Taint­ed do­na­tions from stool bank reignite safe­ty con­cerns about poop trans­plants

Last year, the death of an im­muno-com­pro­mised el­der­ly pa­tient in a fe­cal mi­cro­bio­ta trans­plan­ta­tion (FMT) tri­al at the Mass­a­chu­setts Gen­er­al Hos­pi­tal — due to a stool do­na­tion that con­tained a rare type of E. coli bac­te­ria — sent shiv­ers across the field.

Now, an­oth­er in­ci­dent has come to light — this time em­a­nat­ing from the non-prof­it stool bank Open­Bio­me — in which taint­ed stool made six pa­tients sick, four of whom were hos­pi­tal­ized. Two oth­er FMT re­cip­i­ents whose trans­plants com­prised Open­Bio­me’s prod­uct al­so died.

On Thurs­day, the FDA is­sued a safe­ty alert about the po­ten­tial risk of se­ri­ous or life-threat­en­ing in­fec­tions with the use of fe­cal mi­cro­bio­ta for trans­plan­ta­tion — af­ter it had been no­ti­fied that a com­pa­ny’s FMT prod­uct for treat­ment-re­sis­tant C. diff had caused E. coli in­fec­tions in six pa­tients.

Two pa­tients who re­ceived FMT prod­uct that was pre­pared from stool from two dif­fer­ent donors, de­vel­oped EPEC (en­teropath­o­gen­ic E. coli) in­fec­tions. The oth­er four pa­tients — who re­ceived FMT prod­uct that was pre­pared from stool from a sin­gle donor — con­tract­ed STEC (Shi­ga tox­in-pro­duc­ing E. coli) in­fec­tions. Both types of E. coli are path­o­gen­ic, cause di­ar­rhea, and are as­so­ci­at­ed with oth­er symp­toms such as fever, ab­dom­i­nal pain, and vom­it­ing

Open­Bio­me, in a sep­a­rate press re­lease, dis­closed that the taint­ed stool had, in fact, come from three of its donors — and that it was im­me­di­ate­ly im­ple­ment­ing changes to its screen­ing pro­gram to en­sure all FMT ma­te­r­i­al is screened for these pathogens. All un­used ma­te­r­i­al from these three donors has been re­called and de­stroyed, the com­pa­ny added.

Open­Bio­me had been screen­ing for STEC via an en­zyme im­munoas­say, which had come up neg­a­tive, but fol­low­ing the re­ports of the in­fec­tion, the com­pa­ny test­ed the ma­te­r­i­al us­ing PCR test­ing that showed the pres­ence of Shi­ga tox­in pro­duc­tion. Open­Bio­me has not pre­vi­ous­ly screened donors for EPEC, it said, but fol­low-up PCR test­ing of the donor ma­te­r­i­al al­so gen­er­at­ed a pos­i­tive EPEC sig­nal.

Car­olyn Edel­stein

Open­Bio­me is in the process of eval­u­at­ing whether to use PCR test­ing for oth­er pathogens, the non-prof­it com­pa­ny’s ex­ec­u­tive di­rec­tor Car­olyn Edel­stein told End­points News.

“It’s not ob­vi­ous for every pathogen that we screen for that us­ing the PCR method is not go­ing to lead to dif­fer­ent is­sues re­lat­ed to false pos­i­tives as well as false neg­a­tives,” she cau­tioned.

In ad­di­tion, it was al­so dis­closed that two pa­tients with un­der­ly­ing med­ical con­di­tions had died fol­low­ing FMT pro­ce­dures us­ing stool from Open­Bio­me.

It is not clear if STEC in­fec­tions con­tributed to these deaths, the FDA said ini­tial­ly on Thurs­day. Once the agency re­ceived ad­di­tion­al da­ta from Open­Bio­me, it con­clud­ed that the death of one pa­tient — who re­ceived stool that was found not to be con­t­a­m­i­nat­ed with STEC — was un­re­lat­ed to the Open­Bio­me prod­uct. But with the death of the sec­ond pa­tient, whose do­nat­ed stool was not test­ed for STEC, the link was un­clear, the FDA said. Open­Bio­me con­tend­ed that the treat­ing physi­cian had de­ter­mined that death was un­re­lat­ed to STEC.

De­signed to re­plen­ish gut mi­crobes, FMT has shown high rates of ef­fi­ca­cy in the treat­ment of re­cur­rent C. dif­fi­cile, a stub­born in­fec­tion that has grown re­sis­tant to ex­ist­ing an­tibi­otics and kills more than 29,000 Amer­i­cans each year.

Pi­o­neered in Chi­na, the in­ter­ven­tion has gained trac­tion in the Unit­ed States. But the FDA con­sid­ers it an in­ves­ti­ga­tion­al treat­ment with an un­proven safe­ty and ef­fi­ca­cy pro­file — so far. 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.

