for ba­bies.

Crooke be­lieved that Io­n­is’ tech­nol­o­gy could be quick­ly tai­lored to oth­er rare dis­eases. An­ti­sense drugs are made up of the build­ing blocks of ge­net­ic code, and these blocks can be eas­i­ly arranged in vary­ing se­quences.

“The ques­tion ac­tu­al­ly shift­ed for me to a moral ques­tion,” Crooke said. “How could I not do it?”

In 2019, Crooke an­nounced plans to step down as the head of Io­n­is to fo­cus on n-Lorem. That year, he shared n-Lorem’s plans with Kel­ley af­ter they met again by chance at a sci­en­tif­ic con­fer­ence in San Diego.

It was good tim­ing. In the two years be­tween their first meet­ing and when they re­con­nect­ed, fur­ther ge­net­ic test­ing found that Con­nor’s SCN2A vari­ant was one-of-a-kind, and he wasn’t a can­di­date for a po­ten­tial drug in de­vel­op­ment for the broad­er mu­ta­tion. He was lat­er ac­cept­ed as n-Lorem’s first pa­tient.

“I went from ex­pe­ri­enc­ing the low­est of lows to dis­be­lief that some­one would cre­ate a drug for just one per­son,” Kel­ley said.

Bal­anc­ing act

As a tod­dler, Con­nor bare­ly re­spond­ed when Kel­ley waved a hand in front of his face. He wasn’t ex­pect­ed to live past his 4th birth­day. Not on­ly did he sur­vive, but his fre­quent phys­i­cal and neu­rode­vel­op­ment ex­er­cis­es re­sult­ed in hard-won abil­i­ties.

In 2021, n-Lorem sci­en­tists were busy cook­ing up a med­i­cine to ac­cel­er­ate his progress, and save him from the seizures. A dozen miles from the non­prof­it’s head­quar­ters, Con­nor and Kel­ley shared their hopes for the treat­ment in their kitchen.

“Re­duce seizures first and fore­most,” Kel­ley said. A bal­lad from Ed Sheer­an, Con­nor’s fa­vorite mu­si­cian, played. Sit­ting in a high chair, Con­nor typed on the let­ter­board that he want­ed to “walk and talk.”

The let­ter­board had pro­vid­ed a win­dow in­to a rich in­te­ri­or world that his fam­i­ly didn’t know ex­ist­ed. Months ear­li­er, Con­nor awed his mom by de­scrib­ing her as kind. He joked with his broth­ers, Cameron and Chase. He reeled off rea­sons for why he loves the beach.

Af­ter Kel­ley coaxed a muf­fin piece in­to Con­nor’s mouth, he grew rest­less. He shrieked. Kel­ley tugged Con­nor’s ear. It was hot to the touch, in­di­cat­ing a seizure could be com­ing.

Kel­ley lift­ed Con­nor from the high chair. With her as­sis­tance, they walked out­side in­to a cloud­less fall sun­set. Con­nor stopped shriek­ing.

Dur­ing a phone in­ter­view a year lat­er, Kel­ley ex­pressed grat­i­tude that n-Lorem had freed her from the bur­den of find­ing a treat­ment. But a med­i­cine that was sup­posed to be de­liv­ered with­in 18 months was still in de­vel­op­ment. The seizures con­tin­ued un­abat­ed.

“I’m just need­ing some sort of time­line,” Kel­ley said at the time.

All told, it took more than three years to de­vel­op and get a med­i­cine to Con­nor, in part be­cause n-Lorem’s sci­en­tists strug­gled with a tricky bal­anc­ing act of hin­der­ing Con­nor’s gene mu­ta­tion while leav­ing a healthy copy of the gene alone.

Sci­en­tists test­ed out a litany of com­pounds against reengi­neered cells that ap­prox­i­mat­ed Con­nor’s brain. Even­tu­al­ly they ze­roed in on one med­i­cine, and de­liv­ered it to Rady Chil­dren’s Hos­pi­tal-San Diego.

Not near­ly enough

N-Lorem wants to treat dozens, and even­tu­al­ly thou­sands, of pa­tients like Con­nor. The dream, if re­al­ized, would make n-Lorem the first or­ga­ni­za­tion to scale be­spoke med­i­cines.

“They’ve re­al­ly po­si­tioned them­selves at the edge of per­son­al­ized med­i­cine. No one else has the same am­bi­tions for treat­ing so many ul­tra-rare dis­eases that com­pa­nies aren’t touch­ing,” said Suma Babu, a Har­vard neu­rol­o­gist who is not af­fil­i­at­ed with the non­prof­it.

Nei­ther the sci­ence nor the busi­ness is easy. N-Lorem pro­vides pa­tients with a free life­time sup­ply of a drug that rough­ly costs $700,000 to de­vel­op and man­u­fac­ture. It has raised more than $50 mil­lion to fund med­i­cines, and com­pa­nies like Bio­gen have pro­vid­ed in-kind con­tri­bu­tions.

