Reg­u­la­to­ry in­tel­li­gence: Up­date on re­gen­er­a­tive med­i­cine ad­vanced ther­a­pies des­ig­na­tions

This ar­ti­cle dis­cuss­es the scope and pur­pose of the spe­cial des­ig­na­tion for Re­gen­er­a­tive Med­i­cine Ad­vanced Ther­a­pies (RMAT) cre­at­ed by the pas­sage of the 21st Cen­tu­ry Cures Act. The au­thors ex­plain the ben­e­fits ex­pect­ed to be re­al­ized with RMAT, such as keep­ing the US glob­al­ly com­pet­i­tive in the field. They pro­vide a tal­ly of prod­ucts re­ceiv­ing the spe­cial des­ig­na­tion to date and a cur­rent count, by year, of prod­ucts for which RMAT des­ig­na­tion has been re­quest­ed.

In­tro­duc­tion

Sec­tion 3033 of the 21st Cen­tu­ry Cures Act, ti­tled “Ac­cel­er­at­ed Ap­proval for Re­gen­er­a­tive Ad­vanced Ther­a­pies,” cre­at­ed a spe­cial des­ig­na­tion for Re­gen­er­a­tive Med­i­cine Ad­vanced Ther­a­pies (RMAT). A prod­uct is el­i­gi­ble for RMAT des­ig­na­tion if it is a re­gen­er­a­tive med­i­cine ther­a­py, such as cell ther­a­py, ther­a­peu­tic tis­sue en­gi­neer­ing prod­uct, hu­man cell and tis­sue prod­uct, gene ther­a­py or any com­bi­na­tion prod­uct us­ing such ther­a­pies or prod­ucts, and is in­tend­ed to treat, mod­i­fy, re­verse or cure a se­ri­ous or life-threat­en­ing dis­ease or con­di­tion and pre­lim­i­nary clin­i­cal ev­i­dence in­di­cates that the drug has the po­ten­tial to ad­dress un­met med­ical needs for such dis­ease or con­di­tion.

Oth­er na­tion­al bod­ies have in re­cent years made spe­cial reg­u­la­to­ry pro­vi­sions to rec­og­nize the val­ue of re­gen­er­a­tive med­i­cine prod­ucts. For ex­am­ple, Japan’s SAKI­GAKE des­ig­na­tion,  was in­tro­duced in 2015 to pro­mote R&D of re­gen­er­a­tive med­i­cines and oth­er in­no­vate phar­ma­ceu­ti­cals and med­ical de­vices.

RMAT des­ig­na­tion has helped keep the US com­pet­i­tive in the glob­al field, while ad­dress­ing spe­cif­ic needs and re­quire­ments of re­gen­er­a­tive med­i­cine ad­vanced ther­a­py prod­ucts. The ben­e­fits of an RMAT des­ig­na­tion are the same as the ben­e­fits for break­through ther­a­pies and in­clude in­ter­ac­tions with FDA to ex­pe­dite de­vel­op­ment and re­view of the prod­uct and con­sid­er­a­tion of the prod­uct for pri­or­i­ty re­view or ac­cel­er­at­ed ap­proval. Re­ceiv­ing RMAT des­ig­na­tion al­so al­lows for in­creased flex­i­bil­i­ty in clin­i­cal tri­al de­sign, for in­stance, in the num­ber of clin­i­cal tri­al sites. De­vel­op­ers al­so have the po­ten­tial to use pa­tient reg­istry da­ta and oth­er re­al-world sources in post-ap­proval path­ways.

While de­vel­op­ers seek­ing break­through des­ig­na­tion are re­quired to show that their ther­a­peu­tic can­di­date would pro­vide a sub­stan­tial im­prove­ment over ex­ist­ing ther­a­pies, RMAT des­ig­na­tion on­ly re­quires that the ther­a­py have the po­ten­tial to ad­dress un­met med­ical need.

With RMAT des­ig­na­tions avail­able for more than two years, what have we seen so far?

Table 1 pro­vides FDA’s lat­est tal­ly of RMAT des­ig­na­tions by year. On­ly 2018 rep­re­sents a full year. For 2019, the num­ber of re­quests is at a high­er rate (19 re­quests through 10 April 2019) but the num­ber grant­ed is about the same rate as for 2018 (about 1.5 re­quests grant­ed per month).

