Lou Gehrig gives his farewell speech after being diagnosed with ALS in 1939. Major League Baseball is honoring the slugger Wednesday with the first-ever Lou Gehrig Day. (Credit: Getty Images)

A sim­ple pa­tient sur­vey rev­o­lu­tion­ized ALS drug de­vel­op­ment in the 1990s. Its cre­ator says it may be time for an up­grade

It’s been an­oth­er tough year for ALS ther­a­pies. New tri­als that sparked pa­tient hopes ei­ther fell short of sta­tis­ti­cal sig­nif­i­cance or failed to pro­vide enough ev­i­dence for the FDA to rec­om­mend mov­ing for­ward with­out an­oth­er look. The end re­sult is large­ly more of the same for pa­tients — lit­tle progress in a fa­tal dis­ease with on­ly two ap­proved treat­ments.

That frus­trat­ing slog has stirred pas­sion­ate de­bate with­in the pa­tient and ad­vo­ca­cy com­mu­ni­ties, large­ly around things like tri­al de­sign, com­pas­sion­ate use pro­grams or even what the bar for ap­proval should be. Long over­looked in those dis­cus­sions, how­ev­er, is a tool used to eval­u­ate every ALS ther­a­py that’s draw­ing in­creas­ing scruti­ny.

Jesse Cedar­baum

At first, in the 1990s, this tool changed the land­scape in a big way. A group of ALS re­searchers led by then-Re­gen­eron ex­ec Jesse Cedar­baum came to­geth­er to de­vel­op a rat­ing scale to mea­sure how quick­ly the dis­ease pro­gress­es, and whether ex­per­i­men­tal drugs could af­fect it mean­ing­ful­ly. Known as the ALS Func­tion­al Rat­ing Scale, lat­er re­vised in 1999, this scale has be­come one of the pri­ma­ry meth­ods bio­phar­mas have used to try to de­vel­op ALS drugs over the last 25 to 30 years, and is seen by the FDA as a high­ly use­ful tool when eval­u­at­ing whether or not the ex­per­i­men­tal drugs ac­tu­al­ly work.

But there’s been ex­as­per­a­tion with­in the ALS pa­tient com­mu­ni­ty over the scale it­self, par­tic­u­lar­ly giv­en the het­ero­ge­neous na­ture of the dis­ease. Be­cause the dis­ease can man­i­fest in a va­ri­ety of ways, two pa­tients can be mea­sured at ex­act­ly the same point of pro­gres­sion while pre­sent­ing com­plete­ly dif­fer­ent symp­toms. There are al­so com­plaints over the lack of gran­u­lar­i­ty in some as­pects of the ALS­FRS-R, with pa­tients and some re­searchers de­scrib­ing how the scale may not ac­cu­rate­ly por­tray how quick­ly some pa­tients’ dis­eases progress in some cas­es.

And now Cedar­baum, too, says it may be time to pro­duce a more mod­ern ver­sion of the scale.

“It’s proved to be very, very ro­bust, which pleas­es me a lot, but it’s not a per­fect scale,” Cedar­baum said. “We know so much more about the dis­ease now, med­ical care has changed, so­ci­ety has changed. So many things have changed that it may be time for an up­grade.”

De­vel­op­ing the scale

At its core, the ALS­FRS-R is a pa­tient sur­vey. It com­pris­es sev­er­al ques­tions that gauge how far a pa­tient’s dis­ease has pro­gressed in 12 dif­fer­ent cat­e­gories un­der three main um­brel­las: speech, mo­bil­i­ty and breath­ing dif­fi­cul­ty. Each cat­e­go­ry is then scored from 0 to 4, with 0 rep­re­sent­ing the com­plete need for as­sis­tance and 4 de­not­ing no help need­ed. In clin­i­cal tri­als, the ques­tions are typ­i­cal­ly asked once a month.

When Cedar­baum first start­ed at Re­gen­eron in 1990, there hadn’t been any spon­sored ALS tri­als con­duct­ed up to that point. There was a “hodge­podge” of oth­er sur­veys float­ing around, ask­ing pa­tients ques­tions about their symp­toms and qual­i­ty of life, but it wasn’t clear how they re­lat­ed to one an­oth­er.

