Brad Lon­car­'s AS­CO18 pre­view: Past AS­COs point to the top drugs that will soon el­bow for the Os­cars of can­cer R&D

To pre­pare for the fu­ture, it helps to look back on what has hap­pened in the past. AS­CO is a great bench­mark for do­ing that. Drug de­vel­op­ment does not hap­pen overnight. A pat­tern of re­al progress emerges if you view things in the con­text of two “AS­COs” ago, or five, or ten. I al­ways try to ap­proach it from this macro per­spec­tive as I pre­pare for the con­fer­ence be­cause it helps set the stage for how to­day’s new de­vel­op­ments might fit in.

Con­sid­er the fol­low­ing:

  • One AS­CO ago we were wowed by the abil­i­ty of pre­ci­sion on­col­o­gy to treat pa­tients based on a spe­cif­ic ge­net­ic mu­ta­tion (NTRK) rather than where can­cer orig­i­nat­ed in the body. That drug (larotrec­tinib) is cur­rent­ly in front of FDA and an­oth­er (Keytru­da) has since been the first ap­proved for a non-tu­mor spe­cif­ic in­di­ca­tion. This trend will con­tin­ue. Roche was smart to buy Igny­ta, as these are small but po­tent in­di­ca­tions. They were al­so smart to in­vest in Foun­da­tion Med­i­cine a few AS­COs ago and their fore­sight on that is fi­nal­ly pay­ing off. Ex­pect to be hear­ing about pre­ci­sion strate­gies for many more AS­COs to come.
  • Four AS­COs ago, there were no PD-1s ap­proved. Can you be­lieve that? I know it feels more like a decade, but it is im­por­tant to know that this is still on­ly ear­ly days for the class. In those four years, we have learned what types of can­cers the drugs work for as monother­a­py, in what cas­es com­bi­na­tions are need­ed, how many pa­tients of var­i­ous can­cer types are re­spond­ing, and hints of bio­mark­er strate­gies are start­ing to emerge. No doubt there have been dis­ap­point­ments on the com­bo side of things, but as our un­der­stand­ing of these drugs and the tu­mor mi­croen­vi­ron­ment im­proves, so will the chances of some­thing break­ing through.
  • Cell ther­a­py? One AS­CO ago this was still just a con­cept and many doubt­ed it could cross the reg­u­la­to­ry fin­ish line. Since then we have seen land­mark ap­provals of CD19 CARs and a rush of in­vest­ment from all around the world. I don’t think it is an ex­ag­ger­a­tion to say this is the fastest mov­ing sci­ence in on­col­o­gy. What is on the mar­ket to­day could be ob­so­lete as soon as just a cou­ple AS­COs from now. The next ver­sions of these ther­a­pies are like­ly to be very dy­nam­ic and pow­er­ful.
  • Four AS­COs ago there were al­so no PARP in­hibitors ap­proved. While the first (Lyn­parza) was ahead of its time, it is on­ly now that PARPs are get­ting in­ter­est­ing with new­com­ers on the mar­ket and some com­pelling com­bo tri­als un­der­way. Com­bo da­ta has large­ly been dis­ap­point­ing so far, but I think this is on­ly a mat­ter of time. Mer­ck, a leader in on­col­o­gy, made a sig­nif­i­cant in­vest­ment in a PARP last year and you can bet it is be­cause they see sub­stan­tial util­i­ty in more can­cers to come. 2018 could fi­nal­ly be a break­out year for this class.

With that past his­to­ry in mind, here are things I am watch­ing for at AS­CO 2018 to build on the suc­cess. Note: these are things I’m per­son­al­ly in­ter­est­ed in and this is def­i­nite­ly not an ex­haus­tive list for the en­tire con­fer­ence.


Tar­get­ed Ther­a­pies

Loxo is look­ing like it might be the star of AS­CO two years in a row. Has such a small biotech com­pa­ny ever done that be­fore? Has any com­pa­ny pe­ri­od? Wel­come to 2018, where most of the in­no­va­tion in drug de­vel­op­ment is com­ing from the mid and small cap range of our sec­tor. As far as RET goes, this is clear­ly an ex­cel­lent tar­get. The on­ly ques­tion at this point is whether $LOXO or $BPMC is go­ing to come out on top.


