Parkin­son's trans­plants emerge as stem cell pi­o­neer Jeanne Lor­ing joins R&D race

Jeanne Lor­ing hadn’t stud­ied Parkin­son’s in 22 years when she got an email from a lo­cal neu­rol­o­gist.

The neu­rol­o­gist, Melis­sa Houser, didn’t know Lor­ing had ever pub­lished on the dis­ease. She was just look­ing for a stem cell re­searcher who might hear her out. 

“I think I was just picked out of a hat,” Lor­ing told End­points News. 

At a meet­ing in Lor­ing’s Scripps Re­search of­fice, Houser and a Parkin­son’s nurse prac­ti­tion­er, Sher­rie Gould, asked her why there was so much re­search done in stem cell trans­plants for oth­er neu­rode­gen­er­a­tive dis­eases but not Parkin­son’s. They want­ed to know if she would work on one. 

“Fund­ing,” Lor­ing told them, get me the fund­ing — $200,000 — and I’m yours.

That was in 2011. The decade that en­sued saw sci­en­tists on three con­ti­nents and both North Amer­i­can coasts work, some­times col­lab­o­ra­tive­ly, to use new tech­nol­o­gy to res­ur­rect a vi­sion once dis­card­ed for rea­sons that ex­tend­ed well be­yond sci­en­tif­ic. Now, re­searchers are close­ly watch­ing for the re­sults of the first such trans­plants in Japan while Bay­er-backed Blue­Rock is await­ing on­ly a fi­nal FDA go-ahead to start its tri­als. And af­ter near­ly 10 years of pa­tient and pub­lic-backed re­search, Lor­ing is to­day launch­ing her com­pa­ny, As­pen Neu­ro­science, from stealth mode with a tech­nol­o­gy oth­ers saw as un­work­able and an eye to­ward its own tri­als next year.

Some are even toy­ing around, cau­tious­ly, with the word “cure,” even as oth­ers – in­clud­ing the first doc­tor to ex­e­cute a trans­plant for Parkin­son’s – see more ex­cit­ing de­vel­op­ments else­where.    

“We’ve de­vel­oped symp­to­matic treat­ments,” Blue­Rock de­vel­op­ment VP Mike Scott told End­points.  “But with this re­gen­er­a­tive med­i­cine ap­proach, you’re talk­ing about re­vers­ing lost func­tion. It’s trans­for­ma­tive. It has the po­ten­tial to be a func­tion­al cure.”

As­pen en­ters with one of the most fa­mous names in stem cell re­search. Lor­ing did her PhD on stem cells be­fore most Amer­i­cans had heard of them and was dubbed by the late sci­ence jour­nal­ist Bradley Fikes, “a stem cell evan­ge­list” for her work over the en­su­ing decades. In 2001, she de­vel­oped 9 of the em­bry­on­ic cell lines George W. Bush ap­proved for re­search. 

“She’s one of the god­moth­ers of stem cell ther­a­py,” Scott said. 

Ear­ly promis­es

Lor­ing’s first at­tempt at ap­ply­ing her cell work in biotech came at Hana Bi­o­log­ics in 1987, where she tried to graft dopamine neu­rons in­to rats en­gi­neered with Parkin­son’s. Parkin­son’s symp­toms are caused by these dopamine neu­rons de­cay­ing — which af­fect not on­ly plea­sure, but al­so move­ment and body con­trol — and it had been the­o­rized that a trans­plant could curb or even re­verse the dis­ease. The long­stand­ing car­bidopa lev­odopal, or “L-dopa,” treat­ments sup­ple­ment the lost dopamine but can vary in their ef­fec­tive­ness and don’t re­verse the dam­age.

“There’s no turn­ing back,” Lor­ing said. “The on­ly way to turn back the clock is to re­place those neu­rons.”

The ex­per­i­ment proved promis­ing, but the com­pa­ny failed. Lor­ing pub­lished a pa­per and moved on­to Gen­Pham and Alzheimer’s mice. 

