Unum plays its first glimpse of hu­man da­ta in an $86M IPO, re­veal­ing two deaths and an FDA hold

Chuck Wil­son

Af­ter pro­mot­ing one of his top ex­ecs to pres­i­dent and bring­ing in two new board mem­bers, Unum Ther­a­peu­tics CEO Chuck Wil­son end­ed the week by putting the first snap­shot of pos­i­tive hu­man da­ta from their lead cell ther­a­py for can­cer on dis­play in an $86 mil­lion IPO fil­ing. But with just a hand­ful of pa­tients in the first round of clin­i­cal tri­als, Unum is al­so re­veal­ing pub­licly for the first time that it ran square­ly in­to lethal rates of dose-lim­it­ing tox­i­c­i­ty that killed two pa­tients in one arm and forced it to aban­don their high dose af­ter the FDA slapped a clin­i­cal hold on the study.

That hold was on­ly re­cent­ly lift­ed some­time last month, ac­cord­ing to the fil­ing. Unum kept word of the deaths and the hold out of the news for three months while it was on a road show for the IPO.

In re­sponse to a query, pres­i­dent and CFO Chris­tiana Sta­moulis said in an email:

As you know we are in the qui­et pe­ri­od and un­for­tu­nate­ly we can­not pro­vide any com­ments at this point.

The biotech — one of many that has built a rep around a top team and re­li­able ven­ture back­ers — has been build­ing a new cell ther­a­py that en­gi­neers pa­tient’s T cells in­to a dou­ble wham­my on can­cer cells. The cells are first de­signed to ex­press AC­TR, a chimeric pro­tein en­com­pass­ing pro­teins from T cells and nat­ur­al killer cells, then com­bined with an­oth­er tu­mor-spe­cif­ic drug, whip­ping up a cy­to­tox­ic as­sault on can­cer cells.

The lead drug is AC­TR087, and Unum is al­ready com­par­ing it to Gilead’s Yescar­ta and Kym­ri­ah, the two pi­o­neer­ing CAR-Ts on the mar­ket. A com­bi­na­tion with Rit­ux­an, re­searchers test­ed a low dose (0.5 x 106 AC­TR T cells/kg) in 7 NHL pa­tients and tracked 6 re­spons­es, in­clud­ing two com­plete and a par­tial re­sponse. That looks good com­pared to 39% and 32% com­plete re­sponse rates re­port­ed at three months for Yescar­ta and Kym­ri­ah. And they re­port­ed no se­ri­ous ad­verse events.

The high dose (1.5 x 106 AC­TR T cells/kg) was lethal, killing 2 of just 9 pa­tients in that arm. That’s not the first time se­vere tox­i­c­i­ty has killed pa­tients in an ex­plorato­ry ear­ly-stage cell ther­a­py study, but the lengthy de­lay be­tween the deaths and the SEC fil­ing is like­ly to spur in­tense crit­i­cism. The FDA re­spond­ed by putting the study on hold, some­thing Unum nev­er pre­vi­ous­ly dis­closed. From the S-1:

The se­vere AC­TR087-re­lat­ed SAEs we ob­served in Dose Lev­el Two re­sult­ed in the FDA plac­ing this tri­al on clin­i­cal hold in De­cem­ber 2017 pend­ing sub­mis­sion of cer­tain in­for­ma­tion re­lat­ing to the ATTCK-20-2 clin­i­cal tri­al. The clin­i­cal yy­hold was re­moved in Feb­ru­ary 2018, fol­low­ing re­view of this in­for­ma­tion by the FDA. Sev­er­al pro­to­col and dos­ing changes were made in ear­ly 2018, which we ex­pect to re­duce the in­ci­dence of ad­verse events and bet­ter man­age those events that do oc­cur.

Re­searchers con­clud­ed that there were two cas­es of AC­TR087-re­lat­ed se­vere CRS — one fa­tal — and one pa­tient died from AC­TR087-re­lat­ed neu­ro­tox­i­c­i­ty. There was one fa­tal case of en­te­ro­coc­cal sep­sis con­sid­ered re­lat­ed to AC­TR087 and “one pa­tient sub­se­quent­ly ex­pe­ri­enced a fa­tal case of sep­sis con­sid­ered not re­lat­ed to AC­TR087,” ac­cord­ing to the S-1.