Check­points

  • Mer­ck’s Keynote-042 pre­sen­ta­tion has a chance to be the biggest news com­ing out of AS­CO. This is Keytru­da monother­a­py in pa­tients with >1% PD-L1 ex­pres­sion. We al­ready know the tri­al suc­ceed­ed on OS but what we don’t know yet is if the suc­cess is large­ly due to strong re­spons­es from the high PD-1 pa­tients or if those clos­er to 1% al­so saw com­pelling re­sults. We’ll need to see dif­fer­ent cuts at the da­ta at AS­CO for the an­swer. “Chemo free” is a term that is sneak­ing in­to the ad­ver­tis­ing cam­paigns of these com­pa­nies late­ly. With stel­lar re­sults in low ex­pressers, it would be a big win for im­munother­a­py and the “chemo free” move­ment. Good da­ta here might make treat­ment choic­es (whether to go mono or com­bo) quite dif­fi­cult for some physi­cians and pa­tients in the fu­ture.
  • Bris­tol (does any­body re­mem­ber them?) is pre­sent­ing IO/chemo com­bo da­ta from Check­mate-227 in 1L NSCLC pa­tients with <1% tu­mor PD-L1 ex­pres­sion. The haz­ard ra­tio for PFS from the ab­stract looks com­pa­ra­ble to what Mer­ck has pre­sent­ed in the past and will lend some cre­dence to Bris­tol’s sug­ges­tion that these two drugs are in fact Coke and Pep­si. How­ev­er, we ul­ti­mate­ly have to wait for OS re­sults to make a fi­nal call on that. This is still an im­por­tant pre­sen­ta­tion be­cause Bris­tol could use some good news in 1L lung. AACR il­lus­trat­ed what a tough hill they have to climb to con­vince physi­cians on the va­lid­i­ty of TMB so any pre­sen­ta­tion like this that doesn’t nec­es­sar­i­ly re­ly on it is a wel­come event for them.
  • Roche’s IM­pow­er131 late break­er study­ing Tecen­triq in com­bi­na­tion with chemo in ad­vanced squa­mous NSCLC was set­ting up to be an in­ter­est­ing event (though on­ly PFS da­ta is avail­able). And then the king of lung can­cer Mer­ck an­nounced on Wednes­day that its Keynote-407 study in the squa­mous his­tol­ogy hit on both PFS and OS. When it comes to lung can­cer, all hail the king.

