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.

Holtz­man was the pres­i­dent of DNX, one of the first com­pa­nies to try to use biotech­nol­o­gy to make pig-to-hu­man trans­plants pos­si­ble. He had amassed a pathogen-free porcine fa­cil­i­ty for their work and so oblig­ed, putting some un­lucky hogs on an Ohio State Uni­ver­si­ty plane to Duke, where one of ul­ti­mate­ly four pa­tients treat­ed with the pro­ce­dure sur­vived to re­ceive a new hu­man liv­er. The re­sults were pub­lished in the New Eng­land Jour­nal of Med­i­cine in 1994.

Which is why Holtz­man was shocked and a lit­tle bit con­fused when he read re­ports this week that doc­tors at NYU had con­duct­ed a “ground­break­ing” pro­ce­dure by, with the fam­i­ly’s con­sent, tak­ing a pig kid­ney and su­tur­ing it to the leg of a brain-dead pa­tient for 54 hours.

It was some­thing sci­en­tists could’ve done for years, he said. And it didn’t get them clos­er to ac­tu­al­ly mak­ing an­i­mal-to-hu­man trans­plants pos­si­ble, or ad­dress­ing the field’s main goal: solv­ing a na­tion­al or­gan short­age that kills 20 Amer­i­cans per day.

Steve Holtz­man

“It is hype and bull­shit,” said Holtz­man, who is now the chair­man of a Chi­nese com­pa­ny work­ing on xeno­trans­plan­ta­tion. “It be­longs in the Na­tion­al En­quir­er.”

Oth­er ex­perts with­in the small and large­ly in­su­lar world of xeno­trans­plan­ta­tion — the tech­ni­cal term for an­i­mal-to-hu­man trans­plants — were more sub­dued. Pig kid­neys, they said, are more dif­fi­cult to en­graft in a hu­man than pig liv­ers. And they not­ed Robert Mont­gomery, the NYU sur­geon, and Unit­ed Ther­a­peu­tics, the com­pa­ny that sup­plied the ge­net­i­cal­ly mod­i­fied pig, were not the first ones to con­ceive of this type of pro­ce­dure.

Yet while many were glad to see xeno­trans­plan­ta­tion get main­stream at­ten­tion af­ter two decades in which much of the field worked in ob­scu­ri­ty, they strug­gled to see the ex­act re­search ques­tion the ex­per­i­ment an­swered or the sci­en­tif­ic knowl­edge gained.

Al­though DNX and oth­er 90s-era xeno­trans­plant com­pa­nies flamed out for a va­ri­ety of rea­sons, sci­en­tists have known since the ear­ly 2000s that a sin­gle ge­net­ic ed­it should al­low or­gans to sur­vive for days, if not months, in a pa­tient. The re­al ques­tion is get­ting pig or­gans to con­sis­tent­ly sur­vive long-term, a much high­er im­muno­log­ic hur­dle.

The best some could say was that the work con­firmed what they al­ready knew.

Megan Sykes

“The re­sult doesn’t con­tain any sur­pris­es for those of us in this trans­plant field,” said Megan Sykes, di­rec­tor of Co­lum­bia’s cen­ter for trans­la­tion­al im­munol­o­gy. In that sense, it was a “good first step.”

For those who missed it, on Tues­day night, USA To­day pub­lished an in­tri­cate fea­ture de­tail­ing how, in late Sep­tem­ber, with $3.2 mil­lion in fund­ing from Unit­ed Ther­a­peu­tics, Mont­gomery con­nect­ed a mod­i­fied pig kid­ney to the leg of a 66-year-old woman who had re­cent­ly been de­clared brain-dead.

The pa­tient’s fam­i­ly was ap­proached, with the ad­vice of bioethi­cists, be­cause they want­ed to do­nate her or­gans but they weren’t fit for trans­plant. It of­fered an­oth­er way to help ad­vance med­i­cine that could one day save lives, they ex­plained.

The kid­ney be­gan fil­ter­ing her blood in­to urine with­in min­utes and stayed pink and func­tion­al for just over 2 days. Cru­cial­ly, Mont­gomery said, there was no ev­i­dence of in­stant re­jec­tion.

“As you all know, this is re­al­ly im­por­tant,” he said af­ter­wards. “This is go­ing to take us to the next step, which is hav­ing or­gans avail­able to every­one who needs them at any time.”