Table 1. Met­rics on RMAT Re­quests by Year1
Fis­cal Year To­tal Re­quests
Re­ceived
Grant­ed De­nied With­drawn
2017 31 11 18 2
2018 47 18 27 2
2019 19 4 8 1

So far, no RMAT-des­ig­nat­ed prod­ucts have re­ceived mar­ket­ing ap­proval and no RMAT des­ig­na­tions have been re­port­ed with­drawn or re­scind­ed.

Fig­ure 1 pro­vides met­rics on des­ig­na­tion re­quests by ther­a­peu­tic area as of Sep­tem­ber 2018. The largest cat­e­go­ry is neu­rol­o­gy, fol­lowed by on­col­o­gy. This is sur­pris­ing be­cause sci­en­tif­ic pub­li­ca­tions of re­gen­er­a­tive med­i­cines for on­col­o­gy far out­pace those for neu­rol­o­gy.2

Fig­ure 2 pro­vides met­rics on des­ig­na­tion re­quests by prod­uct type as of March 2019. The great­est num­ber of des­ig­na­tion re­quests have been for cell ther­a­py prod­ucts with al­lo­gene­ic prod­ucts out­pac­ing au­tol­o­gous prod­ucts.

Fig­ure 1. RMAT Des­ig­na­tion Re­quests by Ther­a­peu­tic Area3

Fig­ure 2. RMAT des­ig­na­tion re­quests by prod­uct type4


Table 2 pro­vides a list­ing of the pub­licly an­nounced RMAT des­ig­na­tions. Twen­ty-eight have been an­nounced so far. There have been 33 RMAT des­ig­na­tions grant­ed as of 1 April 2019,3 thus five are cur­rent­ly unan­nounced.