At the same time, Curt Freed and Robert Breeze at the Uni­ver­si­ty of Col­orado im­plant­ed a pa­tient for the first time with hu­man fe­tus-de­rived dopamine cells. From 1988 through 1999, they im­plant­ed 61 pa­tients and pub­lished re­sults show­ing some pa­tient im­prove­ment, but the ther­a­py went nowhere. The prob­lem, Freed said, had lit­tle to do with ef­fi­ca­cy. 

“It was al­most im­pos­si­ble to find the right kind of hu­man fe­tal tis­sue from abor­tion,” Freed, who is not af­fil­i­at­ed with As­pen or Blue­Rock, told End­points. 

The tech­nol­o­gy for an al­ter­na­tive emerged in 2006, when Shinya Ya­mana­ka demon­strat­ed how any liv­ing cell could be chem­i­cal­ly in­duced in­to stem cell state, ef­fec­tive­ly un­teth­er­ing stem cell re­search from its po­lit­i­cal and sourc­ing quan­daries. In 2011, Lorenz Stud­er, founder of the Memo­r­i­al Sloan Ket­ter­ing Cen­ter for Stem Cell Bi­ol­o­gy, pub­lished a Na­ture pa­per show­ing how dopamine neu­rons from these in­duced hu­man stem cells, al­so called in­duced-pluripo­tent stem cells (iPS), could be en­graft­ed on­to rats. Stud­er would go on to build that work in­to Blue­Rock in 2016. 

Lor­ing’s work lead­ing up to that 2011 meet­ing had large­ly been in ge­nomics — in­clud­ing found­ing Ar­cos Bio­sciences, the fore­run­ner of di­a­betes cell trans­plant Vi­a­cyte — and af­ter Gould and peo­ple with Parkin­sons’ raised the nec­es­sary lab funds through a sum­mit of Mt. Kil­i­man­jaro, she took a dif­fer­ent ap­proach than Stud­er and top re­searchers in Japan and Swe­den took. 

Whose cells?

Lor­ing sought to do an au­tol­o­gous as op­posed to an al­lo­gene­ic trans­plant:  Rather than take cells from an­oth­er hu­man, build up a large bank and then im­plant a cer­tain num­ber in­to a pa­tient, she want­ed to take a pa­tient’s own skin cells, turn them in­to stem cells and then dopamine neu­rons and fi­nal­ly im­plant them in­to the brain. 

“We’re the on­ly com­pa­ny do­ing au­tol­o­gous,” Kim Kam­dar, a No­var­tis al­umn and part­ner at Do­main As­so­ci­ates, which pro­vid­ed seed fund­ing, told End­points. “The beau­ty in a way is the per­son­al­ized med­i­cine.”

There were sci­en­tif­ic and eco­nom­ic rea­sons, though, that no oth­er com­pa­ny pur­sued that goal. They may be part of why Blue­Rock launched with $245 mil­lion from Ver­sant Ven­tures and Bay­er, while Lor­ing’s work was kept go­ing through pa­tient fund­ing and emerges now with $6.5 mil­lion in seed cash. (They are hop­ing to close on a Se­ries A in the first quar­ter of 2020.) 

Blue­Rock over years de­vel­oped bil­lions of cells they keep in cryo­genic stor­age in a New York lab. That costs mon­ey, as As­pen ex­ecs not­ed, but Freed and Scott sug­gest­ed that hav­ing to build a new cell line for each pa­tient would, like in­di­vid­u­al­ized CAR-T ther­a­pies, cost far more and in­tro­duced more po­ten­tial pro­duc­tion prob­lems.

“You would need to have a high­ly ro­bust, bul­let­proof, cell repli­ca­tion sys­tem,” Scott said.

Lor­ing says she’s de­vel­oped that. Lean­ing on her ge­nomics back­ground and a ma­chine learn­ing, she says she’s built tech­nol­o­gy to stan­dard­ize the process. She ar­gues that she can save mon­ey by man­u­fac­tur­ing far few­er cell lines.  

