Af­ter big 2016 set­back, field of mi­cro­bio­me-based drugs gets in­jec­tion of promise with pos­i­tive sig­nal from Re­bi­otix piv­otal study

Sev­er­al years ago, as com­pa­nies cap­i­tal­iz­ing on sci­ence that sug­gests flush­ing ‘good’ gut bac­te­ria in­to the sys­tem can treat a pletho­ra of con­di­tions — from C. diff in­fec­tions to obe­si­ty — be­gan to gain trac­tion, the op­por­tu­ni­ties to har­ness the mi­cro­bio­me gar­nered fever­ish promise and gen­er­ous fund­ing. Then, in 2016, Seres Ther­a­peu­tics’ fail­ure in a mid-stage tri­al eval­u­at­ing its “crap­sule” — donor-de­rived processed fe­cal ma­te­r­i­al en­cap­su­lat­ed in a pill — de­railed the emerg­ing field, rel­e­gat­ing the mi­cro­bio­me from hero to ze­ro sta­tus.

The mon­ey has since be­gun to trick­le back in, but the ex­pec­ta­tions are now more down to earth. A num­ber of sig­nif­i­cant da­ta read­outs from key play­ers this year are ex­pect­ed to gen­er­ate con­crete ev­i­dence that the ecosys­tem of gut bac­te­ria has a cru­cial role to play in health. On Wednes­day, Re­bi­otix of­fered the first glimpse of pos­i­tive da­ta from its on­go­ing late-stage study.

The com­pa­ny’s poop-de­rived frozen for­mu­la­tion, RBX2660, which is de­liv­ered in­to pa­tients via an en­e­ma, is be­ing de­vel­oped to re­duce re­cur­rent in­fec­tions of C. diff, a stub­born in­fec­tion that has grown re­sis­tant to ex­ist­ing an­tibi­otics and kills more than 29,000 Amer­i­cans each year.

Lee Jones Re­bi­otix

The 270 pa­tient place­bo-con­trolled study has met the main goal — the pro­por­tion of pa­tients with treat­ment suc­cess with RBX2660 to pre­vent re­cur­rent C. diff with­in 8 weeks ver­sus place­bo, but the full dataset is still to come, the com­pa­ny said, with­out dis­clos­ing any specifics.

“It has been a long time com­ing through a num­ber of ob­sta­cles to be able to pro­vide the da­ta that demon­strates that this is a ther­a­peu­tic op­tion for pa­tients and can be de­vel­oped as a drug prod­uct and can meet the re­quire­ments,” said Lee Jones, chief, and founder of Re­bi­otix, in an in­ter­view.

“It sig­nals to the field that this is re­al.”

Re­bi­otix, found­ed in 2011, was swal­lowed by Swiss drug­mak­er Fer­ring Phar­ma­ceu­ti­cals in 2018.

Per Falk Fer­ring

“I spent the bet­ter part of 34 years ei­ther as a grad stu­dent or as a sci­en­tist or as an in­vestor in this game, so I know how it has evolved,” said Fer­ring’s CSO Per Falk in an in­ter­view. “And this is clear­ly the clos­est we have ever got­ten to see a re­al ap­pli­ca­tion of the knowl­edge that has been build­ing for so long.”

The field of mi­cro­bio­me-based ther­a­peu­tics has grown to be a fe­cund field for drug de­vel­op­ers — big and small — us­ing dif­fer­ent ther­a­peu­tic modal­i­ties, some of which are de­signed to side­step the “ick” fac­tor as­so­ci­at­ed with tra­di­tion­al stool trans­fer or FMT.

The in­ter­ven­tion re­quires a stool sam­ple to be screened, liq­ue­fied, and de­liv­ered to the colon by nasal or rec­tal tube. Pa­tients must ei­ther find their own donor, ob­tain vi­able stool from a li­censed health care provider, or turn to a stool bank, such as Open­Bio­me. Few­er than 3% of the pop­u­la­tion qual­i­fy as healthy donors, ac­cord­ing to the Fe­cal Trans­plant Foun­da­tion.

Orig­i­nal­ly pi­o­neered in Chi­na, FMT has been used in the Unit­ed States for years now as a way to com­bat re­cur­rent C.diff, as the per­pe­trat­ing bac­te­ria have mu­tat­ed to in­creas­ing­ly ren­der tra­di­tion­al an­tibi­otics ob­so­lete. How­ev­er, the FDA con­sid­ers the in­ter­ven­tion an in­ves­ti­ga­tion­al treat­ment with an un­proven safe­ty and ef­fi­ca­cy pro­file. In 2013, the US reg­u­la­tor im­ple­ment­ed a pol­i­cy of “en­force­ment dis­cre­tion” in re­la­tion to FMT for treat­ment-re­frac­to­ry C. diff: While de­vel­op­ers are work­ing on ad­vanc­ing prod­ucts un­der an IND, physi­cians can use FMT prod­ucts af­ter se­cur­ing rea­son­able con­sent from pa­tients.