Cell Ther­a­pies

  • CAR-T was right­ful­ly named AS­CO’s 2018 clin­i­cal Ad­vance of the Year. Will the da­ta con­tin­ue to live up to the ex­cite­ment? Un­for­tu­nate­ly there is on­ly one tru­ly enor­mous CAR-T pre­sen­ta­tion (BC­MA) I see on the sched­ule this year.
  • It was a big deal one AS­CO ago when blue­bird and Leg­end showed ear­ly promise with BC­MA CAR-T. To il­lus­trate that cell ther­a­pies like­ly have util­i­ty be­yond CD19 was a morale boost­er and I’m sure it was ma­jor fac­tor in con­vinc­ing Gilead and Cel­gene to do their big ac­qui­si­tions.
  • How­ev­er, BC­MA isn’t out of the woods yet. In­vestors are ner­vous about re­laps­es/dura­bil­i­ty. What will BC­MA da­ta look like with more time and more pa­tients treat­ed in tri­als? This could be Fri­day’s biggest sto­ry when blue­bird presents an up­date on their BC­MA CAR-T can­di­date bb2121. They al­so have a call sched­uled Fri­day af­ter­noon to dis­cuss the da­ta. We might have to broad­cast it on loud­speak­ers at the un­of­fi­cial tweet­up.
  • Speak­ing of dura­bil­i­ty, CD19 CARs have been de­vel­oped so quick­ly that we don’t ac­tu­al­ly know how durable the re­spons­es will be over the long-term. It has al­ways been a hy­poth­e­sis that dura­bil­i­ty will last for pa­tients who are out a con­sid­er­able amount of time, but com­pa­nies still need to prove it. Gilead had long-term da­ta from ZU­MA-1 in NHL that looked spec­tac­u­lar at ASH, and AS­CO da­ta will like­ly be sim­i­lar­ly good. The more proof these com­pa­nies can show at ma­jor med­ical meet­ings that pa­tients have last­ing re­spons­es, the eas­i­er it will be to over­come the pay­er and lo­gis­tic chal­lenges that have emerged in the ear­ly days of com­mer­cial launch. Gilead will al­so have some Man­tle cell lym­phoma and ALL da­ta.
  • To put it mild­ly, Cel­gene is hav­ing a bad year. Af­ter var­i­ous prob­lems have emerged from past BD deals, they des­per­ate­ly need the Juno ac­qui­si­tion to go smooth­ly. Or to say it in a glass-half-emp­ty kind of way, they can­not have this one blow up in their face too. For­tu­nate­ly, so far Juno da­ta has looked good. There will be a JCAR017 up­date at AS­CO in DL­B­CL and again at EHA. The key here is for it to con­tin­ue to look com­pet­i­tive with Gilead and No­var­tis and that no sur­pris­ing safe­ty is­sues arise.
  • There has al­so been talk this last week about an ab­stract from a Chi­nese group com­par­ing 4-1BB CAR-T (Kym­ri­ah) di­rect­ly to CD28 CAR-T (Yescar­ta) to see if one is bet­ter than the oth­er. Their con­clu­sion was that 4-1BB had en­hanced safe­ty, ef­fi­ca­cy, and ex­pan­sion. Per­son­al­ly, I think this study is flawed and I wouldn’t draw many con­clu­sions about U.S. prod­ucts from it.
  • We know a lot about CAR-T but still know lit­tle about TCRs. When will this ap­proach step up to the plate and have a break­out year? It is still too ear­ly for that, but look for da­ta from Adap­ti­m­mune tar­get­ing NY-ESO and MAGE-A10 and da­ta from NCI tar­get­ing HPV on­co­pro­teins to pro­vide some clues. The fact that Glaxo opt­ed to con­tin­ue their Adap­ti­m­mune col­lab­o­ra­tion is a pos­i­tive sign.

Cy­tokines

Mike Glad­stone

At­las Ven­ture’s Mike Glad­stone had the call of the year last De­cem­ber when he pre­dict­ed 2018 would be the Year of the Cy­tokine. We have since seen Bris­tol pay Nek­tar $1.85 bil­lion up­front to own es­sen­tial­ly 1/3 of its CD122 ag­o­nist and then last month Lil­ly came from out of nowhere to ac­quire Ar­mo for $1.6 bil­lion. The bi­ol­o­gy be­hind cy­tokines brings a fa­mil­iar­i­ty and com­fort fac­tor giv­en the decades it has been re­searched. Will to­day’s new ap­proach­es to har­ness­ing them be the first ma­jor break­through in the IO com­bo race? Al­ready this year $3B+ has been bet on it.

There is a ton rid­ing on the Nek­tar da­ta at AS­CO. Bris­tol is both in need of pos­i­tive news af­ter be­ing rout­ed by Mer­ck in 1L NSCLC at AACR and al­so must jus­ti­fy the cash they threw at Nek­tar to part­ner on this. Ear­ly da­ta at SITC looked stel­lar, but it was just that….ear­ly da­ta. How will the re­sponse rates hold up with more pa­tients on drug and in more types of can­cers? The ab­stract re­lease caused some ner­vous but­ter­flies and so we will have to look to the full AS­CO pre­sen­ta­tion for more com­fort. Nek­tar is host­ing a huge­ly im­por­tant an­a­lyst meet­ing on Sat­ur­day af­ter­noon that is not to be missed.

  • Ar­mo’s peg IL10 looked very com­pelling in pan­cre­at­ic can­cer, NSCLC and RCC. This ap­pears to be a very smart pur­chase by Lil­ly even con­sid­er­ing the ear­ly stage AR­MO is at and the high price of the deal. Will an­oth­er suit­or step up and make things in­ter­est­ing be­fore the June 22 ten­der dead­line?