“They didn’t car­ry equal weight in sum­ming things up,” Cedar­baum said.

In or­der to launch an ALS tri­al for a Re­gen­eron pro­gram, Cedar­baum want­ed to cre­ate some­thing that could mea­sure the course of pa­tients’ dis­eases and how peo­ple are func­tion­ing in mean­ing­ful ways. He set out to en­sure these as­sess­ments would be cor­re­lat­ed with both sur­vival and mus­cle strength, the ba­sic phys­i­o­log­i­cal symp­tom of ALS.

Work­ing this out was no easy task, giv­en all the vari­ables as­so­ci­at­ed with the dis­ease, and he as­sem­bled a cast of char­ac­ters that in­clud­ed sci­en­tists, clin­i­cians and phys­i­cal ther­a­pists from lead­ing ALS cen­ters across the coun­try to solve this prob­lem. They asked them­selves a ques­tion: How can we build a sin­gle rat­ing scale?

The group set­tled on two po­ten­tial mod­els on which to base a new scale. The first was some­thing called the ALS Sever­i­ty Scale, de­vel­oped in the late 1980s by re­searchers at the Uni­ver­si­ty of Wash­ing­ton. This scale at­tempt­ed to eval­u­ate ALS symp­toms nu­mer­i­cal­ly in four cat­e­gories: speech, swal­low­ing, low­er ex­trem­i­ty, and up­per ex­trem­i­ty abil­i­ties. Gen­er­al­ly, it had been used in com­bi­na­tion with a de­vice mea­sur­ing a pa­tients’ breath­ing to try to paint as ac­cu­rate a pic­ture as pos­si­ble re­gard­ing an in­di­vid­u­als’ dis­ease.

The oth­er mod­el pro­posed was based on a rat­ing scale used at the time in Parkin­son’s dis­ease, short­hand­ed as the UP­DRS. This re­lied more heav­i­ly on pa­tient re­spons­es than the ALS Sever­i­ty Scale, ask­ing those with Parkin­son’s about all as­pects of dai­ly liv­ing: walk­ing, for ex­am­ple, or ma­neu­ver­ing in bed and cut­ting food. These things al­so proved im­por­tant to ALS pa­tients to de­ter­mine how they might be feel­ing from one day to the next.

Bor­row­ing from oth­er fields is some­thing that hap­pens all the time in neu­ro­log­i­cal dis­eases, Cedar­baum said. Even though dif­fer­ent dis­eases can im­pair dif­fer­ent parts of the body, ba­sic dai­ly tasks are the same.

“Hu­man be­ings ac­tu­al­ly have a very lim­it­ed phys­i­cal reper­toire, un­less you’re Tom Cruise or an Olympic gym­nast,” Cedar­baum said. “Most of us do the same ba­sic things day in and day out. That’s what the FDA is in­ter­est­ed in when talk­ing about func­tion.”

Out of these ef­forts came the first it­er­a­tion of the ALS Func­tion­al Rat­ing Scale. The group pi­lot­ed the scale in a nat­ur­al his­to­ry study, putting it through what Cedar­baum said was a “very ex­haus­tive clini­met­ric eval­u­a­tion.” Not on­ly did it cor­re­late well with how quick­ly pa­tients pro­gressed, but the in­di­vid­ual do­mains al­so cor­re­lat­ed rea­son­ably well with mus­cle strength and across sec­tions like lung func­tion and abil­i­ty to walk. (Cedar­baum notes he wasn’t list­ed as an au­thor on this study but said it in­cludes the same team with whom he de­vel­oped the scale.)

With­in a few years, the scale start­ed be­com­ing a stan­dard fea­ture in ALS drug tri­als, and by 1994 or 1995 the FDA’s deputy head of neu­rol­o­gy pub­licly en­dorsed the scale, Cedar­baum said. A re­vi­sion was made soon af­ter to more ad­e­quate­ly rep­re­sent res­pi­ra­to­ry func­tion, adding three ques­tions to a sec­tion that had on­ly pre­vi­ous­ly had one. That fi­nal prod­uct be­came the ALS­FRS-Re­vised and it has re­mained “ba­si­cal­ly un­mod­i­fied” since 1999.