Jones has been a vo­cal crit­ic of the en­force­ment dis­cre­tion pol­i­cy, sug­gest­ing that the FDA has in a way gen­er­at­ed a path­way for pa­tients and doc­tors to con­duct stool trans­fers, with­out the req­ui­site safe­ty and over­sight. In ad­di­tion, she said, the pol­i­cy has slowed the process of tri­al en­roll­ment for com­pa­nies like Re­bi­otix and oth­ers in the field.

“What it (en­force­ment dis­cre­tion) did was it changed the re­fer­ral pat­terns,” she said. “It set the whole field back be­cause no­body re­al­ly knows now how those prod­ucts work, or if they were safe … I would say there was a five­fold de­crease in en­roll­ment rates through the course of our pro­grams based on the en­force­ment dis­cre­tion is­sues. We would have had a safe prod­uct out to the for pa­tient use well be­fore the time­frame that we’re talk­ing about now.”

Oth­ers in the field, such as Finch Ther­a­peu­tics CEO Mark Smith (who helped co-found Open­Bio­me) have as­sert­ed that while en­roll­ment in place­bo-con­trolled stud­ies is dif­fi­cult when pa­tients have open-la­bel ac­cess to FMT, it is still fea­si­ble, point­ing out many pa­tients do not even qual­i­fy for clin­i­cal tri­al en­roll­ment due to co­mor­bidi­ties or be­cause they have no ac­cess to sites.

Re­bi­otix’s full late-stage dataset is ex­pect­ed by this fall, but the coro­n­avirus pan­dem­ic has put some­what of a ques­tion mark on that time­line, Lee said.

“Un­for­tu­nate­ly, C. diff keeps go­ing on and in fact, with the ad­vent of a lot of peo­ple head­ing in­to the ICU, we ex­pect to see an uptick in this,” she said of the on­go­ing Phase III study. “So for those sites that are still ac­cept­ing pa­tients, and they’re still do­ing the clin­i­cal pro­gram. What’s dif­fi­cult is that a lot of clin­i­cal peo­ple are ground­ed in terms of trav­el­ing to the site … and so ac­cess to the clin­i­cal sites to do da­ta mon­i­tor­ing is tricky at this point in time.”

Safe­ty con­cerns

While drug de­vel­op­ers such as Re­bi­otix, Finch and Seres con­tin­ue on with their quest to de­vel­op drugs from bugs us­ing do­nat­ed stool, since last sum­mer, a hand­ful of safe­ty is­sues re­lat­ed to the raw ma­te­r­i­al have caused a stir.

Last year, the death of an im­muno-com­pro­mised 73-year old pa­tient in an FMT tri­al con­duct­ed by Mass­a­chu­setts Gen­er­al Hos­pi­tal (MGH) struck a chord with re­searchers, af­ter post-mortem test­ing re­vealed the stool do­na­tion used con­tained a rare type of E. coli bac­te­ria. The in­ci­dent shed light on the non-stan­dard­ized meth­ods dif­fer­ent re­searchers have been em­ploy­ing in or­der to screen and pu­ri­fy the stool used in such tri­als.

Mak­ing mat­ters worse, the FDA is­sued a safe­ty alert in March af­ter E. coli-taint­ed stool from the wide­ly used non-prof­it stool bank Open­Bio­me made six pa­tients sick, four of whom were hos­pi­tal­ized. Two oth­er FMT re­cip­i­ents whose trans­plants com­prised Open­Bio­me’s prod­uct al­so died. Weeks lat­er, the FDA is­sued an­oth­er safe­ty alert high­light­ing the risk of po­ten­tial trans­mis­sion of the new coro­n­avirus from fe­cal mat­ter de­rived from donors used in FMT and said that ad­di­tion­al safe­ty mea­sures are nec­es­sary.

Com­pa­nies in the field are now high­light­ing these in­ci­dents as an­oth­er rea­son to wait for their prod­ucts, which may still be har­nessed from the same raw ma­te­r­i­al, but must un­der­go the same rig­or­ous safe­ty and ef­fi­ca­cy test­ing as any oth­er chem­i­cal or bi­o­log­ic ther­a­py does be­fore hit­ting the mar­ket.

What these FDA alerts show is that with FMT, there will al­ways be an is­sue that must be chased, said Seres’ chief tech­nol­o­gy of­fi­cer John Aunins in a pre­vi­ous in­ter­view. “You didn’t test pre­vi­ous agents, or you use the test that wasn’t sen­si­tive enough or a pathogen emerges and you don’t have a test for it,” he said. “So it’s, it’s just an in­her­ent sit­u­a­tion with that kind of a prod­uct.”

Jones echoed the sen­ti­ment, say­ing she be­lieves the com­pa­ny’s pro­vi­sions for safe­ty will hold it in good stead. “We haven’t had the same is­sues that they’ve (Open­Bio­me) had in terms of safe­ty,” she said.

Has the mo­ment fi­nal­ly ar­rived for val­ue-based health­care?

