Af­ter a PhII cat­a­stro­phe wiped out a bil­lion dol­lars in mar­ket cap, Seres is look­ing for a do-over

Seres CEO Roger Pomer­antz

Last sum­mer, shares of Seres Ther­a­peu­tics $MCRB were shred­ded by a failed Phase II study for their lead mi­cro­bio­me drug pro­gram, wip­ing out a bil­lion dol­lars of mar­ket cap.

The set­back not on­ly raised se­ri­ous ques­tions about Seres and its ex­per­tise in the field, as the most ad­vanced mi­cro­bio­me study in the in­dus­try it al­so cast a pall over the whole field of mi­cro­bio­me R&D, the use of teem­ing mul­ti­tudes of bac­te­ria in the gut to fix what ails you.

Seres’ first tar­get was a tough one. The biotech tack­led re­cur­rent Clostrid­i­um dif­fi­cile in­fec­tion, but fell far short of sta­tis­ti­cal sig­nif­i­cance when com­pared to a place­bo. And the stock has yet to re­cov­er.

But now Seres wants a do-over, tak­ing what it learned from what went wrong and ap­ply­ing it in a new study, once they have a chance to re­view their plans for this drug with the FDA.

“We don’t think we screwed up the tri­al de­sign,” says CEO Roger Pomer­antz, an ex­pe­ri­enced Mer­ck vet who made the switch to biotech, in re­sponse to my first query. “We did learn things in a new field not in­tu­itive­ly ob­vi­ous or the sci­ence had been there 2.5 years ago.” And the re­view in­volved look­ing through every­thing, from CMC to phar­ma­co­dy­nam­ics and phar­ma­co­ki­net­ics, mi­cro­bio­me analy­sis and more.

One key mis­take, says Pomer­antz, was choos­ing the wrong di­ag­nos­tic test. Most of the pa­tients were cho­sen us­ing a poly­merase chain re­ac­tion test, he says, which doesn’t ac­tu­al­ly tell you if the C. dif­fi­cile cy­to­tox­in genes found by the test are pro­duc­ing dis­ease-caus­ing cy­to­tox­ins.

Switch­ing to sam­ples of pa­tients who chose to join the open la­bel ex­ten­sion study, few­er than half of the to­tal of 72 who were en­rolled, the cy­to­tox­in test found that on­ly 44% of the pa­tients who test­ed pos­i­tive with the PCR test al­so test­ed pos­i­tive with the cy­to­tox­in test.

In­ves­ti­ga­tors con­clud­ed that the test re­sults could have been sim­ply screwed up through the use of the wrong test, al­so skew­ing the num­ber of re­cur­rences tracked in the two drug arms. That could be fixed by switch­ing to the cy­to­tox­in test, which they plan to do in the new tri­al.

They al­so found that the dose used was clear­ly “sub­op­ti­mal,” sug­gest­ing a bet­ter dos­ing would have pro­duced much bet­ter re­sults.

But it’s not nec­es­sar­i­ly easy to make that ar­gu­ment at the FDA. Do-overs are not un­com­mon in bio­phar­ma, but they are ex­treme­ly high-risk af­fairs that of­ten do not work out the way they’re planned.

The PCR test that they de­cid­ed to use on the first go is al­so en­dorsed by the Mayo Clin­ic — which has par­tic­i­pat­ed in the tri­al work for Seres — as “high­ly ac­cu­rate.” The cy­to­tox­in test is more cum­ber­some, ac­cord­ing to the clin­ic, takes longer and is some­times paired with an en­zyme im­munoas­say test for ac­cu­ra­cy. Pomer­antz, though, says there have been sev­er­al new pa­pers just this year that high­light the is­sues they ex­pe­ri­enced with the PCR test.

In ad­di­tion, Seres ac­knowl­edges that there was a sig­nif­i­cant­ly high­er rate of se­ri­ous ad­verse events in the drug group, 15% ver­sus 10.3% in the place­bo arm — though the in­ves­ti­ga­tors did not con­sid­er the SAEs drug re­lat­ed.

But Pomer­antz is sat­is­fied that when you break new ground in drug R&D, as Seres is try­ing to do, there will be a con­sid­er­able amount of tri­al and er­ror in the process.

“We re­al­ly are open­ing a new field in med­i­cine,” says the R&D vet. But Seres al­so has a break­through drug des­ig­na­tion with the FDA, which gives the biotech ready ac­cess to reg­u­la­tors. At this point, he adds, it’s too ear­ly to tell ex­act­ly how the agency will re­spond to the pitch. And he isn’t say­ing now what the ob­jec­tive is go­ing to be.

The big ques­tion for Seres is whether the FDA will look over its find­ing and ask for a new Phase II to clear the hur­dle that now ex­ists, or if it will al­low the de­vel­op­er to shape this in­to a piv­otal study that would po­si­tion them to ap­ply for mar­ket­ing ap­proval, if it proves suc­cess­ful. I asked. Pomer­antz, though, just isn’t go­ing there right now.

“I don’t like to get ahead with the FDA,” says the CEO.

But one way or the oth­er the come­back cam­paign is about to take it’s next big step. There’s a lot rid­ing on it.

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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.

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Deborah Dunsire. Lundbeck

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Bright and early European time the company announced that it will pay up to about $2 billion to buy Alder, a little biotech that is far along the path in developing a quarterly IV formulation for a CGRP drug aimed at cutting back the number of crippling migraines patients experience each month.

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Lisa M. DeAngelis, MSKCC

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

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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.

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Tal Zaks. Moderna

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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.

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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.

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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).

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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.

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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.