But Crooke ac­knowl­edged the fi­nan­cial lim­its of the phil­an­thropic mod­el. Its wait­list in­cludes more than 100 pa­tients, and grow­ing. He said the non­prof­it plans to li­cense find­ings from cus­tom med­i­cines that might be ap­plic­a­ble to more com­mon dis­eases.

Meghan Hal­ley, a se­nior re­search schol­ar at Stan­ford’s Cen­ter for Bio­med­ical Ethics, said the plan could push the bound­aries of n-Lorem’s non­prof­it mis­sion. “When li­cens­ing a drug that’s rel­e­vant to com­mon dis­eases, their pric­ing plans mat­ter. Are they think­ing about pa­tient ac­cess like a non­prof­it?” she said.

Crooke said the for-prof­it com­pa­nies that li­cense find­ings should be able to re­coup the much larg­er costs that come with drug de­vel­op­ment for more com­mon con­di­tions. He ar­gued, es­sen­tial­ly, for sub­si­diz­ing ul­tra-rare dis­ease pa­tients who oth­er­wise have few op­tions.

“I have no in­ten­tion of mak­ing a prof­it from these des­per­ate fam­i­lies. But we have to fund what I be­lieve is go­ing to de­mand from many, many thou­sands of pa­tients,” Crooke said.

N-Lorem’s ap­proach con­trasts with oth­er groups en­gaged in in­di­vid­u­al­ized med­i­cine.

The non­prof­it is co-de­vel­op­ing med­i­cines with St. Jude Chil­dren’s Re­search Hos­pi­tal but has oth­er­wise been choosy about part­ner­ships. Crooke be­lieves some labs are cre­at­ing an­ti­sense drugs with­out the req­ui­site ex­pe­ri­ence.

“They may sound sim­ple. They’re not,” Crooke said. “We’re sup­port­ing any group that we think is ca­pa­ble of do­ing that. And we’re anx­ious about oth­ers that may not have demon­strat­ed that abil­i­ty.”

Doc­tors and sci­en­tists who are part of the N=1 Col­lab­o­ra­tive — an in­ter­na­tion­al group named af­ter a clin­i­cal tri­al for one pa­tient — ar­gue that n-Lorem is far from alone in cre­at­ing qual­i­ty an­ti­sense drugs.

Boston Chil­dren’s Hos­pi­tal’s Tim­o­thy Yu, who is a mem­ber of the N=1 Col­lab­o­ra­tive’s steer­ing com­mit­tee, spear­head­ed the first cus­tom med­i­cine in 2017. He says he con­stant­ly re­ceives emails from fam­i­lies plead­ing for help.

So far, his team at Boston Chil­dren’s has man­aged to de­vel­op cus­tom med­i­cines for six pa­tients, and is search­ing for ways to scale. Like­wise, No­bel Prize win­ner Jen­nifer Doud­na wants to cre­ate a blue­print for de­vel­op­ing gene ther­a­pies aimed at rare con­di­tions.

“I’m re­al­ly huge­ly pleased to see the progress,” Yu said of the wider field. “And I’m al­so stark­ly aware that it’s not near­ly enough.”

Par­a­digm shift

It’s not just the sci­ence and eco­nom­ics that are chal­leng­ing. There’s al­so lit­tle reg­u­la­to­ry prece­dent at the FDA for ap­prov­ing drugs for such tiny pop­u­la­tions.

Pe­ter Marks, the FDA’s di­rec­tor of the Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search, has been vo­cal about the agency show­ing more flex­i­bil­i­ty across a range of rare dis­eases.

In June, he over­ruled his staff to ap­prove an ex­pan­sion of Sarep­ta’s treat­ment for Duchenne mus­cu­lar dy­s­tro­phy. The gene ther­a­py now cov­ers all pa­tients de­spite the drug fail­ing a late-stage clin­i­cal tri­al.

And treat­ments for much rar­er con­di­tions than Duchenne mus­cu­lar dy­s­tro­phy can be even tougher to eval­u­ate, es­pe­cial­ly when there aren’t enough pa­tients to car­ry out a place­bo-con­trolled study.

In an in­ter­view with End­points, Marks said the agency is try­ing to find the right reg­u­la­to­ry bal­ance as more ul­tra-rare dis­eases emerge.

“So we have a fair amount we can lean in on,” Marks said. “But I think we have to be care­ful that what we don’t like to do is take the bar and bring it down so low that we ac­tu­al­ly do pa­tients a dis­ser­vice, be­cause stuff starts to get over the fin­ish line that ac­tu­al­ly doesn’t re­al­ly bring much if any clin­i­cal ben­e­fit.”

Rep­re­sen­ta­tives for Every­ONE Med­i­cines, a pri­vate com­pa­ny ded­i­cat­ed to cus­tom drugs, said US, UK and EU reg­u­la­tors are mov­ing to­ward re­lax­ing stan­dards to speed de­vel­op­ment. The trend, the com­pa­ny be­lieves, will make be­spoke med­i­cines more in­vestable.