FMT 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.

Mike Ro­manos

In 2016, cit­ing safe­ty con­cerns, the FDA ad­vo­cat­ed a re­vi­sion to its pol­i­cy on stool banks — fear­ing that us­ing fe­cal mat­ter from a lim­it­ed num­ber of donors could lead to, for in­stance, the trans­mis­sion of in­fec­tious agents in scores of pa­tients. But the draft guid­ance hasn’t yet been im­ple­ment­ed.

Giv­en the death in the MGH tri­al, and now the Open­Bio­me dis­clo­sure — the time has come for tighter FDA reg­u­la­tion, UK-based Mi­cro­bi­ot­i­ca’s CEO Mike Ro­manos not­ed in an in­ter­view with End­points. “I think what this says is that we need stan­dard­ized screen­ing.”

Im­pli­ca­tions be­yond FMT

Mi­cro­bio­me-based ther­a­peu­tics is a fe­cund field for drug de­vel­op­ers — big and small — cap­i­tal­iz­ing on sci­ence that sug­gests flush­ing ‘good’ gut bac­te­ria in­to the sys­tem can treat a pletho­ra of con­di­tions — from C. diff in­fec­tions to obe­si­ty — us­ing dif­fer­ent ther­a­peu­tic modal­i­ties, some of which are de­signed to side­step the “ick” fac­tor as­so­ci­at­ed with tra­di­tion­al stool trans­fer or FMT. Some com­pa­nies, like Mi­cro­bi­ot­i­ca, are go­ing even fur­ther by work­ing on iso­lat­ing an “ide­al mix” of mi­cro­bic ecosys­tems de­rived from stool — but grow­ing them sep­a­rate­ly once the cock­tail of suit­able bac­te­ria has been se­quenced and char­ac­ter­ized.

A few years ago, the spec­tac­u­lar fail­ure of Seres Ther­a­peu­tics’ sem­i­nal Phase II tri­al test­ing its “crap­sule” — donor-de­rived processed fe­cal ma­te­r­i­al en­cap­su­lat­ed in a pill — de­railed the emerg­ing field. “My hope is that this (Open­Bio­me sit­u­a­tion) doesn’t read across to the whole mi­cro­bio­me field be­cause I think the im­pact of Seres hav­ing an un­suc­cess­ful Phase II…af­fect­ed the whole mi­cro­bio­me field,” Ro­manos said.

When End­points reached out to play­ers in the mi­cro­bio­me ther­a­peu­tics space, the dis­par­i­ties in screen­ing pro­to­cols were ap­par­ent.

Seres, which is ex­pect­ed to un­veil key tri­al da­ta this year, point­ed out in a state­ment that its man­u­fac­tur­ing process dous­es sam­ples in ethanol, which would in­ac­ti­vate po­ten­tial pathogens such as STEC.

French mi­cro­bio­me play­er MaaT Phar­ma, which has a Phase II acute GvHD tri­al on­go­ing, said France’s Na­tion­al Agency of Drugs Safe­ty rec­om­mends FMT do­na­tions be test­ed for STEC, us­ing the PCR method, and that it al­so screens for EPEC among oth­er pathogens us­ing PCR test­ing, in an emailed state­ment to End­points.

A range of key tri­als from com­pa­nies in­clud­ing Re­bi­otix and Finch Ther­a­peu­tics — which was found­ed by mem­bers of the Open­Bio­me team — are ex­pect­ed to read out this year.

Ven­ture Cap­i­tal as a Strate­gic Part­ner: Fu­el­ing In­no­va­tion be­yond Fi­nance

The average level of investment required for a biotech start-up to succeed is increasing every year, elevating the pressure even further on venture capital to make smart financial investments. Financial investment alone, however, does not always guarantee that exciting innovations can be transformed into real businesses that make a meaningful difference to patients.

Beyond just capital

At Astellas Venture Management (AVM) – a wholly-owned venture capital organization within Astellas, headquartered in the San Francisco Bay Area – capital is just one of the ingredients we offer to add value to our biotechnology investments and partnerships. We generally take a strategic investor approach for companies in our invested portfolio, providing access to expertise, technology and/or resources in addition to the injection of finance. An equity investment from AVM can include access to Astellas’ research and development (R&D) capabilities and expertise, and a global network of partner academic institutions and biotechnology companies, to help advance and accelerate the start-up’s innovation.

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Vertex says that it’s doing its best to keep working its pipeline strategy, coming up with a plan “to enable virtual clinic visits and home delivery of study drug to ensure study continuity and medical monitoring, and to facilitate study procedures.”

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