FDA lays down the law on gene ther­a­py, of­fer­ing guid­ances on both dis­eases and pro­ce­dures

As first an­nounced in Jan­u­ary, the FDA’s Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search (CBER) on Wednes­day of­fered a swath of new draft guid­ance doc­u­ments on hu­man gene ther­a­pies — of­fer­ing a look at what it ex­pects from an in­dus­try that’s be­gin­ning to take off.

The six guid­ance doc­u­ments fo­cus on de­vel­op­ing he­mo­phil­ia, rare dis­ease and reti­nal dis­or­der gene ther­a­pies, and in­clude one on chem­istry, man­u­fac­tur­ing and con­trol (CMC) in­for­ma­tion, one on long term fol­low-up ob­ser­va­tion­al stud­ies col­lect­ing da­ta on ad­verse events and one on the test­ing of retro­vi­ral vec­tor-based ther­a­pies.

Last De­cem­ber, the FDA ap­proved a new gene ther­a­py, priced at $850,000, from Spark Ther­a­peu­tics for the treat­ment of chil­dren and adult pa­tients with an in­her­it­ed form of vi­sion loss that may re­sult in blind­ness. And back in 2016, FDA be­gan to see the num­ber of gene and cell ther­a­py ap­pli­ca­tions spike.

Last No­vem­ber, the FDA al­so an­nounced its pol­i­cy frame­work for re­gen­er­a­tive med­i­cine, in­clud­ing a draft guid­ance that de­scribes the ex­pe­dit­ed pro­grams, such as the break­through ther­a­py des­ig­na­tion, and the re­gen­er­a­tive med­i­cine ad­vanced ther­a­py (RMAT)  des­ig­na­tion, that may be avail­able to spon­sors of these ther­a­pies. Com­pa­nies have al­ready weighed in on such guid­ance.

(Links to guid­ance doc­u­ments are in head­ers be­low).


The 15-page draft guid­ance pro­vides rec­om­men­da­tions on the clin­i­cal tri­al de­sign and re­lat­ed de­vel­op­ment of co­ag­u­la­tion fac­tor VI­II (he­mo­phil­ia A) and IX (he­mo­phil­ia B) ac­tiv­i­ty as­says, in­clud­ing how to ad­dress dis­crep­an­cies in fac­tor VI­II and fac­tor IX ac­tiv­i­ty as­says.

The draft guid­ance al­so in­cludes rec­om­men­da­tions re­gard­ing pre­clin­i­cal and clin­i­cal con­sid­er­a­tions to sup­port de­vel­op­ment of he­mo­phil­ia gene ther­a­pies (GTs), as well as in­for­ma­tion on ex­pe­dit­ed pro­grams and com­mu­ni­ca­tion with the FDA.

Rare Dis­ease

This 14-page draft guid­ance pro­vides rec­om­men­da­tions on de­vel­op­ing a GT prod­uct in­tend­ed to treat a rare dis­ease in adult and/or pe­di­atric pa­tients. The guid­ance re­lates to the man­u­fac­tur­ing, pre­clin­i­cal, and clin­i­cal tri­al de­sign is­sues for all phas­es of the clin­i­cal de­vel­op­ment pro­gram.

“Such in­for­ma­tion is in­tend­ed to as­sist spon­sors in de­sign­ing clin­i­cal de­vel­op­ment pro­grams for such prod­ucts, where there may be lim­it­ed study pop­u­la­tion size and po­ten­tial fea­si­bil­i­ty and safe­ty is­sues as well as is­sues re­lat­ing to the in­ter­pretabil­i­ty of bioac­tiv­i­ty/ef­fi­ca­cy out­comes that may be unique to rare dis­eases or to the na­ture of the GT prod­uct it­self,” the FDA said.

Reti­nal Dis­or­ders

This 13-page draft guid­ance pro­vides rec­om­men­da­tions to stake­hold­ers de­vel­op­ing GTs for reti­nal dis­or­ders af­fect­ing adult and pe­di­atric pa­tients. The fo­cus per­tains to is­sues spe­cif­ic to GT prod­ucts for reti­nal dis­or­ders and pro­vides rec­om­men­da­tions re­lat­ed to prod­uct de­vel­op­ment, pre­clin­i­cal test­ing and clin­i­cal tri­al de­sign.