The sto­ry was soon picked up by The New York Times, Econ­o­mist, BBC and Al Jazeera, along with AP and Reuters re­ports that were reprint­ed wide­ly. The pro­ce­dure, the Times said, was “a sci­en­tif­ic break­through that one day may yield a vast new sup­ply of or­gans for se­vere­ly ill pa­tients.”

The xeno­trans­plan­ta­tion field has in­deed been inch­ing to­ward that goal for two decades, slow­ly build­ing it­self up af­ter falling apart in the 1990s, when com­pa­nies such as DNX and No­var­tis poured bil­lions in­to en­gi­neer­ing an­i­mals in­to donors. That decade, it be­came clear just how much mod­i­fi­ca­tion a pig — an an­i­mal cho­sen be­cause it was both close to hu­mans and easy to mass pro­duce — would re­quire, while the dis­cov­ery of a porcine virus vague­ly rem­i­nis­cent of HIV alarmed pub­lic health au­thor­i­ties deal­ing with the dead­liest days of the AIDS cri­sis.

Since then, a hand­ful of com­pa­nies have in­tro­duced a slew of new mod­i­fi­ca­tions and strate­gies and test­ed the re­sult­ing or­gans in non-hu­man pri­mates, in some cas­es get­ting the mon­keys to sur­vive for years.

The field, stocked with big and com­pet­i­tive per­son­al­i­ties, be­gan to buzz about who would be the first to do it in hu­mans. The ques­tion is whether or not Mont­gomery’s pro­ce­dure ac­tu­al­ly helped to­ward the goal of do­ing it in a liv­ing pa­tient who will have to be able to sur­vive off the or­gan.

“Peo­ple are chas­ing — who will be first? ‘I want to be first!’ ‘I want to be first!'” said Kaz Ya­ma­da, di­rec­tor of sur­gi­cal re­search, Co­lum­bia Cen­ter for Trans­la­tion­al Im­munol­o­gy. But “our goal is to cure the pa­tient, not to say, ‘I’m first.'”

Mont­gomery’s pro­ce­dure arose out of dis­cus­sions be­tween the trans­plant team at NYU and the uni­ver­si­ty’s renowned bioethi­cist de­part­ment, led by Art Ca­plan, who proac­tive­ly out­lined how, in the right con­di­tions, a brain-dead pa­tient could be the best first test for a xeno­trans­plant. (They al­so ad­vised against grant­i­ng ex­clu­siv­i­ty to any news out­let, fear­ing the me­dia fren­zy that in­deed en­sued when NYU did so. “I don’t win all my fights,” Ca­plan told me.)

But the idea of us­ing the re­cent­ly de­ceased as a test case for xeno­trans­plan­ta­tion goes back to at least Thomas Star­zl, of­ten con­sid­ered the fa­ther of the field, who first pro­posed it in the ear­ly 2000s, said Uni­ver­si­ty of Mi­a­mi sur­geon Joe Tec­tor.

Joe Tec­tor

Long one of the field’s most promi­nent fig­ures, Tec­tor had con­sid­ered do­ing it him­self. But by the 2010s, it no longer seemed nec­es­sary. Al­though Mont­gomery con­sult­ed with him pri­or to the op­er­a­tion, Tec­tor him­self had lost in­ter­est.

“We knew the bi­ol­o­gy,” he said. “We weren’t as com­fort­able that that would give us use­ful in­for­ma­tion.”

A lot had changed since the ear­ly 2000s, when Star­zl first pro­posed the idea.

Mont­gomery said his ex­per­i­ment showed that pa­tients wouldn’t in­stant­ly re­ject the mod­i­fied pig. But the lone ge­net­ic mod­i­fi­ca­tion Unit­ed gave the pig was first done suc­cess­ful­ly 20 years ago. And Ya­ma­da showed back in 2004 that the mod­i­fi­ca­tion — knock­ing out a sug­ar called al­pha-gal that all pri­mates, in­clud­ing hu­mans, have an­ti­bod­ies against — pre­vents pri­mates from in­stant­ly re­ject­ing the or­gans, al­low­ing them to live in that ex­per­i­ment for 83 days.