The scale be­came wide­ly used as the pri­ma­ry end­point in late-stage ALS stud­ies. Close­ly watched tri­als from Bio­gen and Amy­lyx both re­ly on it, as does Brain­storm Stem Cell Ther­a­peu­tics’ wide­ly panned Phase III study. A promi­nent “plat­form study” at Mass Gen­er­al, seek­ing to eval­u­ate a swath of ther­a­pies at once, al­so us­es the scale.

Val­i­dat­ed, but not per­fect

As more and more bio­phar­ma com­pa­nies be­gan con­duct­ing ALS drug tri­als, the ALS­FRS-R con­tin­ued show­ing cor­re­la­tions be­tween dis­ease pro­gres­sion and the ef­fec­tive­ness of those ex­per­i­men­tal drugs, Cedar­baum said. Many lead­ing clin­i­cal re­searchers, in­clud­ing Mass Gen­er­al’s Sab­ri­na Paganoni, who led a Phase II tri­al for a drug be­ing de­vel­oped by Amy­lyx, vouch for its ef­fec­tive­ness and hold the scale up as the gold stan­dard of ALS drug de­vel­op­ment.

Sab­ri­na Paganoni

“Stud­ies have shown over and over that it’s one of the most sci­en­tif­ic ways to de­tect ALS dis­ease pro­gres­sion in re­sponse to treat­ment,” said Paganoni. “There are some chal­lenges with it, how­ev­er as of to­day it is a very help­ful mea­sure and one of the best ways to as­sess clin­i­cal­ly mean­ing­ful ef­fects on a pa­tient pop­u­la­tion.”

The scale even be­came a help­ful com­mu­ni­ca­tion tool at first, Cedar­baum said, with pa­tients able to tell doc­tors at their ap­point­ments how they were feel­ing on a giv­en day us­ing some sort of guide­line. When pa­tients met oth­er pa­tients, they could in­tro­duce them­selves with their ALS­FRS-R score.

A typ­i­cal con­ver­sa­tion might have gone some­thing like, “Hi, I’m so-and-so my score this week is 36, it’s been sta­ble at that lev­el for three months, this is what my doc­tor has done,” Cedar­baum said. “Does any­one have ideas when it’s get­ting worse in this way?”

But the chal­lenges Paganoni al­ludes to, pa­tients say, add to the al­ready im­mense bur­den placed up­on ALS pa­tients who not on­ly have to deal with their dis­ease it­self, but clin­i­cal tri­als and ther­a­pies that can be phys­i­cal­ly stren­u­ous as well.

Gwen Pe­tersen was just 32 years old when she re­ceived her ALS di­ag­no­sis, af­ter more than a year of strug­gling with bal­ance and co­or­di­na­tion. She re­called her hon­ey­moon in the Ital­ian Alps where she strug­gled to nav­i­gate hik­ing the trails and, up­on re­turn­ing home, saw a host of dif­fer­ent doc­tors to try to fig­ure out what was go­ing on. They ini­tial­ly at­trib­uted her prob­lems to anx­i­ety and or­tho­sta­t­ic hy­poten­sion, a chron­ic, ex­tend­ed ver­sion of the drop in blood pres­sure one ex­pe­ri­ences when stand­ing up too quick­ly.

When doc­tors de­ter­mined ALS to be the cause in 2018, Pe­tersen im­me­di­ate­ly got to work on a jour­ney she says many pa­tients and fam­i­lies face af­ter di­ag­no­sis — per­form­ing an ex­haus­tive in­ter­net search of ex­per­i­men­tal ther­a­pies and ALS clin­i­cal tri­als, while send­ing a flur­ry of emails and phone calls to par­tic­i­pat­ing cen­ters. For Pe­tersen, who now spends her time work­ing with the I Am ALS ad­vo­ca­cy group, that jour­ney brought her to Brain­Storm and their Phase III study for the cell ther­a­py pro­gram known as NurOwn.