RBC Capital Markets’ Healthcare Technology Analyst, Sean Dodge, spotlights a new breed of tech-enabled providers who are rapidly transforming the way clinicians deliver healthcare, and explores the key question: can this accelerating revolution overturn the US healthcare system?

Key points

Tech-enabled healthcare providers are poised to help the US transition to value, not volume, as the basis for reward.
The move to value-based care has policy momentum, but is risky and complex for clinicians.
Outsourced tech specialists are emerging to provide the required expertise, while healthcare and tech are also converging through M&A.
Value-based care remains in its early stages, but the transition is accelerating and represents a huge addressable market.

Lat­est on ul­tra-rare dis­ease ap­proval; Pos­i­tive, if mixed, signs for Bio­gen's ALS drug; Clay Sie­gall finds a new job; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Over the last four years, we’ve honored 80 women whose extraordinary accomplishments have changed the game in biopharma R&D. You can now nominate someone to be highlighted in this year’s special report. Details are here.

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FDA spells out how can­cer drug de­vel­op­ers can use one tri­al for both ac­cel­er­at­ed and full ap­provals

The FDA’s Oncology Center of Excellence has been a bright spot within the agency in terms of speeding new treatments to patients. That flexibility was on full display this morning as FDA released new draft guidance spelling out exactly how oncology drug developers can fulfill both the accelerated and full approval’s requirements with just a single randomized controlled trial.

While Congress recently passed legislation that will allow FDA to require confirmatory trials to be recruiting and ongoing prior to granting an accelerated approval, the agency is now making clear that the initial trial used to win the AA, if designed appropriately, can also serve as the trial for converting the accelerated approval into a full approval.

No­vo Nordisk oral semaglu­tide tri­al shows re­duc­tion in blood sug­ar, plus weight loss

Novo Nordisk is testing higher levels of its oral version of its GLP-1, semaglutide, and its type 2 diabetes trial results released today show reductions in blood sugar as well as weight loss.

In the Phase IIIb trial, Novo compared its oral semaglutide in 25 mg and 50 mg doses with the 14 mg version that’s currently the maximum approved dose. The trial looked at how the doses compared when added to a stable dose of one to three oral antidiabetic medicines in people with type 2 diabetes who were in need of an intensified treatment.

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Clay Siegall, Morphimmune CEO

Up­dat­ed: Ex-Seagen chief Clay Sie­gall emerges as CEO of pri­vate biotech

Clay Siegall will be back in the CEO seat, taking the helm of a private startup working on targeted cancer therapies.

It’s been almost a year since Siegall resigned from Seagen, the biotech he co-founded and led for more than 20 years, in the wake of domestic violence allegations by his then-wife. His eventual successor, David Epstein, sold the company to Pfizer in a $43 billion deal unveiled last week.

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FDA ad­vi­sors unan­i­mous­ly rec­om­mend ac­cel­er­at­ed ap­proval for Bio­gen's ALS drug

A panel of outside advisors to the FDA unanimously recommended that the agency grant accelerated approval to Biogen’s ALS drug tofersen despite the drug failing the primary goal of its Phase III study, an endorsement that could pave a path forward for the treatment.

By a 9-0 vote, members of the Peripheral and Central Nervous System Drugs Advisory Committee said there was sufficient evidence that tofersen’s effect on a certain protein associated with ALS is reasonably likely to predict a benefit for patients. But panelists stopped short of advocating for a full approval, voting 3-5 against (with one abstention) and largely citing the failed pivotal study.

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Sijmen de Vries, Pharming CEO

FDA ap­proves Pharm­ing drug for ul­tra-rare im­mun­od­e­fi­cien­cy dis­ease

US regulators cleared an ultra-rare drug from Pharming Group, by way of Novartis, on Friday afternoon.

The Dutch biotech said the FDA greenlit leniolisib for an immunodeficiency disease known as activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome, or APDS. People 12 years and older can receive the oral drug, to be marketed as Joenja, beginning early next month, Pharming said, five days ahead of the decision deadline set by the FDA as part of a priority review.

Ly­me vac­cine test com­ple­tion is pushed back by a year as Pfiz­er, Val­ne­va say they'll ad­just tri­al

Valneva and Pfizer have adjusted the end date for the Phase III study of their investigational Lyme disease vaccine, pushing it back by a year after issues at a contract researcher led to thousands of US patients being dropped from the test.

In a March 20 update to clinicaltrials.gov, Valneva and Pfizer moved the primary completion date on the trial, called VALOR, from the end of 2024 to the end of 2025.

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Zhi Hong, Brii Biosciences CEO

Brii Bio­sciences stops man­u­fac­tur­ing Covid-19 an­ti­body com­bo, plans to with­draw EUA re­quest

Brii Biosciences said it will stop manufacturing its Covid-19 antibody combination, sold in China, and is working to withdraw its emergency use authorization request in the US, which it started in October 2021.

The Beijing and North Carolina biotech commercially launched the treatment in China last July but is now axing the work and reverting resources to other “high-priority programs,” per a Friday update. The focus now is namely hepatitis B viral infection, postpartum depression and major depressive disorders.

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