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.

2023 Spot­light on the Fu­ture of Drug De­vel­op­ment for Small and Mid-Sized Biotechs

In the context of today’s global economic environment, there is an increasing need to work smarter, faster and leaner across all facets of the life sciences industry.  This is particularly true for small and mid-sized biotech companies, many of which are facing declining valuations and competing for increasingly limited funding to propel their science forward.  It is important to recognize that within this framework, many of these smaller companies already find themselves resource-challenged to design and manage clinical studies themselves because they don’t have large teams or in-house experts in navigating the various aspects of the drug development journey. This can be particularly challenging for the most complex and difficult to treat diseases where no previous pathway exists and patients are urgently awaiting breakthroughs.

Up­dat­ed: FDA re­mains silent on or­phan drug ex­clu­siv­i­ty af­ter last year's court loss

Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

Albert Bourla, Pfizer CEO (Efren Landaos/Sipa USA/Sipa via AP Images)

Pfiz­er makes an­oth­er bil­lion-dol­lar in­vest­ment in Eu­rope and ex­pands again in Michi­gan

Pfizer is continuing its run of manufacturing site expansions with two new large investments in the US and Europe.

The New York-based pharma giant’s site in Kalamazoo, MI, has seen a lot of attention over the past year. As a major piece of the manufacturing network for Covid-19 vaccines and antivirals, Pfizer is gearing up to place more money into the site. Pfizer announced it will place $750 million into the facility, mainly to establish “modular aseptic processing” (MAP) production and create around 300 jobs at the site.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,000+ biopharma pros reading Endpoints daily — and it's free.

Vas Narasimhan, Novartis CEO (Thibault Camus/AP Images, Pool)

No­var­tis bol­sters Plu­vic­to's case in prostate can­cer with PhI­II re­sults

The prognosis is poor for metastatic castration-resistant prostate cancer (mCRPC) patients. Novartis wants to change that by making its recently approved Pluvicto available to patients earlier in their course of treatment.

The Swiss pharma giant unveiled Phase III results Monday suggesting that Pluvicto was able to halt disease progression in certain prostate cancer patients when administered after androgen-receptor pathway inhibitor (ARPI) therapy, but without prior taxane-based chemotherapy. The drug is currently approved for patients after they’ve received both ARPI and chemo.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,000+ biopharma pros reading Endpoints daily — and it's free.

Nkarta CEO Paul Hastings at Endpoints' #BIO22 panel (J.T. MacMillan Photography for Endpoints News)

Nkar­ta un­der­scores safe­ty of CAR-NK, boasts ear­ly re­spons­es

The first generation of personalized CAR-T therapies made big waves in the treatment of lymphoma for their stunning efficacy. Nkarta is hoping its off-the-shelf natural killer cell approach will stand out on safety — while keeping some of those impressive numbers on responses.

In a new update from its Phase I dose escalation study, the South San Francisco-based biotech reported that seven out of 10 patients treated with the highest doses of its NK cell therapy, NKX019, achieved a complete response, translating to a complete response rate of 70%.

Pfiz­er-backed Me­di­ar Ther­a­peu­tics ropes in an­oth­er Big Phar­ma in­vestor

A biotech centered on treating fibrosis — born out of Mass General and Brigham and Women’s Hospital — has received a financial boost.

According to an SEC filing, the company has raised $31,761,186 in its latest funding round, which includes 17 investors. The filing lists six names attached to the company, including Meredith Fisher, a partner at Mass General Brigham Ventures and Mediar’s acting CEO.

Sekar Kathiresan, Verve Therapeutics CEO

Verve re­veals let­ter from FDA that lays out con­di­tions to lift base edit­ing tri­al hold

We now know why Verve’s lead candidate was placed on hold last month by US regulators.

In an SEC filing, Verve laid out the FDA’s conditions for lifting the hold on its lead therapy, VERVE-101. That includes submitting preclinical data about potency differences in human versus non-human cells, risks of gene editing germline cells, and off-target analyses in non-hepatocyte cell types.

The FDA also wants clinical data from the ongoing Heart-1 trial, and to modify the trial protocol in the US to add additional contraceptive measures and increase the length of a staggering interval between the dosing of participants.

Rick Modi, Affinia Therapeutics CEO

Ver­tex-part­nered gene ther­a­py biotech Affinia scraps IPO plans

Affinia Therapeutics has ditched its plans to go public in a relatively closed-door market that has not favored Nasdaq debuts for the drug development industry most of this year. A pandemic surge in 2020 and 2021 opened the doors for many preclinical startups, which caught Affinia’s attention and gave the gene therapy biotech confidence in the beginning days of 2022 to send in its S-1.

But on Friday, Affinia threw in the S-1 towel and concluded now is not the time to step onto Wall Street. The biotech has put out few public announcements since the spring of this year. Endpoints News picked the startup as one of its 11 biotechs to watch last year.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,000+ biopharma pros reading Endpoints daily — and it's free.

Af­ter M&A fell through, Ther­a­peu­tic­sMD sells hor­mone ther­a­py, con­tra­cep­tive ring for $140M cash plus roy­al­ties

TherapeuticsMD, a women’s health company whose one-time billion-dollar valuation seems a distant memory as its blockbuster aspirations petered out, is finally cashing out.

Australia’s Mayne Pharma is paying $140 million upfront to license essentially TherapeuticsMD’s whole portfolio, including two prescription drugs that treat conditions relating to menopause, a contraceptive vaginal ring as well as its prescription prenatal vitamin brands.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,000+ biopharma pros reading Endpoints daily — and it's free.