While par­tic­i­pat­ing in the NurOwn tri­al — a process that re­quired sev­en lum­bar punc­tures con­duct­ed in spe­cial­ized clin­ics with three need­ing overnight hos­pi­tal stays — Pe­tersen says she be­came dis­il­lu­sioned with the scale when she re­al­ized how it tries to ho­mog­e­nize a het­ero­ge­neous dis­ease. Be­cause the dis­ease can man­i­fest in a va­ri­ety of ways, two pa­tients can score ex­act­ly the same on the ALS­FRS-R while pre­sent­ing com­plete­ly dif­fer­ent symp­toms, she said.

Pe­tersen fur­ther de­scribed the test as “painful­ly sub­jec­tive,” claim­ing scores can vary de­pend­ing on the per­son ask­ing the sur­vey ques­tions, the kind of day pa­tients are hav­ing or the time of day it­self.

“If you asked me, “How’s your speech?”; nor­mal­ly I would say it’s slow but in­tel­li­gi­ble,” Pe­tersen said. “If you asked me the same ques­tion af­ter a long day of meet­ings when my voice is fried and I need to re­peat my­self, well that’s a dif­fer­ent an­swer.”

The scale’s lack of gran­u­lar­i­ty has al­so both­ered Phil Green, an­oth­er I Am ALS ad­vo­cate and Brain­Storm pa­tient that took part in the Phase III. Green, al­so di­ag­nosed in 2018, told End­points that not hav­ing frac­tion­al an­swers for the ques­tions doesn’t give an ac­cu­rate sense of how quick­ly some­one’s dis­ease can progress. One per­son can walk for a mile and be com­plete­ly fine, but af­ter a month be­come ex­haust­ed sim­ply walk­ing out­side to their mail­box. Those two cas­es, Green said, will score the same on the ALS­FRS-R am­bu­la­to­ry ques­tion.

“I like to use a fruit anal­o­gy,” Green said. “If we think ALS is an ap­ple, you may have dif­fer­ent va­ri­eties of ap­ple that taste dif­fer­ent­ly, may rot or ripen at dif­fer­ent rates, have dif­fer­ent col­ors, dif­fer­ent sizes. But we’re all con­sid­er­ing them to be the same be­cause they’re all ap­ples, and that’s not true.”

Paganoni pushed back on some of these con­cerns, point­ing to stud­ies that sug­gest ALS­FRS-R can re­li­ably show whether a drug slows dis­ease pro­gres­sion. Clin­i­cians who ask the ques­tions un­der­go rig­or­ous train­ing in or­der to use the scale the way it was in­tend­ed, she said. And the lack of avail­able ALS treat­ments is not a re­sult of the scale’s short­com­ings.

“I’m not say­ing that the ALS­FRS-R is per­fect and we should nev­er move for­ward,” Paganoni said. “It would be great to de­vel­op more sen­si­tive scales, as well as more sci­en­tif­ic bio­mark­ers… there is a lot of work go­ing in this di­rec­tion, but it’s not that easy. That’s why we don’t have an al­ter­na­tive yet.”

Ad­dress­ing the con­cerns

Cedar­baum, too, said he’s aware of these com­plaints and has been try­ing to push the ALS As­so­ci­a­tion to con­vene a con­fer­ence or meet­ing to re­view and up­date the ALS­FRS-R. He not­ed that the Parkin­son’s scale was up­dat­ed in 2008 based on changes rec­om­mend­ed by the Move­ment Dis­or­der So­ci­ety with the scale con­tin­u­ing to be re­vised — most re­cent­ly in 2019.

“One thing the field could re­al­ly, re­al­ly ben­e­fit from,” Cedar­baum said, “is com­ing to­geth­er and hav­ing ex­pert groups of pa­tients and not just physi­cians but clin­i­cians, oth­er peo­ple like OTs, PT, speech ther­a­pists, who work with ALS pa­tients all the time, come to­geth­er and say, ‘OK, this was a great scale for the ‘90s and the first quar­ter of the 2000s, but we can do bet­ter.’”

