Should J&J win an OK for a flawed de­pres­sion drug af­ter no­table tri­al fail­ures? FDA re­view of­fers a path for­ward

Should the FDA ig­nore its gold stan­dard and ap­prove J&J’s top drug prospect es­ke­t­a­mine with­out sol­id sup­port­ing ev­i­dence from two well-con­trolled stud­ies? Even af­ter it failed in oth­er stud­ies and presents some se­ri­ous safe­ty is­sues to deal with?

In an in­ter­nal re­view post­ed on­line this morn­ing, reg­u­la­tors posed those ques­tions to an ex­pert com­mit­tee this morn­ing pick­ing up the phar­ma gi­ant’s pitch for their ver­sion of the par­ty drug ke­t­a­mine. Their an­swer may well in­flu­ence the en­tire field of de­pres­sion drug re­search, where fail­ures are far more com­mon than suc­cess.

J&J has a lot rid­ing on this one. The phar­ma gi­ant has tapped es­ke­t­a­mine as one of its top late-stage ef­forts, putting it in a line­up of po­ten­tial block­busters the com­pa­ny is push­ing to beef up rev­enue.

The agency has al­ready blessed J&J with its break­through ther­a­py des­ig­na­tion for es­ke­t­a­mine, im­pressed by the mid-stage da­ta that was pro­duced to show how its in­tranasal ther­a­py brought swift re­lief to pa­tients suf­fer­ing from deep de­pres­sion.

That as­pect of the drug is well known. Ke­t­a­mine — known in par­ty cir­cles as Spe­cial K  — is a horse tran­quil­iz­er that al­so has pro­duced a fast ef­fect in a long range of aca­d­e­m­ic stud­ies over the years. In com­ing up with its own ver­sion, J&J is look­ing to keep the swift im­pact and lose the hal­lu­cino­genic qual­i­ties that make it a con­trolled sub­stance.

De­pres­sion, though, is a mass mar­ket, and the bar on an ap­proval is high, as Richard Pops could tell you af­ter Alk­er­mes was re­peat­ed­ly slapped down on ‘5461. An­ti­de­pres­sants on the mar­ket, though, are of­ten used ran­dom­ly, in se­quence, to find one that can pro­duce an ef­fect — of­ten tak­ing weeks to be­gin work­ing.

For its stud­ies, J&J re­searchers re­cruit­ed heav­i­ly pre-treat­ed pa­tients in des­per­ate need of a ther­a­py. They were start­ed on a new an­ti­de­pres­sant plus es­ke­t­a­mine, fig­ur­ing that an­ti­de­pres­sants usu­al­ly act so slow­ly it wouldn’t in­ter­fere with es­ke­t­a­mine’s fast ac­tion.

As the re­view notes, J&J has pos­i­tive re­sults from “the flex­i­ble-dose tri­al in adults younger than 65 years of age and the ran­dom­ized with­draw­al study.” With­draw­al stud­ies, though, are gen­er­al­ly not rec­og­nized as a well con­trolled study that qual­i­fies as one of the 2 typ­i­cal­ly need­ed stud­ies for an ap­proval.

Then there were the fail­ures — which, by the way, are quite com­mon in de­pres­sion. One rea­son why J&J ran 5 stud­ies is to give them­selves bet­ter odds at suc­cess, rather than re­strict­ing them­selves to 2 piv­otals.

In the fixed-dose study of adults younger than 65 years of age, the pre­spec­i­fied analy­sis plan dic­tat­ed that ef­fi­ca­cy of the 84-mg dose would be eval­u­at­ed first, fol­lowed by eval­u­a­tion of the 56-mg dose. How­ev­er, the 84-mg dose did not sep­a­rate from place­bo and the test­ing se­quence end­ed there. The geri­atric study in­clud­ed flex­i­ble dos­es rang­ing from 28 to 84 mg; the ef­fect of es­ke­t­a­mine in the com­bined dose group was not sta­tis­ti­cal­ly su­pe­ri­or to place­bo (1-sided p = 0.029).

The safe­ty pro­file is al­so far from be­nign, in­clud­ing se­da­tion, dis­so­cia­tive be­hav­ior and in­creased blood pres­sure as pri­ma­ry con­cerns. And none of that was new to the R&D team when they start­ed the work.

To get an OK here will al­so clear­ly re­quire a de­tailed risk mit­i­ga­tion plan, and the FDA wants its ex­perts to weigh in on that as well. The pro­posed REMS in­cludes 2 hours of mon­i­tor­ing af­ter the drug is giv­en to the pa­tient. There will be no dis­tri­b­u­tion of the drug to pa­tients — to avoid abuse — and the plan now is to in­clude a pa­tient reg­istry to track risks.

The FDA’s in­ter­nal re­view nei­ther sug­gests an ap­proval is war­rant­ed or that the pan­el should vote no. The agency has al­ready proved its will­ing­ness to forego the 2-tri­al stan­dard, at least in oth­er dis­eases. The big ques­tion is whether the ex­perts will go for a new and clear­ly im­per­fect drug to add for a group of pa­tients with nowhere else to turn. Un­der those cir­cum­stances, J&J seems to have pret­ty good odds of suc­cess in a field bet­ter known for re­peat­ed set­backs.

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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Step­ping on Roche's toes, Mer­ck cuts in­to SCLC niche with third-line Keytru­da OK

In the in­creas­ing­ly crowd­ed check­point race, small cell lung can­cer has been a rare area where Roche, a sec­ond run­ner-up, has a lead over the en­trenched lead­ers Mer­ck and Bris­tol-My­ers Squibb. But Mer­ck is fi­nal­ly mak­ing some head­way in that di­rec­tion with the lat­est ap­proval for its PD-1 star.

The lat­est green light en­dors­es Keytru­da in the third-line treat­ment of metasta­t­ic SCLC, where it would be giv­en to pa­tients whose dis­ease ei­ther don’t re­spond to or re­lapse af­ter chemother­a­py, which would have fol­lowed at least one pri­or line of ther­a­py.

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.