Cy­tokine re­lease storms and neu­ro­tox­i­c­i­ty are not new in the cell ther­a­py world, as Juno found out through a string of deaths linked to their first dead­ly, and now dis­card­ed, CAR-T. Gilead’s Kite and No­var­tis, though, were able to com­plete reg­is­tra­tion stud­ies with­out rais­ing the same con­cerns.

Safe­ty con­cerns are a key fea­ture in cell ther­a­py re­search, but the FDA rules put a wall around in­for­ma­tion and pre­vent the agency from dis­cussing any of this, leav­ing biotechs some wide dis­cre­tion on how they han­dle this in­for­ma­tion. As we saw with Sol­id Bio­science’s 11th hour up­date about a par­tial tri­al hold for their Duchenne MD gene ther­a­py due to safe­ty con­cerns, pri­vate biotechs can re­ly on the FDA’s si­lence to keep safe­ty is­sues a se­cret, wait­ing un­til SEC rules re­quire a dis­clo­sure. And for promi­nent bioethi­cists in the field, that’s a prob­lem­at­ic is­sue.

I asked bioethi­cist Arthur Ca­plan at New York Uni­ver­si­ty’s Lan­gone Med­ical Cen­ter what his per­spec­tive was. His an­swer, by e-mail:

Don’t know Unum case, but I do know of nu­mer­ous in­stances in which com­pa­nies had deaths dur­ing ear­ly clin­i­cal tri­als that they chose not to pub­licly dis­close. They told the FDA but FDA does not re­veal in­for­ma­tion in­clud­ing deaths that are of­fered as part of com­mer­cial de­vel­op­ment.

Ab­surd­ly more weight is giv­en to keep­ing deaths a se­cret in or­der to bol­ster the fi­nan­cial prospects of new com­pa­nies and their in­vestors than to pro­tect­ing the wel­fare of hu­man sub­jects and ul­ti­mate­ly the safe­ty of the pub­lic should drugs or ther­a­pies be ap­proved in the USA or oth­er na­tions.

At a min­i­mum re­searchers ought to know if a path they are pur­su­ing has re­sult­ed in death(s) so as not to repli­cate the risks for their sub­jects.  How best to do this I am not sure but putting trade se­cre­cy over hu­man wel­fare is a sad or­der­ing of pri­or­i­ties.

Unum has three dif­fer­ent Phase I pro­grams in the clin­ic, with an­oth­er head­ed to hu­man stud­ies in the near fu­ture. The biotech has a col­lab­o­ra­tion deal in place with Seat­tle Ge­net­ics which com­bines a BC­MA ther­a­py with AC­TR087 for mul­ti­ple myelo­ma.

Seat­tle Ge­net­ics has paid over $32.5 mil­lion in the deal so far, with ven­ture back­ers com­ing up with $77.3 mil­lion.

One of the big ad­van­tages that Unum hopes to prove is that by con­cen­trat­ing on CD16 bind­ing they can use the same ba­sic ap­proach for all their ther­a­pies, mak­ing it sim­pler to de­sign and man­u­fac­ture than the break­through drugs now on or close to the mar­ket.

For a ven­ture-backed com­pa­ny, Unum al­so re­vealed an un­usu­al­ly high re­serve of stock for two key play­ers at the biotech: Dario Cam­pana, the sci­en­tif­ic founder and a well known cell ther­a­py ex­pert, and CEO Wil­son. Each owns 21.7% of the stock.

At­las, mean­while, owns 13.9% while F-Prime is in it for 9.9%.

Karen Fer­rante and Robert Perez joined Uum’s board last week, while CFO Chris­tiana Sta­moulis added the pres­i­dent’s ti­tle to her re­sume. Bruce Booth at At­las is chair­man of the board.

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What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

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