He stressed that it’s im­por­tant to find the cor­rect lan­guage for ques­tions de­ter­min­ing what might ex­ist be­tween a 3 and a 4 on the scale, and float­ed how a 3.5 could rep­re­sent pa­tients strug­gling to eat cer­tain foods but not hav­ing pro­gressed to the drop­ping of a full point. Such ques­tions ide­al­ly would be craft­ed with heavy pa­tient in­put, which is a more mod­ern way of do­ing things com­pared to when the ALS­FRS-R was first de­vel­oped in the 1990s, he said.

“This is the kind of thing that can be learned by talk­ing to pa­tients,” Cedar­baum said, “Let’s go back and find peo­ple who were re­cent­ly di­ag­nosed, or talk to peo­ple ear­li­er in their dis­ease, and say, ‘Let’s go back to be­fore your di­ag­no­sis, what was go­ing on in that year or two? What were you think­ing you were hav­ing prob­lems with? What were you telling peo­ple?’

“We can talk with spous­es or care­givers,” he con­tin­ued. “‘What was your spouse or loved one telling you wasn’t quite right about what was go­ing on?’ And then we can use that in­for­ma­tion to frame out maybe new gra­da­tions in that ear­ly phase of the dis­ease that will help. These are the kinds of things that would need to be con­sid­ered in any up­grade.”

Mer­it Cud­kow­icz

With the way the ques­tions are cur­rent­ly con­struct­ed, the scale cur­rent­ly ex­hibits phe­nom­e­na known as “floor and ceil­ing ef­fects,” said Mer­it Cud­kow­icz, an­oth­er Mass Gen­er­al re­searcher and one of the lead in­ves­ti­ga­tors of the Brain­Storm study. Sim­ply put, the ALS­FRS-R cor­re­lates less well with pa­tients who have very ear­ly-stage and very late-stage dis­ease. But Cud­kow­icz says in the mid­dle, where most tri­al par­tic­i­pants ex­ist, the scale does show mean­ing­ful changes.

Cedar­baum added that there sim­ply aren’t any da­ta from peo­ple who are in these stages of the dis­ease — all of the da­ta on the scale comes from clin­i­cal tri­als, he said, which re­cruit pa­tients with spe­cif­ic in­clu­sion and ex­clu­sion cri­te­ria.

Cud­kow­icz ac­knowl­edged Brain­Storm pa­tients’ com­plaints around the scale, and said that as some­one who helped de­sign the tri­al, she could take the heat. Brain­Storm’s study no­tably missed its pri­ma­ry goal and the com­pa­ny was di­rect­ly re­buked re­cent­ly by the FDA for tout­ing a study that missed every end­point. Cud­kow­icz, though, says the flop was like­ly due more to a tri­al de­sign fail­ure than the ALS­FRS-R’s short­com­ings. But the way pa­tients were re­cruit­ed and placed in­to a three-month lead-in pe­ri­od be­fore be­ing ran­dom­ized to place­bo on­ly com­pound­ed some of these faults.

“It was ac­tu­al­ly de­signed to pick peo­ple who were pro­gress­ing fast in or­der to be able to pick up a pos­i­tive treat­ment ef­fect in six months,” Cud­kow­icz said. “But the com­bi­na­tion of the lead-in and pick­ing fast pro­gressers meant that by the time peo­ple were treat­ed, they were in a much sick­er state than would have been op­ti­mal to start treat­ment.”

Brain­Storm claimed to see a po­ten­tial­ly pos­i­tive sig­nal among pa­tients who hadn’t yet pro­gressed far with their dis­eases. Even though the FDA has pub­licly dis­avowed the Phase III da­ta, Brain­Storm is pur­su­ing an ap­proval in this sub­pop­u­la­tion and de­clined to com­ment on the NurOwn Phase III tri­al specif­i­cal­ly, giv­en the pend­ing reg­u­la­to­ry dis­cus­sions.

But Cedar­baum not­ed there’s a dis­tinct, even es­sen­tial, ad­van­tage in dis­till­ing a het­eroge­nous dis­ease in­to a sin­gle num­ber. The scale arose out of the need for drug­mak­ers to be able to pre­cise­ly de­ter­mine how their ex­per­i­men­tal ther­a­pies are work­ing. When bio­phar­mas ul­ti­mate­ly have to present their find­ings to reg­u­la­tors, he said, they can on­ly use one num­ber to show sta­tis­ti­cal sig­nif­i­cance.