This 54-page draft guid­ance pro­vides spon­sors of a GT in­ves­ti­ga­tion­al new drug ap­pli­ca­tion (IND) with rec­om­men­da­tions re­gard­ing CMC in­for­ma­tion re­quired to as­sure prod­uct safe­ty, iden­ti­ty, qual­i­ty, pu­ri­ty and strength (in­clud­ing po­ten­cy) of the in­ves­ti­ga­tion­al prod­uct.

The draft ap­plies to GTs and to com­bi­na­tion prod­ucts that con­tain a hu­man gene ther­a­py in com­bi­na­tion with a drug or de­vice.

“The field of gene ther­a­py has pro­gressed rapid­ly since FDA is­sued the April 2008 guid­ance. There­fore, FDA is up­dat­ing the guid­ance to pro­vide cur­rent FDA rec­om­men­da­tions re­gard­ing the CMC con­tent of a gene ther­a­py IND,” the FDA said.

When fi­nal­ized, the draft is in­tend­ed to su­per­sede the doc­u­ment en­ti­tled “Guid­ance for FDA Re­view­ers and Spon­sors: Con­tent and Re­view of Chem­istry, Man­u­fac­tur­ing, and Con­trol (CMC) In­for­ma­tion for Hu­man Gene Ther­a­py In­ves­ti­ga­tion­al New Drug Ap­pli­ca­tions (INDs),” from April 2008.

Long Term Fol­low-Up

This 36-page draft guid­ance pro­vides spon­sors with rec­om­men­da­tions re­gard­ing the de­sign of pro­to­cols for long term fol­low-up ob­ser­va­tion­al stud­ies for the col­lec­tion of da­ta on de­layed ad­verse events fol­low­ing the ad­min­is­tra­tion of a GT.

When fi­nal­ized, the draft is in­tend­ed to su­per­sede the doc­u­ment en­ti­tled “Guid­ance for In­dus­try: Gene Ther­a­py Clin­i­cal Tri­als–Ob­serv­ing Par­tic­i­pants for De­layed Ad­verse Events” from No­vem­ber 2006. This draft, when fi­nal­ized, is al­so in­tend­ed to sup­ple­ment the guid­ance dis­cussed be­low.

Test­ing of Retro­vi­ral Vec­tor-Based Hu­man Gene Ther­a­pies

This 16-page draft pro­vides spon­sors of retro­vi­ral vec­tor-based hu­man GTs with rec­om­men­da­tions re­gard­ing the test­ing for repli­ca­tion com­pe­tent retro­virus (RCR) dur­ing the man­u­fac­ture of retro­vi­ral vec­tor-based prod­ucts, and dur­ing fol­low-up mon­i­tor­ing of pa­tients who have re­ceived retro­vi­ral vec­tor-based prod­ucts.

“Rec­om­men­da­tions in­clude the iden­ti­fi­ca­tion and amount of ma­te­r­i­al to be test­ed, and gen­er­al test­ing meth­ods,” the FDA said. “In ad­di­tion, rec­om­men­da­tions are pro­vid­ed on mon­i­tor­ing pa­tients for ev­i­dence of retro­vi­ral in­fec­tion af­ter ad­min­is­tra­tion of retro­vi­ral vec­tor-based gene ther­a­py prod­ucts.”

When fi­nal­ized, the draft is in­tend­ed to su­per­sede the doc­u­ment en­ti­tled “Guid­ance for In­dus­try: Sup­ple­men­tal Guid­ance on Test­ing for Repli­ca­tion Com­pe­tent Retro­virus in Retro­vi­ral Vec­tor Based Gene Ther­a­py Prod­ucts and Dur­ing Fol­low-up of Pa­tients in Clin­i­cal Tri­als Us­ing Retro­vi­ral Vec­tors,” from No­vem­ber 2006.

The draft guid­ance, when fi­nal­ized, is al­so in­tend­ed to sup­ple­ment the long term fol­low-up and CMC guid­ance doc­u­ments dis­cussed above.