The plat­form will al­so al­low them to pre­dict and pre­vent mu­ta­tions in the cell lines, Lor­ing said, and be­cause the cells are from the pa­tient, their body will ac­cept them.

“We won’t have to im­muno­sup­press them,” she said.

Scott ac­knowl­edged As­pen’s im­muno­sup­pres­sion ben­e­fits. Blue­Rock plans to im­muno­sup­press pa­tients in its first clin­i­cal tri­al. But it’s not ac­tu­al­ly clear that pa­tients need the ubiq­ui­tous post-trans­plant drugs for a stem cell brain pro­ce­dure be­cause the im­mune sys­tem op­er­ates dif­fer­ent­ly be­yond the blood-brain bar­ri­er. Blue­Rock hopes to even­tu­al­ly stop giv­ing the drugs.

Freed gave im­muno­sup­pres­sants to every oth­er pa­tient ear­ly on, and then stopped giv­ing them en­tire­ly. His team has done 15 au­top­sies of for­mer pa­tients, he said, and not one showed a trans­plant wiped out by re­jec­tion.

“Our stud­ies have shown im­muno­sup­pres­sion is not re­quired,” Freed said.

The key ques­tion, though – will any of this be ef­fec­tive – may take a while to an­swer.

Does it work?

At the end of last year, re­searchers at Ky­oto Uni­ver­si­ty im­plant­ed the first of sev­en pa­tients with al­lo­gene­ic stem cells. Sci­en­tists are still ea­ger­ly wait­ing for the pro­ce­dure’s re­sults as it can take up to 6 or even 12 months be­fore the im­plant cells will ful­ly con­nect with the oth­ers and pa­tients be­gin to show re­sponse.

That de­lay, among oth­er is­sues, has some in the Parkin­son’s com­mu­ni­ty look­ing to­wards oth­er so­lu­tions. David Sulz­er, a neu­ro­bi­ol­o­gy pro­fes­sor at Co­lum­bia Uni­ver­si­ty who last year re­ceived a grant to help re­search the role of au­toim­mu­ni­ty in Parkin­son’s, said trans­plants have po­ten­tial – one day.

“It’s go­ing to need a lot of work,” Sulz­er told End­points, not­ing skep­ti­cism about cell lines and where cells will be in­sert­ed.

Among oth­er pos­si­ble ob­sta­cles is the fact that re­searchers don’t un­der­stand what caus­es Parkin­son’s at the deep­est lev­el.

It’s pos­si­ble, Scott said, that what­ev­er killed the first neu­rons will kill the new ones.

Freed for his part has moved on. He says most of his re­search on trans­plants showed they work es­sen­tial­ly the same as an l-dopa. It didn’t re­turn lost func­tion but pumped out dopamine at a steady pace, sav­ing pa­tients from hav­ing symp­toms os­cil­late through­out the day. He’s moved on to phenyl­bu­tyrate, a drug he thinks can halt the dis­ease. Oth­er re­searchers are work­ing on gene ther­a­pies.

The new­er trans­plants, though, promise im­prove­ments on Freed’s work and pa­tients backed it hop­ing for a sig­nif­i­cant rem­e­dy in their life­time. Af­ter the Kil­i­man­jaro fundrais­er for Lor­ing, Gould found­ed Sum­mit for Stem Cell to con­tin­ue back­ing her. Jen­nifer Raub, who has Parkin­son’s, lat­er be­came pres­i­dent, turned it in­to a 501c(3) and once raised over $1 mil­lion in a night to help find some­thing that had broad­er, more con­sis­tent and long-last­ing ef­fects than the l-dopa she was tak­ing.

“I made a con­scious choice, as many do, to seek an al­ter­na­tive to car­bidopa lev­odopa rather than wait un­til I can no longer func­tion,” she wrote to End­points

For Lor­ing, now in her 60s, As­pen rep­re­sents a unique op­por­tu­ni­ty. Her work has changed med­i­cine, but so far she’s di­rect­ly de­vel­oped no new FDA-ap­proved drugs. She hopes to be­gin test­ing a po­ten­tial one next year. They’ve al­ready be­gun find­ing pa­tients.