For Con­nor’s drug, the FDA ini­tial­ly de­mand­ed a test to mea­sure whether there was a bi­o­log­i­cal sign the drug was work­ing at the mol­e­c­u­lar lev­el. The agency ul­ti­mate­ly agreed with the ar­gu­ment that it wasn’t fea­si­ble to de­vel­op a test for such a rare case, and let the study go ahead.

Gi­ant steps

Af­ter doc­tors at Rady Chil­dren’s Hos­pi­tal-San Diego in­ject­ed Con­nor with the an­ti­sense drug, he slept in a hos­pi­tal bed. Be­side him, Kel­ley cried with hap­pi­ness.

“Oh my God, we re­al­ly ac­com­plished this,” she re­mem­bers say­ing.

Two sub­se­quent dos­es slashed Con­nor’s seizures, ac­cord­ing to elec­troen­cephalo­gram read­ings that pick up on ab­nor­mal brain waves and Kel­ley’s seizure logs.

That type of care­ful mon­i­tor­ing is typ­i­cal of epilep­sy stud­ies, but al­so serves to guard against Kel­ley’s vul­ner­a­bil­i­ty to the place­bo ef­fect. She’s much more in­volved than par­ents typ­i­cal­ly are dur­ing a drug study.

But there seemed to be oth­er clear signs the drug was help­ing. Con­nor typed on his wood­en key­board that his brain felt calmer. He slept bet­ter. He didn’t burst in­to hys­ter­ics as much.

Last month, weak sun­light fil­tered in­to the play­room at the Dal­by fam­i­ly’s home. Kel­ley and Con­nor laughed as he pushed but­tons on a toy.

She gave him a hand up, and Con­nor stepped across a plush rug, and then lam­i­nate floor­ing. Kel­ley beamed. He had been walk­ing with­out as­sis­tance for two weeks, af­ter nev­er tak­ing more than a few steps on his own.

In a hall­way, Con­nor looked back and reached for his mom’s hand. “You got it. Bal­ance your­self and keep go­ing. I’m go­ing to let go again,” Kel­ley said.

Con­nor paced the ground-lev­el rooms, back and forth. “He’s show­ing off,” Kel­ley said with a laugh.

Olivia Kim-Mc­Manus, a neu­rol­o­gist at Rady Chil­dren’s Hos­pi­tal-San Diego and the prin­ci­pal in­ves­ti­ga­tor for the study, said in a video in­ter­view the med­i­cine ap­peared to be meet­ing the two pri­ma­ry study goals: re­duce seizures and im­prove Con­nor’s move­ment dis­or­der. Walk­ing wasn’t ex­pect­ed.

“There’s cer­tain things that you think you might see. It wasn’t re­al­ly on my radar that he would be do­ing that,” she said.

Plans call for in­creas­ing the dose of the med­i­cine over time. But just be­fore this sto­ry was pub­lished, Kel­ley told End­points that she was try­ing to get the ad­min­is­tra­tion of the drug moved to every month, in­stead of every few months. The ef­fects, in­clud­ing Con­nor walk­ing unas­sist­ed, start to wane af­ter 30 days.

“He’s re­al­ly up and down, and I’m re­al­ly up­set,” Kel­ley said.

In a state­ment for­ward­ed by a spokesper­son, n-Lorem said it will con­tin­ue to in­crease the dose and ad­just the fre­quen­cy to max­i­mize the drug’s ben­e­fit.

“See­ing a wan­ing of ben­e­fit at such a low dose as we move in­to the next treat­ment win­dow is to be ex­pect­ed. What we find so re­mark­able is the mag­ni­tude of his re­sponse at such a low dose.  This gives us great hope that this med­i­cine could re­al­ly change the course of his dis­ease,” the group said.

So far, n-Lorem has cre­at­ed 17 drugs, some of which have been ad­min­is­tered to pa­tients, while oth­er drugs are un­der­go­ing reg­u­la­to­ry re­view. The non­prof­it de­clined to say how many peo­ple have re­ceived med­i­cines. A fi­nal ver­dict on these treat­ments, in­clud­ing Con­nor’s med­i­cine, won’t be ren­dered un­til more time pass­es and the re­sults are pub­lished in a peer-re­viewed jour­nal. And many more pa­tients await treat­ment.

The fu­ture, while slow to ar­rive, could mean few­er di­ag­nos­tic odysseys, and an eas­i­er path for cus­tom med­i­cines. From n-Lorem to Boston Chil­dren’s and be­yond, ef­forts are afoot to pair ex­haus­tive new­born screen­ing with be­spoke drug de­vel­op­ment. That way, dis­eases are halt­ed be­fore un­leash­ing the worst symp­toms.

In San Diego, there’s no re­vers­ing time for Con­nor, who re­cent­ly turned 15. But Kel­ley is hope­ful.

“It feels like I’m see­ing more of him,” she said.