First pub­lished here. Reg­u­la­to­ry Fo­cus is the flag­ship on­line pub­li­ca­tion of the Reg­u­la­to­ry Af­fairs Pro­fes­sion­als So­ci­ety (RAPS), the largest glob­al or­ga­ni­za­tion of and for those in­volved with the reg­u­la­tion of health­care and re­lat­ed prod­ucts, in­clud­ing med­ical de­vices, phar­ma­ceu­ti­cals, bi­o­log­ics and nu­tri­tion­al prod­ucts. Email news@raps.org for more in­for­ma­tion. 


Zachary Brennan

managing editor, RAPS

The top 10 block­buster drugs in the late-stage pipeline — Eval­u­ate adds 6 new ther­a­pies to heavy-hit­ter list

Vertex comes in for a substantial amount of criticism for its no-holds-barred tactical approach toward wresting the price it wants for its commercial drugs in Europe. But the flip side of that coin is a highly admired R&D and commercial operation that regularly wins kudos from analysts for their ability to engineer greater cash flow from the breakthrough drugs they create.

Both aspects needed for success in this business are on display in the program backing Vertex’s triple for cystic fibrosis. VX-659/VX-445 + Tezacaftor + Ivacaftor — it’s been whittled down to 445 now — was singled out by Evaluate Pharma as the late-stage therapy most likely to win the crown for drug sales in 5 years, with a projected peak revenue forecast of $4.3 billion.

The latest annual list, which you can see here in their latest world preview, includes a roster of some of the most closely watched development programs in biopharma. And Evaluate has added 6 must-watch experimental drugs to the top 10 as drugs fail or go on to a first approval. With apologies to the list maker, I revamped this to rank the top 10 by projected 2024 sales, instead of Evaluate's net present value rankings.

It's how we roll at Endpoints News.

Here is a quick summary of the rest of the top 10:

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How small- to mid-sized biotechs can adopt pa­tient cen­tric­i­ty in their on­col­o­gy tri­als

By Lucy Clos­sick Thom­son, Se­nior Di­rec­tor of On­col­o­gy Pro­ject Man­age­ment, Icon

Clin­i­cal tri­als in on­col­o­gy can be cost­ly and chal­leng­ing to man­age. One fac­tor that could re­duce costs and re­duce bar­ri­ers is har­ness­ing the pa­tient voice in tri­al de­sign to help ac­cel­er­ate pa­tient en­roll­ment. Now is the time to adopt pa­tient-cen­tric strate­gies that not on­ly fo­cus on pa­tient needs, but al­so can main­tain cost ef­fi­cien­cy.

John Reed at JPM 2019. Jeff Rumans for Endpoints News

Sanofi's John Reed con­tin­ues to re­or­ga­nize R&D, cut­ting 466 jobs while boost­ing can­cer, gene ther­a­py re­search

The R&D reorganization inside Sanofi is continuing, more than a year after the pharma giant brought in John Reed to head the research arm of the Paris-based company.
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UP­DAT­ED: Chica­go biotech ar­gues blue­bird, Third Rock 'killed' its ri­val, pi­o­neer­ing tha­lassemia gene ther­a­py in law­suit

Blue­bird bio $BLUE chief Nick Leschly court­ed con­tro­ver­sy last week when he re­vealed the com­pa­ny’s be­ta tha­lassemia treat­ment will car­ry a jaw-drop­ping $1.8 mil­lion price tag over a 5-year pe­ri­od in Eu­rope — mak­ing it the plan­et’s sec­ond most ex­pen­sive ther­a­py be­hind No­var­tis’ $NVS fresh­ly ap­proved spinal mus­cu­lar at­ro­phy ther­a­py, Zol­gens­ma, at $2.1 mil­lion. A Chica­go biotech, mean­while, has been fum­ing at the side­lines. In a law­suit filed ear­li­er this month, Er­rant Gene Ther­a­peu­tics al­leged that blue­bird and ven­ture cap­i­tal group Third Rock un­law­ful­ly prised a vi­ral vec­tor, de­vel­oped in part­ner­ship with the Memo­r­i­al Sloan Ket­ter­ing Can­cer Cen­ter (MSK), from its grasp, and thwart­ed the de­vel­op­ment of its sem­i­nal gene ther­a­py.