While Cedar­baum rec­og­nizes pa­tients’ mis­giv­ings over this as­pect of the ALS­FRS-R, prog­noses among sim­i­lar scor­ing in­di­vid­u­als are rel­a­tive­ly com­pa­ra­ble, re­gard­less of how the dis­ease man­i­fest­ed or how symp­toms are pre­sent­ing.

“The at­tempt to ho­mog­e­nize is prized for clin­i­cal tri­als,” Cedar­baum said. “The pa­tients might feel like it puts them in a meat grinder, but that’s done de­lib­er­ate­ly so sta­tis­ti­cians can deal with it suf­fi­cient­ly in com­mu­ni­cat­ing with FDA.”

The path for­ward

Many of the pa­tients’ com­plaints stem from the fact that there are no con­sis­tent bio­mark­ers in ALS, leav­ing drug­mak­ers to use the ALS­FRS-R or some oth­er mea­sure­ment in­stead, Green said. One of the most promis­ing bio­mark­ers that could prove to be the miss­ing piece is some­thing called neu­ro­fil­a­ment. Nor­mal­ly found in nerve cells, it’s a pro­tein that leaks in­to blood and cere­brospinal flu­id when those cells be­come in­jured.

Much like cho­les­terol is el­e­vat­ed in in­di­vid­u­als with heart dis­ease, neu­ro­fil­a­ment lev­els in the blood­stream and CSF have gen­er­al­ly been found to be high­er in ALS pa­tients, Cud­kow­icz ex­plains. Many ALS stud­ies al­ready look at neu­ro­fil­a­ment lev­els as sec­ondary mea­sures, but there hasn’t been much work yet in tar­get­ing these pro­teins specif­i­cal­ly.

The tri­al that’s come the clos­est to show­ing a re­la­tion­ship is Bio­gen’s Phase I/II for an ex­per­i­men­tal drug called tofersen, Cud­kow­icz said, which showed a clin­i­cal ben­e­fit in ad­di­tion to about 50% low­er neu­ro­fil­a­ment lev­els. But that study was very small with on­ly four peo­ple test­ed on the high dose, she added, and even though it looked like there wasn’t much pro­gres­sion com­pared to the place­bo, it’s still “way too small” for any­one to say.

Brain­Storm had done ex­ten­sive bio­mark­er re­search be­fore con­duct­ing its stud­ies, and it’s one of the things that im­pressed Pe­tersen and Green be­fore they signed up for the ex­per­i­men­tal ther­a­pies. Cud­kow­icz not­ed their tri­al saw low­ered lev­els of neu­roin­flam­ma­tion — some­thing Brain­Storm says cor­re­lat­ed to a po­ten­tial clin­i­cal ben­e­fit in that small group — de­spite NurOwn’s ma­jor whiffs on the pri­ma­ry and sec­ondary end­points.

In the Phase III NurOwn study, re­searchers looked at three dif­fer­ent kinds of bio­mark­ers, Brain­storm pres­i­dent and CMO Ralph Kern said. The first looked at neu­roin­flam­ma­tion by ex­am­in­ing lev­els of cy­tokines and ef­fec­tor mol­e­cules; the sec­ond ex­am­ined neu­ronal in­jury and neu­rode­gen­er­a­tion bio­mark­ers, the um­brel­la con­tain­ing neu­ro­fil­a­ment; and the third ex­plored how re­pair mol­e­cules de­liv­ered ap­pro­pri­ate car­go to in­jured cells.

Though each bio­mark­er serves a dif­fer­ent pur­pose, when tak­en to­geth­er they paint a “com­pre­hen­sive pic­ture,” Kern said.

And that bio­mark­er re­search is al­so one of the rea­sons Green feels that the Phase III study shouldn’t be dis­count­ed as a fail­ure. If the NurOwn ther­a­py can show a po­ten­tial ben­e­fit for a small group of pa­tients, Green ar­gues, then Brain­Storm and the FDA should be do­ing every­thing in their pow­er to make it avail­able to that group of pa­tients. In ALS, every lit­tle thing helps, he said.