That find­ing has been held up re­peat­ed­ly, ex­perts say, with some mon­keys liv­ing for hun­dreds of days af­ter re­ceiv­ing or­gans from pigs mod­i­fied with that ed­it alone.

There’s dis­agree­ment with­in the xeno­trans­plan­ta­tion on how many ed­its will ul­ti­mate­ly be need­ed: Tec­tor’s pigs have three; eGe­n­e­sis, the well-backed Har­vard-spin­out, and Qi­han Biotech, its Chi­nese off­shoot that Holtz­man now chairs, have test­ed dozens; at Co­lum­bia, Ya­ma­da and Sykes use on­ly the one ed­it but al­so trans­plant a pig’s thy­mus, along­side the kid­ney, to try to get long-term T cell tol­er­ance.

The groups are now com­pet­ing to get the right FDA-ap­proved fa­cil­i­ties and sup­ply chains to make do­na­tions from a pig to a liv­ing pa­tient pos­si­ble, to show they can get con­sis­tent long-term sur­vival in mon­keys. All agreed that there were am­ple da­ta show­ing hu­mans wouldn’t re­ject a mod­i­fied pig or­gan in­stant­ly, or in the 54 hours Mont­go­mo­ery stud­ied.

For Tec­tor, it was “com­fort­ing,” he said, to now have val­i­da­tion in hu­mans, even if he wouldn’t have done it him­self. Oth­ers were less san­guine.

“I can’t imag­ine that things would be so much dif­fer­ent in hu­mans to think that this was re­al­ly in­for­ma­tive,” said Jim Mark­mann, chief of trans­plant at Mass­a­chu­setts Gen­er­al. (Mark­mann is al­so a sci­en­tif­ic ad­vi­sor for eGe­n­e­sis.) “I think it was more sen­sa­tion­al­ism.”

Unit­ed Ther­a­peu­tics, a com­pa­ny that has long court­ed both hype and se­cre­cy, did not re­spond to an in­ter­view re­quest or de­tailed ques­tions. At a press con­fer­ence Thurs­day, Mont­gomery said he used a pig that on­ly had the sin­gle ed­it be­cause al­pha-gal is the most im­por­tant knock­out for pre­vent­ing im­me­di­ate re­jec­tion and be­cause the FDA had al­ready cleared pigs with the ed­it for con­sump­tion and some re­search pur­pos­es.

He ar­gued that you could nev­er be sure the an­i­mal re­sults will trans­late in­to hu­mans un­til it’s ac­tu­al­ly done. And he said a full peer-re­viewed pub­li­ca­tion out­lin­ing the pro­ce­dure and its re­sults was com­ing.

“There have been many oth­er ex­am­ples of pre­clin­i­cal pri­mate stud­ies that have not trans­lat­ed well in­to what hap­pens in hu­mans,” he said. “We do have quite a bit of non­hu­man pri­mate da­ta but whether we’re go­ing to see the same things when we go to hu­man tri­als is re­al­ly not some­thing that we can re­ly up­on.”

Still, there was at least one point he and many of the out­side ex­perts agreed up­on. Al­though Holtz­man feared that the hype around the op­er­a­tion could de­tract from “peo­ple with in­tegri­ty and sci­en­tif­ic chops … who are the best hope for mak­ing this stuff hap­pen,” Sykes and Mark­mann ar­gued that it could ac­tu­al­ly help xeno­trans­plan­ta­tion, even if it con­tributed noth­ing to the sci­ence.

Mak­ing pig-to-hu­man trans­plants a re­al­i­ty will re­quire not on­ly strong re­sults in mon­key stud­ies, but al­so the trust of reg­u­la­tors and the pub­lic.

That has not al­ways been easy to win, but know­ing that noth­ing cat­a­stroph­ic hap­pened for at least the first 54 hours might help. Sykes, asked if she would have done the ex­per­i­ment, said that might be not be the right ques­tion.

“I’m hap­py to reap the ben­e­fits of it hav­ing been done,” Sykes said. “Of peo­ple hav­ing as­sur­ance that some­thing bad is not go­ing to hap­pen. I think that’s help­ful.”

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

All about Omi­cron; We need more Covid an­tivi­rals; GSK snags Pfiz­er’s vac­cine ex­ec; Janet Wood­cock’s fu­ture at FDA; 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.