A new num­ber 1 drug? Keytru­da tapped to top the 10 biggest block­busters on the world stage by 2024

Analysts may be fretting about Keytruda’s longterm prospects as a host of rival therapies elbow their way to the market. But the folks at Evaluate Pharma are confident that last year’s $7 billion earner is headed for glory, tapping it to beat out the current #1 therapy Humira as AbbVie watches that franchise swoon over the next 5 years.

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John Chiminski, Catalent CEO - File Photo

'It's a growth play': Catal­ent ac­quires Bris­tol-My­er­s' Eu­ro­pean launch pad, ex­pand­ing glob­al CD­MO ops

Catalent is staying on the growth track.

Just two months after committing $1.2 billion to pick up Paragon and take a deep dive into the sizzling hot gene therapy manufacturing sector, the CDMO is bouncing right back with a deal to buy out Bristol-Myers’ central launchpad for new therapies in Europe, acquiring a complex in Anagni, Italy, southwest of Rome, that will significantly expand its capacity on the continent.

There are no terms being offered, but this is no small deal. The Anagni campus employs some 700 staffers, and Catalent is planning to go right in — once the deal closes late this year — with a blueprint to build up the operations further as they expand on oral solid, biologics, and sterile product manufacturing and packaging.

This is an uncommon deal, Catalent CEO John Chiminski tells me. But it offers a shortcut for rapid growth that cuts years out of developing a green fields project. That’s time Catalent doesn’t have as the industry undergoes unprecedented expansion around the world.

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Arc­turus ex­pands col­lab­o­ra­tion, adding $30M cash; Ku­ra shoots for $100M raise

→  Rare dis­ease play­er Ul­tragenyx $RARE is ex­pand­ing its al­liance with Arc­turus $ARCT, pay­ing $24 mil­lion for eq­ui­ty and an­oth­er $6 mil­lion in an up­front as the two part­ners ex­pand their col­lab­o­ra­tion to in­clude up to 12 tar­gets. “This ex­pand­ed col­lab­o­ra­tion fur­ther so­lid­i­fies our mR­NA plat­form by adding ad­di­tion­al tar­gets and ex­pand­ing our abil­i­ty to po­ten­tial­ly treat more dis­eases,” said Emil Kakkis, the CEO at Ul­tragenyx. “We are pleased with the progress of our on­go­ing col­lab­o­ra­tion. Our most ad­vanced mR­NA pro­gram, UX053 for the treat­ment of Glyco­gen Stor­age Dis­ease Type III, is ex­pect­ed to move in­to the clin­ic next year, and we look for­ward to fur­ther build­ing up­on the ini­tial suc­cess of this part­ner­ship.”

Neil Woodford. Woodford Investment Management via YouTube

Wood­ford braces po­lit­i­cal storm as UK fi­nan­cial reg­u­la­tors scru­ti­nize fund sus­pen­sion

The shock of Neil Wood­ford’s de­ci­sion to block with­drawals for his flag­ship fund is still rip­pling through the rest of his port­fo­lio — and be­yond. Un­der po­lit­i­cal pres­sure, UK fi­nan­cial reg­u­la­tors are now tak­ing a hard look while in­vestors con­tin­ue to flee.

In a re­sponse let­ter to an MP, the Fi­nan­cial Con­duct Au­thor­i­ty re­vealed that it’s opened an in­ves­ti­ga­tion in­to the sus­pen­sion fol­low­ing months of en­gage­ment with Link Fund So­lu­tions, which tech­ni­cal­ly del­e­gat­ed Wood­ford’s firm to man­age its funds.

Gilead baits new al­liance with $45M up­front, div­ing in­to the busy pro­tein degra­da­tion field

Gilead is jump­ing on board the pro­tein degra­da­tion band­wag­on. And they’re turn­ing to a low-pro­file Third Rock start­up for the ex­per­tise. But if you were look­ing for a trans­for­ma­tion­al deal to kick up fresh en­thu­si­asm for Gilead, you’ll have to re­main pa­tient.

This one will have a long way to go be­fore they get in­to the clin­ic.

The big biotech said Wednes­day morn­ing that it is pay­ing $45 mil­lion up­front and re­serv­ing a whop­ping $2.3 bil­lion in biotech bucks if San Fran­cis­co-based Nurix can point the way to new can­cer ther­a­pies, as well as drugs for oth­er, un­spec­i­fied dis­eases.