“From an over­all sys­temic per­spec­tive, we re­al­ly need to re­think what a win looks like in ALS clin­i­cal tri­als,” Green said. “It’s time that we have a work­ing meet­ing with all of the stake­hold­ers to re­al­ly fig­ure out how to fix the ther­a­peu­tic de­vel­op­ment process in ALS, be­cause we’ve had so many failed tri­als in our dis­ease. But maybe it’s not the ther­a­pies that are fail­ing, it’s the process in which they’re be­ing eval­u­at­ed that’s fail­ing the ther­a­pies.”

Joshua Co­hen

Not every­one is on board the neu­ro­fil­a­ment train, how­ev­er, with the folks at Amy­lyx ex­press­ing doubt that it might be the key re­searchers are look­ing for. Find­ing a clin­i­cal bio­mark­er for any neu­ro­log­i­cal dis­ease would amount to a “holy grail,” CEO Joshua Co­hen said, but added there’s still a lot more work that needs to be done for some­thing to de­fin­i­tive­ly re­place the ALS­FRS-R.

It’s worth not­ing that Amy­lyx’s pro­gram, which hit sta­tis­ti­cal sig­nif­i­cance in the ALS­FRS-R scale and will be sub­mit­ted for ap­proval in Eu­rope and Cana­da by the end of the year, showed no cor­re­la­tion be­tween slow­ing pro­gres­sion and neu­ro­fil­a­ment lev­els — a fact Co­hen of­fered up freely.

But the ques­tion for him comes down to how much stock you then put in­to the mea­sure­ment tests. If the drug is shown to im­prove the neu­ro­fil­a­ment lev­els, or im­prove­ments in an­oth­er bio­mark­er, but not slow dis­ease pro­gres­sion ac­cord­ing to the ALS­FRS-R, is that some­thing that should be giv­en to pa­tients?

“At the end of the day, if the drug is not im­pact­ing peo­ple’s dai­ly func­tions — if it’s im­pact­ing the blood bio­mark­er but not the func­tion — I’m not sure that’s op­ti­mal,” Co­hen said. “I think what would re­al­ly make a bio­mark­er con­vinc­ing is one im­pact­ing that bio­mark­er would al­so cor­re­spond­ing­ly im­pact that func­tion. And I think to date we just don’t have that.”

Go­ing for­ward, com­pa­nies and in­ves­ti­ga­tors are con­tin­u­ing to tweak and ex­per­i­ment with ALS tri­al de­signs with the aim of in­clud­ing more pa­tient in­put. There are oth­er meth­ods out there be­ing de­vel­oped to pro­vide ei­ther a more gran­u­lar rat­ing scale or a more com­pre­hen­sive look at how drugs cor­re­late to symp­toms, in­clud­ing a new­er rat­ing sur­vey called the Rasch-Built Over­all Amy­otroph­ic Lat­er­al Scle­ro­sis Dis­abil­i­ty Scale, or ROADS. Pe­tersen and Green both feel ROADS is less sub­jec­tive than the ALS­FRS-R and are try­ing to push com­pa­nies to in­clude it in fu­ture drug tri­als.

Clene Nanomed­i­cine, a biotech de­vel­op­ing an ALS treat­ment made from gold nanocrys­tals, is try­ing to sup­ple­ment po­ten­tial­ly reg­is­tra­tional da­ta from the HEALEY plat­form study with an­oth­er tri­al in Aus­tralia us­ing an ap­proach called MU­NIX(4). Here, re­searchers place elec­trodes on pa­tients’ mus­cles and com­pare how they con­tract with elec­tric stim­u­la­tion to how pa­tients can move them on their own.

Clene not­ed that most US com­pa­nies don’t use MU­NIX any­more be­cause it’s much more time-con­sum­ing and ex­pen­sive to ad­min­is­ter com­pared to some­thing like the ALS­FRS-R, which is rel­a­tive­ly cheap and on­ly takes about 10 to 15 min­utes.