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Usama Malik

Ex-Im­munomedics CFO charged with in­sid­er trad­ing, faces up to 20 years in prison af­ter al­leged­ly tip­ping off girl­friend and rel­a­tives of a PhI­II suc­cess

The former CFO of Immunomedics, who helped steer the company to its $21 billion buyout by Gilead last year, has been charged with insider trading, the Department of Justice announced Thursday.

Usama Malik tipped off his then-girlfriend and four others that a Phase III study for Trodelvy would be stopped early four days before Immunomedics publicly announced the result in April 2020, DoJ alleged in its complaint. The individuals then purchased Immunomedics shares, selling them after the news broke and Immunomedics’ stock price doubled.

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Merck's new antiviral molnupiravir (Quality Stock Arts / Shutterstock)

As Omi­cron spread looms, oral an­tivi­rals ap­pear to be one of the best de­fens­es — now we just need more

After South African scientists reported a new Covid-19 variant — dubbed Omicron by the WHO — scientists became concerned about how effective vaccines and monoclonal antibodies might be against it, which has more than 30 mutations in the spike protein.

“I think it is super worrisome,” Dartmouth professor and Adagio co-founder and CEO Tillman Gerngross told Endpoints News this weekend. Moderna CEO Stéphane Bancel echoed similar concerns, telling the Financial Times that experts warned him, “This is not going to be good.”

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Pfiz­er, Am­gen and Janssen seek fur­ther clar­i­ty on FDA's new ben­e­fit-risk guid­ance

Three top biopharma companies are seeking more details from the FDA on how the agency conducts its benefit-risk assessments for new drugs and biologics.

While Pfizer, Amgen and Janssen praised the agency for further spelling out its thinking on the subject in a new draft guidance, including a discussion of patient experience data as part of the assessment, the companies said the FDA could’ve included more specifics in the 20-page draft document.

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

With gener­ic com­pe­ti­tion heat­ing up, Vas Narasimhan out­lines No­var­tis' growth plans at R&D day

Thursday marks Novartis’ annual R&D day, and with it comes CEO Vas Narasimhan’s attempt to spotlight the company’s pipeline strategy and emerging stars.

The biggest question entering Thursday’s presentation dealt with how the big biopharma will make up revenues from upcoming generic competition — Novartis says within the next five years, generics will eat away roughly $9 billion in sales. To offset this, Narasimhan outlined a strategy for 4% growth or higher until 2026, focusing on six key medicines he believes will see multibillion dollar profits during this time.

In­cor­po­rat­ing Ex­ter­nal Da­ta in­to Clin­i­cal Tri­als: Com­par­ing Dig­i­tal Twins to Ex­ter­nal Con­trol Arms

Most drug development professionals are familiar with the nerve-racking wait for the read-out of a large trial. If it’s negative, is the investigational therapy ineffective? Or could the failure result from an unforeseen flaw in the design or execution of the protocol, rather than a lack of efficacy? The team could spend weeks analyzing data, but a definitive answer may be elusive due to insufficient power for such analyses in the already completed trial. These problems are only made worse if the trial had lower enrollment, or higher dropout than expected due to an unanticipated event like COVID-19. And if a trial is negative, the next one is likely to be larger and more costly — if it happens at all.

Reshma Kewalramani, Vertex CEO (Vertex via YouTube)

Bat­tling a line­up of skep­tics, Ver­tex claims an­oth­er ear­ly clin­i­cal win — this time in kid­ney dis­ease

Vertex claimed its second early-stage win of the fall Wednesday, announcing positive results in a small study on a genetically defined form of kidney disease.

The 16-patient, Phase II trial focused on patients with focal segmental glomerulosclerosis, a rare disease where kidneys are unable to filter blood properly. Over 13 weeks on an experimental pill, the level of protein in the patients’ urine fell by an average of 47.6%.

Ab­b­Vie tacks on a new warn­ing to Rin­voq la­bel as safe­ty frets crimp JAK class

The safety problems that continue to plague the JAK class as new data highlight some severe side effects are casting a large shadow over AbbVie’s Rinvoq.

As a result of a recent readout highlighting major adverse cardiac events (MACE), malignancy, mortality and thrombosis with Xeljanz a couple of months ago, AbbVie put out a notice late Friday afternoon that it is adding the new class risks to its label for their rival drug.

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