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.

Con­quer­ing a silent killer: HDV and Eiger Bio­Phar­ma­ceu­ti­cals

Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV) that results in the most severe form of human viral hepatitis for which there is no approved therapy.

HDV is a single-stranded, circular RNA virus that requires the envelope protein (HBsAg) of the hepatitis B virus (HBV) for its own assembly. As a result, hepatitis delta virus (HDV) infection occurs only as a co-infection in individuals infected with HBV. However, HDV/HBV co-infections lead to more serious liver disease than HBV infection alone. HDV is associated with faster progression to liver fibrosis (progressing to cirrhosis in about 80% of individuals in 5-10 years), increased risk of liver cancer, and early decompensated cirrhosis and liver failure.
HDV is the most severe form of viral hepatitis with no approved treatment.
Approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not appreciably impact HBsAg and have no impact on HDV. Investigational agents in development for HBV target multiple new mechanisms. Aspirations are high, but a functional cure for HBV has not been achieved nor is one anticipated in the forseeable future. Without clearance of HBsAg, anti-HBV investigational treatments are not expected to impact the deadly course of HDV infection anytime soon.

UP­DAT­ED: In a land­mark first glimpse of hu­man da­ta from Ver­tex, CRISPR/Cas9 gene ther­a­py sig­nals ear­ly ben­e­fit

Preliminary data on two patients with blood disorders that have been administered with Vertex and partner CRISPR Therapeutics’ gene-editing therapy suggest the technology is safe and effective, marking the first instance of the benefit of the use of CRISPR/Cas9 technology in humans suffering from disease.

Patients in these phase I/II studies give up peripheral blood from which hematopoietic stem and progenitor cells are isolated. The cells are tinkered with using CRISPR/Cas9 technology, and the edited cells — CTX001 — are infused back into the patient via a stem cell transplant. The objective of CTX001 is to fix the errant hemoglobin gene in patents with two blood disorders: beta-thalassemia and sickle cell disease, by unleashing the production of fetal hemoglobin.

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UP­DAT­ED: Make that 2 ap­proved RNAi drugs at Al­ny­lam af­ter the FDA of­fers a speedy OK on ul­tra-rare dis­ease drug

Seventeen years into the game, Alnylam’s pivot into commercial operations is picking up speed.
The bellwether biotech $ALNY has nabbed their second FDA OK for an RNAi drug, this time for givosiran, the only therapy now approved for acute hepatic porphyria. This second approval came months ahead of the February deadline — even after winning priority review following their ‘breakthrough’ title earlier.
AHP is an extremely rare disease, with some 3,000 patients in Europe and the US, not all diagnosed, and analysts have projected peak revenue of $600 million to $700 million a year. The drug will be sold as Givlaari.

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David Ricks. Eli Lilly

Eli Lil­ly touts $400M man­u­fac­tur­ing ex­pan­sion, 100 new jobs to much fan­fare in In­di­anapo­lis — even though it's been chop­ping staff

Eli Lilly is pouring in $400 million to beef up manufacturing facilities at its home base of Indianapolis. The investment, which was lauded by the city’s mayor, is expected to create 100 new jobs.

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Am­gen chops 172 more staffers in R&D, op­er­a­tions and sales amid neu­ro­science ex­it, rev­enue down­turn

Neuroscience wasn’t the only unit that’s being hit by a reorganization underway at Amgen. As well as axing 149 employees in its Cambridge office, the company has disclosed that 172 others nationwide, including some from its Thousand Oaks, CA headquarters, are being let go.

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Stephen Hahn (via Senate HELP Committee)

Stephen Hahn gets through Sen­ate’s soft­ball job in­ter­view — but most­ly plays dodge­ball on the is­sues fac­ing the FDA

Anyone looking for fresh insights on what kind of FDA commissioner Stephen Hahn will be got precious few clues during Wednesday’s Senate hearing on the nomination.

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Op­di­vo/Yer­voy com­bo for melanoma fails in key pa­tient pop­u­la­tion

Bristol-Myers Squibb’s efforts to expand their checkpoint inhibitor combination have run into another recalcitrant cancer.

The NJ-based pharma announced that a combination of Yervoy and Opdivo didn’t beat out Opdivo alone in patients with resected high-risk melanoma who had very low levels of PD-L1. The drug combo couldn’t improve recurrence-free survival in these post-surgery patients.

Ver­tex's stel­lar quar­ter car­ries on with French re­im­burse­ment deal

Vertex’s golden quarter just got brighter. About a month after the US drugmaker finally clinched a deal with UK authorities to cover its slate of cystic fibrosis (CF) drugs following years of protracted negotiations, the company on Wednesday secured a deal with France for its CF therapy, Orkambi.

After the UK, France has one of the largest CF populations outside the United States. Achieving French reimbursement unlocks an ~7000-patient CF population, around ~2500-3000 of which will likely be eligible to receive (and be reimbursed for) Orkambi, Stifel’s Paul Matteis wrote in a note.

Nello Mainolfi, Kymera via Youtube

Kymera hands the helm to No­var­tis vet — and found­ing CSO — Nel­lo Main­olfi

Kymera Therapeutics is turning to a co-founder to run the company.
The protein degradation specialist with a deep-pocket syndicate behind them has opted to give the helm officially to Nello Mainolfi. The new CEO is a veteran of the Novartis Institutes for Biomedical Research. He joined Atlas Venture in their entrepreneur-in-residence program and helped launch Kymera as the CSO three years ago with Atlas’ Bruce Booth.
The boast at Kymera is that they’re angling to create a new class of protein degraders, a popular field where there’s been a variety of startups. One of its chief advocates is NIBR head Jay Bradner, who launched C4 just ahead of joining Novartis, where he’s also been doing new work in the field.