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.

Alice Shaw, Lung Cancer Foundation of America

Top ALK ex­pert and can­cer drug re­searcher Al­ice Shaw bids adieu to acad­e­mia, hel­lo to No­var­tis

Jay Bradner has recruited a marquee oncology drug researcher into the ranks of the Novartis Institutes for BioMedical Research. Alice Shaw is jumping from prestigious posts intertwined through Mass General, Harvard and Dana-Farber to take the lead of NIBR’s translational clinical oncology group.

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Hal Barron, GSK's president of R&D and CSO, speaks to Endpoints News founder and editor John Carroll in London at Endpoints' #UKBIO19 summit on October 8, 2019

[Video] Cel­e­brat­ing tri­al fail­ures, chang­ing the cul­ture and al­ly­ing with Cal­i­for­nia dream­ers: R&D chief Hal Bar­ron talks about a new era at GSK

Last week I had a chance to sit down with Hal Barron at Endpoints’ #UKBIO19 summit to discuss his views on R&D at GSK, a topic that has been central to his life since he took the top research post close to 2 years ago. During the conversation, Barron talked about changing the culture at GSK, a move that involves several new approaches — one of which involves celebrating their setbacks as they shift resources to the most promising programs in the pipeline. Barron also discussed his new alliances in the Bay Area — including his collaboration pact with Lyell, which we covered here — frankly assesses the pluses and minuses of the UK drug development scene, and talks about his plans for making GSK a much more effective drug developer.

This is one discussion you won’t want to miss. Insider and Enterprise subscribers can log-in to watch the video.

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Med­ical an­i­ma­tion: Mak­ing it eas­i­er for the site and the pa­tient to un­der­stand

Medical animation has in recent years become an increasingly important tool for conveying niche information to a varied audience, particularly to those audiences without expertise in the specialist area. Science programmes today, for example, have moved from the piece-to-camera of the university professor explaining how a complex disease mechanism works, to actually showing the viewer first-hand what it might look like to shrink ourselves down to the size of an ant’s foot, and travel inside the human body to witness these processes in action. Effectively communicating a complex disease pathophysiology, or the novel mechanism of action of a new drug, can be complex. This is especially difficult when the audience domain knowledge is limited or non-existent. Medical animation can help with this communication challenge in several ways.
Improved accessibility to visualisation
Visualisation is a core component of our ability to understand a concept. Ask 10 people to visualise an apple, and each will come up with a slightly different image, some apples smaller than others, some more round, some with bites taken. Acceptable, you say, we can move on to the next part of the story. Now ask 10 people to visualise how HIV’s capsid protein gets arranged into the hexamers and pentamers that form the viral capsid that holds HIV’s genetic material. This request may pose a challenge even to someone with some virology knowledge, and it is that inability to effectively visualise what is going on that holds us back from fully understanding the rest of the story. So how does medical animation help us to overcome this visualisation challenge?

Flu Virus (Source: CDC)

FDA ex­pands Xofluza ap­proval as Roche strug­gles to catch loom­ing flu mar­ket

As a potentially powerful flu season looms, so does a big test for Roche and its new flu drug, Xofluza. The Swiss giant just got a small boost in advance of that test as the FDA expanded Xofluza’s indication to include patients at high risk of developing flu-related complications.

Xofluza (baloxavir marboxil) was approved last October in the US, the first landmark flu drug approval in 20 years and a much-needed green light for a company that had watched its leading flu drug Tamiflu get eaten alive by generics. Like its predecessor, the pill offered a reduction in flu symptoms but not a cure.

EMA backs sev­en ther­a­pies, in­clud­ing Mer­ck­'s Ebo­la vac­cine

The first-ever Ebola vaccine is on the precipice of approval after the European Medicine’s Agency (EMA) backed the Merck product in this week’s roster of recommendations.

The drugmaker $MRK began developing the vaccine, christened Ervebo, during the West African outbreak that occurred between 2014 and 2016, killing more than 11,000.

The current outbreak in the Democratic Republic of Congo (DRC) has shown case fatality rates of approximately 67%, the agency estimated. Earlier this year, the WHO declared the outbreak — which so far has infected more than 3,000 people — a public health emergency of international concern.

Ronald Herb­st fol­lows Med­Im­mune ex­o­dus to Pyx­is CSO post; Jeff God­dard to suc­ceed CEO of AIT Bio­science

→ The outflow of top execs from MedImmune continues to fill the leadership ranks of smaller biotechs. The latest to take off is Ronald Herbst, the head of oncology research, who’s assuming the CSO post at Pyxis Oncology.  

Herbst was part of the old MedImmune organization AstraZeneca CEO Pascal Soriot restructured earlier this year, reorganizing the company and eliminating the storied subsidiary as a separate organization.

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Mi­rati preps its first look at their KRAS G12C con­tender, and they have to clear a high bar for suc­cess

If you’re a big KRAS G12C fan, mark your calendars for October 28 at 4:20 pm EDT.

That’s when Mirati $MRTX will unveil its first peek at the early clinical data available on MRTX849 in presentations at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston.

Mirati has been experiencing the full effect of a rival’s initial success at targeting the G12C pocket found on KRAS, offering the biotech some support on the concept they’re after — and biotech fans a race to the top. Amgen made a big splash with its first positive snapshot on lung cancer, but deflated sky-high expectations as it proved harder to find similar benefits in other types of cancers.

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The FDA will hus­tle up an ex­pe­dit­ed re­view for As­traZeneca’s next shot at a block­buster can­cer drug fran­chise

AstraZeneca paid a hefty price to partner with Daiichi Sankyo on their experimental antibody drug conjugate for HER2 positive breast cancer. And they’ve been rewarded with a fast ride through the FDA, with a straight shot at creating another blockbuster oncology franchise.

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Sean Parker, AP

Sean Park­er helps cre­ate a CRISPRed cell ther­a­py 2.0 play — and he’s got a high-pro­file set of lead­ers on the team

You can rack up one more high-profile debut effort in the wave of activity forming around cell therapy 2.0. It’s another appealing Bay Area group that’s attracted some of the top hands in the business to a multi-year effort to create a breakthrough. And they have $85 million in hand to make that first big step to the clinic.

Today it’s Ken Drazan and the team at South San Francisco-based ArsenalBio that are coming from behind the curtain for a public bow, backed by billionaire Sean Parker and a collection of investors that includes Beth Seidenberg’s new venture investment operation based in LA.
Drazan — a J&J Innovation vet with a long record of entrepreneurial endeavors — exited the stage in 2018 when his last mission ended as he stepped aside as president of Grail. It wasn’t long, though, before he was helping out with a business plan for ArsenalBio that revolved around the work of a large group of interconnected scientists supported by the Parker Institute for Cancer Immunology.

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