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.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

So — that pig-to-hu­man trans­plant; Po­ten­tial di­a­betes cure reach­es pa­tient; Ac­cused MIT sci­en­tist lash­es back; 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.

We’re incredibly excited to welcome Beth Bulik, seasoned pharma marketing reporter, to the team. You can find much of her work in our new Marketing channel — and in her weekly newsletter, Endpoints PharmaRx, which will launch in early November. Add it to your subscriptions here.

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NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

No, sci­en­tists are not any clos­er to pig-to-hu­man trans­plants than they were last week

Steve Holtzman was awoken by a 1 a.m. call from a doctor at Duke University asking if he could put some pigs on a plane and fly them from Ohio to North Carolina that day. A motorcyclist had gotten into a horrific crash, the doctor explained. He believed the pigs’ livers, sutured onto the patient’s skin like an external filter, might be able to tide the young man over until a donor liver became available.

UP­DAT­ED: Agenus calls out FDA for play­ing fa­vorites with Mer­ck, pulls cer­vi­cal can­cer BLA at agen­cy's re­quest

While criticizing the FDA for what may be some favoritism towards Merck, Agenus on Friday officially pulled its accelerated BLA for its anti-PD-1 inhibitor balstilimab as a potential second-line treatment for cervical cancer because of the recent full approval for Merck’s Keytruda in the same indication.

The company said the BLA, which was due for an FDA decision by Dec. 16, was withdrawn “when the window for accelerated approval of balstilimab closed,” thanks to the conversion of Keytruda’s accelerated approval to a full approval four months prior to its PDUFA date.

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No­vo CEO Lars Fruer­gaard Jør­gensen on R&D risk, the deal strat­e­gy and tar­gets for gen­der di­ver­si­ty

 

I kicked off our European R&D summit last week with a conversation involving Novo Nordisk CEO Lars Fruergaard Jørgensen. Novo is aiming to launch a new era of obesity management with a new approval for semaglutide. And Jørgensen had a lot to say about what comes next in R&D, how they manage risk and gender diversity targets at the trendsetting European pharma giant.

John Carroll: I’m here with Lars Jørgensen, the CEO of Novo Nordisk. Lars, it’s been a really interesting year so far with Novo Nordisk, right? You’ve projected a new era of growing sales. You’ve been able to expand on the GLP-1 franchise that was already well established in diabetes now going into obesity. And I think a tremendous number of people are really interested in how that’s working out. You have forecast a growing amount of sales. We don’t know specifically how that might play out. I know a lot of the analysts have different ideas, how those numbers might play out, but that we are in fact embarking on a new era for Novo Nordisk in terms of what the company’s capable of doing and what it’s able to do and what it wants to do. And I wanted to start off by asking you about obesity in particular. Semaglutide has been approved in the United States for obesity. It’s an area of R&D that’s been very troubled for decades. There have been weight loss drugs that have come along. They’ve attracted a lot of attention, but they haven’t actually ever gained traction in the market. My first question is what’s different this time about obesity? What is different about this drug and why do you expect it to work now whereas previous drugs haven’t?

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How to col­lect and sub­mit RWD to win ap­proval for a new drug in­di­ca­tion: FDA spells it out in a long-await­ed guid­ance

Real-world data are messy. There can be differences in the standards used to collect different types of data, differences in terminologies and curation strategies, and even in the way data are exchanged.

While acknowledging this somewhat controlled chaos, the FDA is now explaining how biopharma companies can submit study data derived from real-world data (RWD) sources in applicable regulatory submissions, including new drug indications.

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David Livingston (Credit: Michael Sazel for CeMM)

Renowned Dana-Far­ber sci­en­tist, men­tor and bio­phar­ma ad­vi­sor David Liv­ingston has died

David Livingston, the Dana-Farber/Harvard Med scientist who helped shine a light on some of the key molecular drivers of breast and ovarian cancer, died unexpectedly last Sunday.

One of the senior leaders at Dana-Farber during his nearly half century of work there, Livingston was credited with shedding light on the genes that regulate cell growth, with insights into inherited BRCA1 and BRCA2 mutations that helped lay the scientific foundation for targeted therapies and earlier detection that have transformed the field.

Pascal Soriot, AstraZeneca CEO (via Getty images)

UP­DAT­ED: FDA slaps As­traZeneca's MCL-1 can­cer drug with a hold af­ter safe­ty is­sue — 2 years af­ter Am­gen axed a trou­bled ri­val

There are new questions being posed about a class of cancer drugs in the wake of the second FDA-enforced clinical hold in the field.

Two years after the FDA hit Amgen with a clinical hold on its MCL-1 inhibitor AMG 397 following signs of cardiac toxicity, AstraZeneca says that regulators hit them with a hold on their rival therapy of the same class.

The pharma giant noted on clinicaltrials.gov that its Phase I/II study for the MCL-1 drug AZD5991 “has been put on hold to allow further evaluation of safety related information.”

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Sur­geons suc­cess­ful­ly at­tach pig kid­ney to a hu­man for the first time, us­ing tech from Unit­ed's Re­vivi­cor

In a first, researchers reportedly successfully transplanted a pig kidney into a human without triggering an immediate immune response this week. And the technology came from the biotech United Therapeutics.

Surgeons spent three days attaching the kidney to the patient’s blood vessels, but when all was said and done, the kidney appeared to be functioning normally in early testing, Reuters and the New York Times were among those to report. The kidney came from a genetically altered pig developed through United’s Revivicor unit.

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