Table 2. List­ing of Pub­licly An­nounced RMAT Des­ig­na­tions
Prod­uct Name Spon­sor Date Award­ed De­scrip­tion
HU­MA­CYL  Hu­ma­cyte 20 March 2017 acel­lu­lar ves­sel for vas­cu­lar ac­cess in he­modial­y­sis pa­tients
RVT-802  En­zy­vant 17 April 2017 al­lo­gene­ic thymic tis­sue for Di­ge­orge Syn­drome
jCell  jCyte 2 May 2017 hu­man reti­nal prog­en­i­tor cells for re­tini­tis pig­men­tosa
Ixmy­lo­cel-T  Veri­cel 10 May 2017 au­tol­o­gous ex­pand­ed mul­ti­cel­lu­lar ther­a­py for heart fail­ure due to is­chemic di­lat­ed car­diomy­opa­thy
Strat­a­Graft Mallinck­rodt 18 Ju­ly 2017 tis­sue en­gi­neered full thick­ness re­gen­er­a­tive skin tis­sue for deep par­tial thick­ness burns
ATIR101  Kiadis 20 Sep­tem­ber 2017 cell ther­a­py for leukemia
Lenti­Glo­bin  Blue­bird 1 Oc­to­ber 2017 gene ther­a­py for sick­le cell dis­ease
AST-OP­CI  As­te­r­ias 2 Oc­to­ber 2017 cell ther­a­py for spinal cord in­jury
Mul­ti­Stem  Ather­sys 5 Oc­to­ber 2017 cell ther­a­py is­chemic stroke
JCAR017  Juno (Cel­gene) 1 No­vem­ber 2017 car-t ther­a­py for re­lapsed or re­frac­to­ry dif­fuse large b-cell lym­phoma
CE­VA101  Cel­l­va­tion (Fortress Biotech) 8 No­vem­ber 2017 cell ther­a­py for trau­mat­ic brain in­jury
MPC-150-IM 
Revas­cor
Mesoblast 21 De­cem­ber 2017 mes­enchy­mal pre­cur­sor cell ther­a­py for heart fail­ure
EB-101  Abeona 29 Jan­u­ary 2018 gene ther­a­py for re­ces­sive dy­s­troph­ic epi­der­mol­y­sis bul­losa
CAP-1002  Capri­cor 5 Feb­ru­ary 2018 cell ther­a­py for duchenne mus­cu­lar dy­s­tro­phy
Am­nioFix  MiMedx 9 March 2018 tis­sue en­gi­neered al­lo­gene­ic mi­cronized de­hy­drat­ed hu­man am­nion/chori­on mem­brane for os­teoarthri­tis of the knee
ABO-102  Abeona 23 April 2018 gene ther­a­py for San­fil­ip­po Syn­drome type a
VM202 Vi­roMed May 2018 gene ther­a­py for painful di­a­bet­ic pe­riph­er­al neu­ropa­thy
NSR-REP1  Night­star Ther­a­peu­tics 14 June 2018 gene ther­a­py for choroi­dere­ma
CLBS14-NOR­DA  Cal­adrius Bio­sciences 19 June 2018 No-Op­tion Re­frac­to­ry Dis­abling Angi­na (NOR­DA)
VY-AADC  Voy­ager 21 June 2018 gene ther­a­py for Parkin­son’s dis­ease
Romye­lo­cel-L  Celler­ant 2 Ju­ly 2018 cell ther­a­py for pre­ven­tion of in­fec­tions dur­ing neu­trope­nia
AT132 Au­dentes Ther­a­peu­tics 21 Au­gust 2018 gene ther­a­py for X-linked my­otubu­lar my­opa­thy
Avance Ax­o­Gen 29 Oc­to­ber 2018 tis­sue en­gi­neered nerve graft for pe­riph­er­al nerve re­pair
P-BC­MA-101 Po­sei­da Ther­a­peu­tics No­vem­ber 5, 2018 gene mod­i­fied CAR-T cell ther­a­py for re­lapsed/re­frac­to­ry mul­ti­ple myelo­ma
Li­fileu­cel Io­vance Bio­ther­a­peu­tics 6 No­vem­ber 2018 adop­tive gene-mod­i­fied cell ther­a­py for metasta­t­ic melanoma
RP-L102 Rock­et Phar­ma­ceu­ti­cals 27 No­vem­ber 2018 lentivi­ral vec­tor-based gene ther­a­py for Fan­coni ane­mia
FCR001 Ta­laris Ther­a­peu­tics (Re­generex) 18 April 2019 al­lo­gene­ic cell ther­a­py for im­mune tol­er­ance in kid­ney trans­plant
ECT-001 Ex­CellThera 23 April 2019 mul­ti­ple myelo­ma, high-risk leukemia, and oth­er hema­to­log­ic ma­lig­nan­cies

In the fol­low­ing month, the Al­liance for Re­gen­er­a­tive Med­i­cine plans to launch a data­base uti­liz­ing pub­licly avail­able and com­pa­ny-pro­vid­ed in­for­ma­tion to cre­ate a pub­lic list of RMAT re­cip­i­ents, as well as oth­er ex­pe­dit­ed ap­proval des­ig­na­tions award­ed in the Unit­ed States, Eu­rope, and Japan.

Clear­ly, the RMAT des­ig­na­tion pro­gram has been very ac­tive for FDA and pop­u­lar for spon­sors. We look for­ward to see­ing the first prod­ucts ap­proved un­der this pro­gram.

Ref­er­ences

  1. Cu­mu­la­tive CBER Re­gen­er­a­tive Med­i­cine Ad­vanced Ther­a­py (RMAT) Des­ig­na­tion Re­quests Re­ceived by Fis­cal Year. FDA web­site. https://www.fda.gov/vac­cines-blood-bi­o­log­ics/cel­lu­lar-gene-ther­a­py-prod­ucts/cu­mu­la­tive-cber-re­gen­er­a­tive-med­i­cine-ad­vanced-ther­a­py-rmat-des­ig­na­tion-re­quests-re­ceived-fis­cal. Ac­cessed 6 May 2019.
  2. Based on PubMed search com­par­ing “re­gen­er­a­tive med­i­cine on­col­o­gy” to “re­gen­er­a­tive med­i­cine neu­rol­o­gy” or “cell gene ther­a­py neu­rol­o­gy” to “cell gene ther­a­py on­col­o­gy,” 3 May 2019.
  3. Bryan WW. “Re­gen­er­a­tive Med­i­cine Ad­vanced Ther­a­py (RMAT) Des­ig­na­tion.” Amer­i­can So­ci­ety of Gene and Cell Ther­a­py. Li­ai­son Meet­ing. 13 Sep­tem­ber 2018.
  4. From Wil­son Bryan pre­sen­ta­tion to the Al­liance for Re­gen­er­a­tive Med­i­cine Li­ai­son Meet­ing on 28 March 2019.