Rob Ether­ing­ton

“In a way, if you think about HEALEY like this, HEALEY’s look­ing at their sec­ondary [end­point] as lung func­tion and hand­held diom­e­try,” Clene CEO Rob Ether­ing­ton said. “And that’s ef­fec­tive­ly akin in a US mod­el to what MU­NIX is. So we see some in­ter­est­ing in­verse cor­re­la­tions be­tween these two da­ta.”

One po­ten­tial bio­mark­er that’s piqued Cedar­baum’s in­ter­est is MRIs of pa­tients’ brains and spinal cords, be­cause it could give re­searchers a bet­ter idea of when neu­rons start be­com­ing dam­aged or dy­ing off. It’s a method that’s gained promi­nence in stud­ies of Alzheimer’s dis­ease, and such cell loss would re­sult in a quan­tifi­able shrink­ing of the brain in ALS pa­tients, he said.

But the ALS­FRS-R like­ly isn’t go­ing away any­time soon. Cedar­baum feels sim­i­lar­ly to Amy­lyx, say­ing that he doesn’t be­lieve some­thing like neu­ro­fil­a­ment or an­oth­er bio­mark­er will ever ful­ly re­place the scale, ei­ther in its cur­rent form or an up­dat­ed ver­sion. There is too lit­tle known about how neu­ro­fil­a­ment di­rect­ly cor­re­lates with how pa­tients feel, which Cedar­baum puts atop his per­son­al list of pri­or­i­ties.

Though a drug may keep neu­ro­fil­a­ment down for an ex­tend­ed pe­ri­od of time — Cedar­baum of­fered a year or two as an ex­am­ple — it’s not yet clear whether the ALS­FRS-R scores will con­tin­ue go­ing down. And when all is said and done, the best way Cedar­baum feels a drug or ther­a­py can help pa­tients is by ask­ing them.

“The bot­tom line is the ALS­FRS-R is a good scale, it’s clear­ly good enough be­cause now we see it can show treat­ment dif­fer­ences,” Cedar­baum said. “But a lot has hap­pened in 25 years that a new ver­sion of the scale could im­prove on.”

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.

Joshua Brumm, Dyne Therapeutics CEO

FDA or­ders DMD tri­al halt, rais­ing ques­tions about a whole class of promis­ing drugs

Dyne Therapeutics’ stock took a nasty hit this morning after the biotech put out word that the FDA had slapped a clinical hold on their top program for Duchenne muscular dystrophy. And now speculation is bouncing around Biotwitter that there could be a class effect at work here that would implicate other drug developers in the freeze.

Dyne execs didn’t have a whole lot to say about why the FDA sidelined their IND for DYNE-251 in DMD while “requesting additional clinical and non-clinical information for” the drug.

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Chamath Palihapitiya and Pablo Legorreta

Bil­lion­aires Chamath Pal­i­hapi­tiya and Pablo Legor­re­ta hatch an $825M SPAC for cell ther­a­py biotech

Three years after Royalty Pharma chief Pablo Legorreta led a group of investors to buy up a pair of biotechs and create a new startup called ProKidney, the biotech is jumping straight into an $825 million public shell created by SPAC king and tech billionaire Chamath Palihapitiya.

ProKidney was founded 6 years ago but really got going at the beginning of 2019 with the $62 million acquisition of inRegen, which was working on an autologous — from the patient — cell therapy for kidney disease. After extracting kidney cells from patients, researchers expand the cells in the lab and then inject them back into patients, aiming to restore the kidneys of patients suffering from CKD.

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Michel Vounatsos, Biogen CEO (Credit: World Economic Forum/Ciaran McCrickard)

An un­ortho­dox pro­pos­al for Bio­gen's Medicare-man­dat­ed Aduhelm tri­al

Biogen has gone full blitz since Medicare announced it would only cover its new Alzheimer’s drug when used in clinical trials, accusing the agency of discriminating against Alzheimer’s patients and trying to get physicians to change regulators’ minds.  Critics, meanwhile, cheered what they see as a necessary wall protecting payers and patients from an unproven and unsafe drug.

Far less attention, though, has gone to what a Medicare-funded clinical trial would actually look like. Biogen has operated as if it would be a standard late-stage Alzheimer’s trial, enrolling a couple thousand patients and giving half placebo.

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