Cal­i­for­nia up­start Xyphos wants to tack­le CAR-T's big prob­lems

A San Fran­cis­co biotech that’s been de­vel­op­ing an­tibi­otics for the past decade has spun out a new on­col­o­gy start­up that bor­rows ideas from ex­ist­ing CAR-T and an­ti­body ther­a­pies — and com­bines them.

That’s ac­cord­ing to the start­up’s founder and CEO Jim Knighton. The new spin­out, called Xyphos, con­sid­ers its tech “sec­ond gen­er­a­tion CAR-T” as it ad­dress­es many of the field’s no­to­ri­ous chal­lenges (in an­i­mal mod­els, at least).

“We’ve tak­en all the work that Kite, Juno, and No­var­tis have done in CAR and come up with a new set of ideas that builds on what they start­ed to ad­dress some if not all of (CAR-T’s) short­com­ings,” Knighton said.

CAR-T’s chal­lenges

Jim Knighton

Al­though these ex­per­i­men­tal im­munother­a­pies show im­mense up­side, CAR-T ther­a­pies are not per­fect. For one, they can trig­ger tox­i­c­i­ty and po­ten­tial­ly fa­tal im­mune re­ac­tions in can­cer pa­tients.

“In a sense, the prod­uct is too ef­fec­tive and caus­es such a large re­ac­tion that pa­tients ex­pe­ri­ence tox­i­c­i­ty,” said Ezra Co­hen, an on­col­o­gist and can­cer re­searcher at UC San Diego. “Some have even died.”

Knighton said the tech be­ing de­vel­oped at Xyphos might hur­dle these chal­lenges by us­ing its new­ly en­gi­neered CAR in com­bi­na­tion with a mod­i­fied an­ti­body ther­a­py. In short, the com­pa­ny’s CAR has been en­gi­neered to be in­ert when it en­ters the pa­tient’s body. The CAR will not bind to (or at­tack) any­thing. It’s on­ly ac­ti­vat­ed when the pa­tient is dosed with Xyh­pos’ spe­cial­ly en­gi­neered an­ti­body, which the com­pa­ny calls a “Mi­ca­body.” Once the two are bound, the CAR is ac­ti­vat­ed and does its killer work.

If, how­ev­er, the can­cer pa­tient be­gins ex­pe­ri­enc­ing tox­i­c­i­ty, the doc­tor could stop the an­ti­body ther­a­py. The an­ti­body then cy­cles out of the pa­tient, and the CARs re­vert to harm­less, in­ac­tive T cells. Its sort of like switch­ing T cells on and off when need­ed.

Knighton said the idea works in mice, and now he needs mon­ey to move the re­search fur­ther along.

Co­hen, an in­ter­na­tion­al­ly rec­og­nized ex­pert on nov­el can­cer ther­a­pies and the di­rec­tor of Moore’s Can­cer Cen­ter in San Diego, said in­no­va­tion in CAR-T is cer­tain­ly due.

“The ap­proved prod­ucts in CAR-T are quite sim­ple in de­sign,” Co­hen said. “A lot of us are think­ing about sec­ond, third, and fourth gen­er­a­tion CAR-T. How do we mod­i­fy it? Make it stronger? Con­trol it? The next wave of CARs will be tremen­dous­ly bet­ter.”

The spin­out’s ori­gin

The tech be­hind Xyphos has been qui­et­ly stud­ied in the labs of an an­tibi­otics com­pa­ny called Avid­Bi­otics since about 2012. Why is an an­tibi­otics com­pa­ny dab­bling in can­cer drugs? Knight said there’s no shared tech­nol­o­gy be­tween Avid­Bi­otics and Xyphos. In­stead, the re­search was the re­sult of “cor­po­rate ADD.”

David Mar­tin

“We had an idea. Rather than go­ing out and start­ing a new com­pa­ny, we just hired a cou­ple of peo­ple in­ter­nal­ly to work on the prob­lem in­de­pen­dent­ly,” Knighton said.

Now the tech is de­vel­oped enough to split from Avid­Bi­otics. In fact, the com­pa­ny is split­ting in­to two new parts: one on­col­o­gy com­pa­ny (Xyphos) and a new­ly formed an­tibi­otics com­pa­ny called Py­lum Bio­sciences, which will car­ry on Avid­Bi­otics’ re­search pro­grams.

Knighton is serv­ing as CEO of Xyphos, while Avid­Bi­otics’ for­mer chief ex­ec­u­tive David Mar­tin will lead Py­lum as CEO. As of now, there are no ex­ec­u­tives with on­col­o­gy back­grounds work­ing at Xyphos.

The mon­ey

Knighton said both new en­ti­ties will need to raise $20 mil­lion to $30 mil­lion right away be­fore beef­ing up the C-suite with ex­pe­ri­enced folks.

Avid­Bi­otics has raised $38 mil­lion since its 2006 in­cep­tion, pri­mar­i­ly from cor­po­rate col­lab­o­ra­tions with DuPont (now DowDuPont) and Cu­bist (be­fore Mer­ck’s ac­qui­si­tion). That cap­i­tal al­so in­cludes NIH grants, and con­tri­bu­tions from friends, fam­i­ly and the founders.

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

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