Janet Lynch Lam­bert joined the Al­liance for Re­gen­er­a­tive Med­i­cine (ARM) in 2017 as the or­ga­ni­za­tion’s first CEO. She most re­cent­ly served as the act­ing head of en­gage­ment for the All of Us Re­search Pro­gram at the Na­tion­al In­sti­tutes of Health and as head of the Out­reach Of­fice in the Of­fice of the NIH Di­rec­tor. Pri­or to join­ing NIH, she was vice pres­i­dent of gov­ern­ment re­la­tions and head of the Wash­ing­ton of­fice of Life Tech­nolo­gies.

William Si­et­se­ma is vice pres­i­dent, glob­al reg­u­la­to­ry af­fairs at Cal­adrius Bio­sciences, a com­pa­ny that fo­cus­es on in­no­v­a­tive cell ther­a­pies for dif­fi­cult-to-treat dis­eases. Pri­or to Cal­adrius, he was glob­al reg­u­la­to­ry lead at Am­gen and vice pres­i­dent, glob­al reg­u­la­to­ry con­sult­ing and sub­mis­sions at Kendle In­ter­na­tion­al/INC Re­search and ad­junct pro­fes­sor of phar­ma­ceu­ti­cal sci­ences at the Uni­ver­si­ty of Cincin­nati, Col­lege of Phar­ma­cy. He may be con­tact­ed at william@si­et­se­ma.com.


First pub­lished in Reg­u­la­to­ry Fo­cus™ by the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety, the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care prod­ucts. Click here for more in­for­ma­tion.

It’s fi­nal­ly over: Bio­gen, Ei­sai scrap big Alzheimer’s PhI­I­Is af­ter a pre­dictable BACE cat­a­stro­phe rais­es safe­ty fears

Months after analysts and investors called on Biogen and Eisai to scrap their BACE drug for Alzheimer’s and move on in the wake of a string of late-stage failures and rising safety fears, the partners have called it quits. And they said they were dropping the drug — elenbecestat — after the independent monitoring board raised concerns about…safety.

We don’t know exactly what researchers found in this latest catastrophe, but the companies noted in their release that investigators had determined that the drug was flunking the risk/benefit analysis.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,700+ biopharma pros reading Endpoints daily — and it's free.

It's not per­fect, but it's a good start: FDA pan­elists large­ly en­dorse Aim­mune's peanut al­ler­gy ther­a­py

Two days after a fairly benign review from FDA staff, an independent panel of experts largely endorsed the efficacy and safety of Aimmune’s peanut allergy therapy, laying the groundwork for approval with a risk evaluation and mitigation strategy (REMS).

Traditionally, peanut allergies are managed by avoidance, but the threat of accidental exposure cannot be nullified. Some allergists have devised a way to dose patients off-label with peanut protein derived from supermarket products to wean them off their allergies. But the idea behind Aimmune’s product was to standardize the peanut protein, and track the process of desensitization — so when accidental exposure in the real world invariably occurs, patients are less likely to experience a life-threatening allergic reaction.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,700+ biopharma pros reading Endpoints daily — and it's free.

Lisa M. DeAngelis, MSKCC

MSK picks brain can­cer ex­pert Lisa DeAn­ge­lis as its next CMO — fol­low­ing José Basel­ga’s con­tro­ver­sial ex­it

It’s official. Memorial Sloan Kettering has picked a brain cancer expert as its new physician-in-chief and CMO, replacing José Baselga, who left under a cloud after being singled out by The New York Times and ProPublica for failing to properly air his lucrative industry ties.