Oth­er IO

  • Pri­vate­ly held Check­mate Phar­ma pre­sent­ed com­pelling da­ta from its TLR9 ag­o­nist dur­ing a ple­nary at AACR, but none of the pub­licly trad­ed TLR9 com­pa­nies (Dy­navax, Idera) have been able to match the ex­cite­ment. Why? Dy­navax trad­ed sharply down when in­vestors re­ex­am­ined the 60% ORR pub­lished in its ab­stract (PD1 naïve melanoma) af­ter re­al­iz­ing that 5 non-evalu­able pa­tients had been left out of the analy­sis. Will the high­er 60%+ num­ber turn out to be true as more da­ta is re­port­ed at the con­fer­ence?
  • It is al­ways im­por­tant when you get a first glimpse at clin­i­cal da­ta from a com­pa­ny with a unique new plat­form. Cy­tomX and its pro­body plat­form is that com­pa­ny at AS­CO 2018. Can they main­tain com­pa­ra­ble ef­fi­ca­cy to check­points while low­er­ing the tox­i­c­i­ties?
  • One of the biggest dis­ap­point­ments from the ab­stract re­lease day was Jounce and its ICOS ag­o­nist. While most on Wall Street threw in the tow­el, there are still a few be­liev­ers in this con­cept who are hang­ing on. The im­munother­a­py su­per­star founders of the com­pa­ny will be giv­ing a talk at an an­a­lyst event on Mon­day night. Jounce (and their part­ner Cel­gene) needs to walk out of Chica­go with some kind of pos­i­tive be­cause they have no oth­er as­sets (be­sides a PD-1) any­where near the clin­ic.
  • Mer­ck KGaA’s PD-L1/TGF-β trap fu­sion pro­tein looks promis­ing in HPV as­so­ci­at­ed can­cers and will be a much-dis­cussed tri­al. The TGF-β path­way and how it con­tributes to im­muno­sup­pres­sion is a hot top­ic in gen­er­al and there are a cou­ple of ab­stracts ad­dress­ing this. Ex­pect to see a few new com­pa­nies IPO soon with TGF-β pro­grams in their pipeline. One just hap­pened on Thurs­day.
  • Re­gen­eron might be the on­ly com­pa­ny (out of dozens) de­vel­op­ing a new PD-1 that re­al­ly mat­ters from a com­pet­i­tive stand­point. This is be­cause 1) they are Re­gen­eron and there­fore con­duct ter­rif­ic sci­ence and 2) they have done a good job of rac­ing theirs through the clin­ic. How does Cemi­plimab stack up against Keytru­da and Op­di­vo? Can they ac­tu­al­ly com­pete com­mer­cial­ly in ex­ist­ing in­di­ca­tions or will they have to set­tle for us­ing this as a com­bo de­vel­op­ment tool like every­one else?
  • I pre­dict that one fu­ture AS­CO will be the Year of Bi-specifics. We are not there yet, but watch for a hand­ful of ear­ly stud­ies this year to be­gin to set the stage.

Oth­er Ther­a­pies

  • There has been much an­tic­i­pa­tion for PARPs to shine in com­bi­na­tion with PD-1s, but the da­ta has been lack­ing so far. Why? Tesaro’s TNBC da­ta from TOPA­CIO doesn’t look much bet­ter than what we’d ex­pect to see with monother­a­py un­for­tu­nate­ly. Speak­ing of monother­a­py, QUADRA doesn’t seem to shake the ground in late stage ovar­i­an ei­ther. The com­pa­ny’s stock has prac­ti­cal­ly gone down every day for a year and many are wait­ing for it to get cheap enough to fi­nal­ly be ac­quired. That might not hap­pen at any price un­til they can demon­strate broad­er util­i­ty.
  • With Ro­va-T con­tin­u­ing its cold streak this year, we are look­ing to­wards oth­ers for pos­i­tive da­ta in SCLC. PD-1s, PARPs, and lur­binecte­din are pos­si­ble can­di­dates for this ter­ri­bly ag­gres­sive can­cer and huge un­met need.
  • An­ti­body-drug con­ju­gates are still a thing, though much less to­day than back in the glo­ry days when Roche was the dar­ling of AS­CO with T-DM1. Im­munomedics re­cent­ly filed its BLA for sac­i­tuzum­ab govite­can in triple-neg­a­tive breast can­cer. This us­es SN-38, the ac­tive metabo­lite of irinote­can, con­ju­gat­ed to Trop-2. Da­ta from their study pre­sent­ed at AS­CO will help us bet­ter un­der­stand the ap­prov­abil­i­ty and com­mer­cial vi­a­bil­i­ty of the drug.

