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.

A New Fron­tier: The In­ner Ear

What happens when a successful biotech venture capitalist is unexpectedly diagnosed with a chronic, life-disrupting vertigo disorder? Innovation in neurotology.

That venture capitalist was Jay Lichter, Ph.D., and after learning there was no FDA-approved drug treatment for his condition, Ménière’s disease, he decided to create a company to bring drug development to neurotology. Otonomy was founded in 2008 and is dedicated to finding new drug treatments for the hugely underserved community living with balance and hearing disorders. Helping patients like Jay has been the driving force behind Otonomy, a company heading into a transformative 2020 with three clinical trial readouts: Phase 3 in Ménière’s disease, Phase 2 in tinnitus, and Phase 1/2 in hearing loss. These catalysts, together with others in the field, highlight the emerging opportunity in neurotology.
Otonomy is leading the way in neurotology
Neurotology, or the treatment of inner ear neurological disorders, is a large and untapped market for drug developers: one in eight individuals in the U.S. have moderate-to-severe hearing loss, tinnitus or vertigo disorders such as Ménière’s disease.1 With no FDA-approved drug treatments available for these conditions, the burden on patients—including social anxiety, lower quality of life, reduced work productivity, and higher rates of depression—can be significant.2, 3, 4

Joe Jimenez, Getty

Ex-No­var­tis CEO Joe Jimenez is tak­ing an­oth­er crack at open­ing a new chap­ter in his ca­reer — and that in­cludes a new board seat and a $250M start­up

Joe Jimenez is back.

The ex-CEO of Novartis has taken a board seat on Century Therapeutics, the Versant and Bayer-backed startup focused on coming up with a brand new twist on cell therapies for cancer — a field where Jimenez made his mark backing the first personalized CAR-T approved for use.

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Can we make the an­tibi­ot­ic mar­ket great again?

The standard for-profit model in drug development is straightforward. Spend millions, even billions, to develop a medicine from scratch. The return on investment (and ideally a tidy profit) comes via volume and/or price, depending on the disease. But the string of big pharma exits and slew of biotech bankruptcies indicate that the model is sorely flawed when it comes to antibiotics.

The industry players contributing to the arsenal of antimicrobials are fast dwindling, and the pipeline for new antibiotics is embarrassingly sparse, the WHO has warned. Drugmakers are enticed by greener pastures, compared to the long, arduous and expensive path to antibiotic approval that offers little financial gain as treatments are typically priced cheaply, and often lose potency over time as microbes grow resistant to them.

The FTC and New York state ac­cuse Mar­tin Shkre­li of run­ning a drug mo­nop­oly. They plan to squash it — and per­ma­nent­ly ex­ile him

Pharma bro Martin Shkreli was jailed, publicly pilloried and forced to confront some lawmakers in Washington riled by his move to take an old generic and move the price from $17.50 per pill to $750. But through 4 years of controversy and public revulsion, his company never backed away from the price — left uncontrolled by a laissez faire federal policy on a drug’s cost.

Now the FTC and the state of New York plan to pry his fingers off the drug once and for all and open it up to some cheap competition. And their lawsuit is asking that Shkreli — with several years left on his prison sentence — be banned permanently from the pharma industry.

UP­DAT­ED: Ac­celeron res­ur­rects block­buster hopes for so­tater­cept with pos­i­tive PhII — and shares rock­et up

Acceleron $XLRN says that its first major trial readout of 2020 is a success.

In a Phase II study of 106 patients with pulmonary arterial hypertension (PAH), Acceleron’s experimental drug sotatercept hit its primary endpoint: a significant reduction in pulmonary vascular resistance. The drug also met three different secondary endpoints, including the 6-minute walking test.

“We’re thrilled to report such positive topline results from the PULSAR trial,” Acceleron CEO Habib Dable said in a statement. The company said in a conference call they plan on discussing a Phase III trial design with regulators.

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Amber Saltzman (Ohana)

Flag­ship's first ven­ture of 2020 is out, and it's all about sperm

A couple years ago, Amber Salzman got a call as she was returning East full-time after a two-year stint running a gene therapy company in California.

It was from someone at Flagship Pioneering, the deep-pocketed biotech venture firm. They had a new company with a new way of thinking about sperm. It had been incubating for over a year, and now they wanted her to run it.

“It exactly fit,” Salzman told Endpoints News. “I just thought I had to do something.”

Pfiz­er ax­es 6 ear­ly to late-stage can­cer stud­ies from the pipeline — with one oth­er cut for sick­le cell dis­ease

Pfizer trimmed a group of 3 R&D programs using their PD-L1 Bavencio — partnered with Merck KGaA — in their latest pipeline cull.

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UP­DAT­ED: In­cyte scores much need­ed PhI­II suc­cess — and of course it’s de­liv­ered by rux­oli­tinib

Incyte’s efforts to breathe a second life into ruxolitinib — its JAK inhibitor sold in pill form as Jakafi — has been greeted with clear, if preliminary and unsurprising, Phase III success.

Topline data from the TRuE-AD2 cements ruxolitinib’s foundational importance for Incyte, and gives analysts hope that there might yet be room for growth in a pipeline that’s suffered multiple R&D setbacks.

Stephen Hahn, AP

The FDA un­veils a new reg­u­la­to­ry frame­work to speed along gene ther­a­pies, re­ward­ing the lead­ing play­ers

Bioregnum Opinion Column by John Carroll

The emphasis at the FDA over the past 5 years or so has been on assisting drug developers as much as they can to speed up regulatory reviews and push more drugs into the market. And they are now crafting a final set of regulations aimed at flagging through a whole new generation of gene therapies in clinical testing at a rapid clip.

In a set of 6 prospective guidances posted on the FDA web site Tuesday morning, FDA commissioner Stephen Hahn committed the agency to staying flexible in handing out designations that are critical to gaining early approvals for drugs that claim to be once-and-done but don’t have anything close to the data needed to prove it.

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