“It would be the cul­mi­na­tion of my ca­reer,” she said, “and I’ve in­vest­ed most of my life.”

Biotech and Big Phar­ma: A blue­print for a suc­cess­ful part­ner­ship

Strategic partnerships have long been an important contributor to how drugs are discovered and developed. For decades, big pharma companies have been forming alliances with biotech innovators to increase R&D productivity, expand geographical reach and better manage late-stage commercialization costs.

Noël Brown, Managing Director and Head of Biotechnology Investment Banking, and Greg Wiederrecht, Ph.D., Managing Director in the Global Healthcare Investment Banking Group at RBC Capital Markets, are no strangers to the importance of these tie-ups. Noël has over 20 years of investment banking experience in the industry. Before moving to the banking world in 2015, Greg was the Vice President and Head of External Scientific Affairs (ESA) at Merck, where he was responsible for the scientific assessment of strategic partnership opportunities worldwide.

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Novartis’ hopes of turning one of the most surprising trial data points of the last decade into a lung cancer drug has taken another setback.

The Swiss pharma announced Monday that its IL-1 inhibitor canakinumab did not significantly extend the lives or slow the disease progression of patients with previously untreated locally advanced or metastatic non-small cell lung cancer when compared to standard of-care alone.

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Robert Califf (Pablo Martinez Monsivais, AP Images, File)

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For once in this long, dramatic road to finding a new FDA commissioner, there’s been some continuity. Both CNN and Politico reported this weekend that Rob Califf met with President Biden to discuss the permanent commish role, following earlier news broken by the Washington Post that all signs point to Califf.

Although there may be a few Democrats who continue to grandstand about the dangers of COI (Califf has worked for Verily, sits on the board of Centessa Pharmaceuticals, and has other ties to industry research), with the pandemic ongoing and the need for some kind of continuity at FDA mounting, Califf is likely to meet the same fate as when he first won Senate confirmation in 2016, by a vote of 89-4 — Bernie Sanders and 6 others didn’t vote.

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AstraZeneca CEO Pascal Soriot (Raphael Lafargue/Abaca/Sipa USA)

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A combo of Imfinzi (durvalumab) and chemotherapy significantly extended the lives of first-line patients with advanced biliary tract cancer over chemo alone, according to topline results from the Phase III TOPAZ-1 study revealed Monday.

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Sean Ianchulev, Eyenovia CEO and CMO

Re­cent court de­ci­sion push­es FDA to re­ject and re­clas­si­fy drug-de­vice com­bo, crush­ing shares

Back in April, the FDA lost a crucial court case in which its broad discretion of regulating medical products that might satisfy the legal definitions of either “drug” and/or “medical device” was sharply curtailed.

In addition to the appeals court ruling that Genus Medical Technologies’ contrast agent barium sulfate (aka Vanilla SilQ) should not be considered a drug, as the FDA had initially ruled, but as a medical device, the agency also was forced to spell out which drugs would transition to devices as a result of the ruling.

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Peter Greenleaf, Aurinia CEO

Af­ter pass­ing on Ac­celeron, Bris­tol My­ers eyes bolt-on ac­qui­si­tion of au­toim­mune spe­cial­ist — re­port

Bristol Myers Squibb is looking to beef up its autoimmune portfolio by scooping up Aurinia Pharmaceuticals, Bloomberg reported.

The recent overtures to Aurinia, relayed by anonymous insiders, came just as Bristol Myers turned down buyout talks with partners at Acceleron — which Merck ultimately struck a deal to acquire for $11.5 billion. Bristol Myers has reportedly decided to cash out on its minority stake, likely bagging $1.3 billion in the process, while keeping the royalty deals on two of Acceleron’s blood disorder drugs.

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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.

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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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