Thanks a lot for your in­ter­est. These have been some of the things I am watch­ing and I hope it helps. Best of luck to all the com­pa­nies, re­searchers, physi­cians, and pa­tients who will no doubt make 2018 an­oth­er great AS­CO.


Brad Lon­car is an in­de­pen­dent in­vestor fo­cused on biotech­nol­o­gy. He can be reached on Twit­ter at @Brad­Lon­car.

Im­age: 2017 an­nu­al meet­ing. AS­CO

Part club, part guide, part land­lord: Arie Bellde­grun is blue­print­ing a string of be­spoke biotech com­plex­es in glob­al boom­towns — start­ing with Boston

The biotech industry is getting a landlord, unlike anything it’s ever known before.

Inspired by his recent experiences scrounging for space in Boston and the Bay Area, master biotech builder, investor, and global dealmaker Arie Belldegrun has organized a new venture to build a new, 250,000 square foot biopharma building in Boston’s Seaport district — home to Vertex and a number of up-and-coming biotech players.

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Novotech CRO Ex­pands Chi­na Team as Biotech De­mand for Clin­i­cal Tri­als In­creas­es up to 79%

An increase in demand of up to 79% for clinical trials in China has prompted Novotech the Asia-Pacific CRO to rapidly expand the China team, appointing expert local clinical executives to their Shanghai and Hong Kong offices. The company is planning to expand their team by 30% over the next quarter.

Novotech China has seen considerable demand recently which is borne out by research from GlobalData:
A global migration of clinical research is occurring from high-income countries to low and middle-income countries with emerging economies. Over the period 2017 to 2018, for example, the number of clinical trial sites opened by biotech companies in Asia-Pacific increased by 35% compared to 8% in the rest of the world, with growth as high as 79% in China.
Novotech CEO Dr John Moller said China offers the largest population in the world, rapid economic growth, and an increasing willingness by government to invest in research and development.
Novotech’s 23 years of experience working in the region means we are the ideal CRO partner for USA biotechs wanting to tap the research expertise and opportunities that China offers.
There are over 22,000 active investigators in Greater China, with about 5,000 investigators with experience on at least 3 studies (source GlobalData).

UP­DAT­ED: With loom­ing ‘apoc­a­lypse of drug re­sis­tance,’ Mer­ck’s com­bi­na­tion an­tibi­ot­ic scores FDA ap­proval on two fronts

Merck — one of the last large biopharmaceuticals companies in the beleaguered field of antibiotic drug development — on Wednesday said the FDA had sanctioned the approval of its combination antibacterial for the treatment of complicated urinary tract and intra-abdominal infections.

To curb the rise of drug-resistant bacteria and maintain the efficacy of the therapy, Recarbrio (and other antibacterials) — the drug must be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible gram-negative bacteria, Merck $MRK said.

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John McHutchison in 2012. Getty Images

The $1.1M good­bye: Gilead CSO John McHutchi­son is out as Daniel O’Day shakes up the se­nior team

Just a little more than a year after John McHutchison grabbed a promotion to become CSO at Gilead in the wake of Norbert Bischofberger’s exit, he’s out amid a shakeup of the senior team that is also triggering the departure of two other top execs.

Gilead stated that McHutchison “has decided to step down” from the job as of August 2nd. And their SEC filing notes that he’ll be getting a $1.1 million check to settle up on his contract.

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Thomas Gajewski, David Steinberg. (CRI, Pyxis)

Bay­er, Long­wood back star re­searcher's deep dive in­to the tu­mor mi­croen­vi­ron­ment for new I/O tar­gets

From PD-1 targeting to the RAS pathway to the STING complex, Thomas Gajewski has spent the past two decades of his career decoding the various ways the immune system can be unleashed to defend against cancer. So when the University of Chicago professor comes around to putting all his findings into a new platform for finding new targets, VCs and pharma groups alike pay attention.