His replacement, who now will be in charge of MSK’s cutting-edge research work as well as the cancer care delivered by hundreds of practitioners, is Lisa M. DeAngelis. DeAngelis had been chair of the neurology department and co-founder of MSK’s brain tumor center and was moved in to the acting CMO role in the wake of Baselga’s departure.

Penn team adapts CAR-T tech, reengi­neer­ing mouse cells to treat car­diac fi­bro­sis

After establishing itself as one of the pioneer research centers in the world for CAR-T cancer therapies, creating new attack vehicles to eradicate cancer cells, a team at Penn Medicine has begun the tricky transition of using the basic technology for heart repair work.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,700+ biopharma pros reading Endpoints daily — and it's free.

Tal Zaks. Moderna

The mR­NA uni­corn Mod­er­na has more ear­ly-stage hu­man da­ta it wants to show off — reach­ing new peaks in prov­ing the po­ten­tial

The whole messenger RNA field has attracted billions of dollars in public and private investor cash gambled on the prospect of getting in on the ground floor. And this morning Boston-based Moderna, one of the leaders in the field, wants to show off a few more of the cards it has to play to prove to you that they’re really in the game.

The whole hand, of course, has yet to be dealt. And there’s no telling who gets to walk with a share of the pot. But any cards on display at this point — especially after being accused of keeping its deck under lock and key — will attract plenty of attention from some very wary, and wired, observers.

“In terms of the complexity and unmet need,” says Tal Zaks, the chief medical officer, “this is peak for what we’ve accomplished.”

Moderna has two Phase I studies it wants to talk about now.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,700+ biopharma pros reading Endpoints daily — and it's free.

Sanofi takes a $260M hit to ex­tri­cate it­self from a dis­as­trous al­liance with Lex­i­con

Sanofi spent $300 million in cash to get into a $1.7 billion alliance with Lexicon on their SGLT1/2 diabetes drug sotagliflozin. And now that the drug has been spurned by the FDA after burning through a program that provided mixed late-stage data and a late shot at a last-place finish, the French pharma giant is forking over another $260 million to get out of the deal.

Sanofi’s unhappiness was already apparent when the company — now under new CEO Paul Hudson — posted a statement back in July that they were dropping the deal. But it wasn’t that simple. 

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 59,700+ biopharma pros reading Endpoints daily — and it's free.

Rit­ter bombs fi­nal PhI­II for sole lac­tose in­tol­er­ance drug — shares plum­met

More than two years ago Ritter Pharmaceuticals managed to find enough silver lining in its Phase IIb/III study — after missing the top-line mark — to propel its lactose intolerance toward a confirmatory trial. But as it turned out, the enthusiasm only set the biotech and its investors up to be sorely disappointed.

This time around there’s little left to salvage. Not only did RP-G28 fail to beat placebo in reducing lactose intolerance symptoms, patients in the treatment group actually averaged a smaller improvement. On a composite score measuring symptoms like abdominal pain, cramping, bloating and gas, patients given the drug had a mean reduction of 3.159 while the placebo cohort saw a 3.420 drop on average (one-sided p-value = 0.0106).

Ear­ly snap­shot of Ad­verum's eye gene ther­a­py sparks con­cern about vi­sion loss

An early-stage update on Adverum Biotechnologies’ intravitreal gene therapy has triggered investor concern, after patients with wet age-related macular degeneration (AMD) saw their vision deteriorate, despite signs that the treatment is improving retinal anatomy.

Adverum, on Wednesday, unveiled 24-week data from the OPTIC trial of its experimental therapy, ADVM-022, in six patients who have been administered with one dose of the therapy. On average, patients in the trial had severe disease with an average of 6.2 anti-VEGF injections in the eight months prior to screening and an average annualized injection frequency of 9.3 injections.

Alex Ar­faei trades his an­a­lyst's post for a new role as biotech VC; Sanofi vet heads to Vi­for

Too often, Alex Arfaei arrived too late. 

An analyst at BMO Capital Markets, he’d meet with biotech or pharmaceutical heads for their IPO or secondary funding and his brain, trained on a biology degree and six years at Merck and Endo, would spring with questions: Why this biomarker? Why this design? Why not this endpoint? Not that he could do anything about it. These execs were coming for clinical money; their decisions had been made and finalized long ago.