“He’s been studying T cells for 20 years, plus he’s one of the world’s leaders if not the world leader in the space,” David Steinberg, partner at Longwood Fund, said. “Furthermore, let me add he did a lot of the foundational research and also some of the seminal clinical trials in the existing set of I/O agents. He understands the space really well, he understands the current strengths, and I think he understood really well what was missing, so he knew where to look.”

Kamala Harris speaking yesterday at the Des Moines Register Iowa Presidential Candidate Forum [via Getty]

Who’s the tough­est on drug prices? A game of po­lit­i­cal one-up­man­ship is dri­ving the pol­i­cy de­bate in Wash­ing­ton

Earlier this week we got a look at Senator Kamala Harris’ position on drug prices. She’s proposing that HHS take an average price from single-payer systems like the UK, Germany and Canada — which leverage market access for lower prices — and use that to set the US price. Anything drug companies collect above that would be taxed at a rate of 100%.

And the rhetoric is scathing:
While families struggle to make it to the end of the month, pharmaceutical companies are turning record profits. They’re spending nearly as much on advertising as R&D. They’re manipulating their market power to hike prices on lifesaving generic drugs. They’re making twice the profit of the average industry in America and still increased drug prices by 10.5% over the past six months alone. Meanwhile, they are charging dramatically higher prices to American consumers.
That’s an escalation on Joe Biden’s plan, which includes drug importation from those cheaper markets as well as allowing Medicare to negotiate prices — something that virtually all Dems agree on now.

SJ Lee [File photo]

Go­ing in­side cells, Sung Joo Lee has sketched some big goals for his small — but glob­al — team of drug hunters

For a small biotech based in South Korea with a research arm in Cambridge, MA, Orum Therapeutics has sketched out some big goals aimed at developing antibodies for intracellular targets. And now they have a new $30 million round to push the work forward, aiming at a slate of currently undruggable quests.

Orum has been working on a platform tech out of Ajou University that relies on endocytosis to smuggle antibodies and their cargo inside a cell. They’ve published work in Nature that illustrates its preclinical potential in RAS mutations, and KRAS is on their list of targets. 

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Astel­las buys in­to Fre­quen­cy's re­gen­er­a­tive med strat­e­gy with a $625M al­liance on hear­ing loss

The executive team at Frequency Therapeutics never oversold the results of their maiden Phase I/II study for a new drug to rectify hearing loss. It was, they said back in April, primarily about safety and tolerability, where their drug FX-322 performed as they had hoped. 

That early glimpse of efficacy everyone searches for in their first try on humans? 

(I)mprovements in hearing function, including audiometry and word scores, were observed in multiple FX-322 treated patients.

We don’t know exactly what that means. But whatever the details, Astellas found enough in the data to jump in with a sizable collaboration deal.

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H1 analy­sis: The high-stakes ta­ble in the biotech deals casi­no is pay­ing out some record-set­ting win­nings

For years the big trend among dealmakers at the major players has been centered on ratcheting down upfront payments in favor of bigger milestones. Better known as biobucks for some. But with the top 15 companies competing for the kind of “transformative” pacts that can whip up some excitement on Wall Street, with some big biotechs like Regeneron now weighing in as well, cash is king at the high stakes table.

We asked Chris Dokomajilar, the head of DealForma, to crunch the numbers for us, looking over the top 20 deals for the past decade and breaking it all down into the top alliances already created in 2019. Gilead has clearly tipped the scales in terms of the coin of the bio-realm, with its record-setting $5 billion upfront to tie up to Galapagos’ entire pipeline.

Dokomajilar notes:

We’re going to need a ‘three comma club’ for the deals with over $1 billion in total upfront cash and equity. The $100 million-plus club is getting crowded at 164 deals in the last decade with new deals being added towards the top of the chart. 2019 already has 14 deals with at least $100 million in upfront cash and equity for a total year-to-date of over $9 billion. That beats last year’s $8 billion and sets a record.

Add upfronts and equity payments and you get $11.5 billion for the year, just shy of last year’s record-setting $11.8 billion.

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