Sar­co­ma ex­pert George Demetri grades the lat­est state­ment on Nanobi­otix's late-stage drug NBTXR3

The first glance at Nanobi­otix’s re­cent round of da­ta for its drug NBTXR3 re­vealed pos­i­tive, but not pow­er­ful, da­ta when used against soft tis­sue sar­co­ma. The p val­ues were with­in the mark for sta­tis­ti­cal sig­nif­i­cance, but just bare­ly. So I asked sar­co­ma ex­pert George Demetri from Dana-Far­ber if he would take a look and give me his opin­ion.

Demetri took his dig­i­tal high­lighter and went to work on the biotech’s PR, scor­ing the re­sults and of­fer­ing re­marks on var­i­ous as­pects of the com­pa­ny state­ment that I found il­lu­mi­nat­ing. Rather than in­ter­pret them, I thought it would be more fun to re­pro­duce the whole thing here, with his com­ments high­light­ed in ital­ics.


NANOBI­OTIX An­nounces Pos­i­tive Phase II/III Topline Da­ta in Soft Tis­sue Sar­co­ma with NBTXR3

Paris, France and Cam­bridge, Mass­a­chu­setts, June 21, 2018 — NANOBI­OTIX (Eu­ronext: NANO – ISIN: FR0011341205), a late clin­i­cal-stage nanomed­i­cine com­pa­ny pi­o­neer­ing new ap­proach­es in the treat­ment of can­cer, an­nounced to­day pos­i­tive topline re­sults of the Phase II/III act.in.sarc tri­al eval­u­at­ing NBTXR3 in Soft Tis­sue Sar­co­ma (STS).

“Da­ta are ex­cep­tion­al and show with­out any doubt an im­prove­ment of ra­di­a­tion ther­a­py im­pact with a sig­nif­i­cant num­ber of com­plete re­sponse. NBTXR3 can bring re­al ben­e­fit to pa­tients and it can change the stan­dard of care. This in­no­va­tion will play a role in many oth­er in­di­ca­tions and par­tic­u­lar­ly where ra­dio­ther­a­py is used alone.”

GD: I think we re­al­ly need to be rig­or­ous about where the out­comes from LO­CAL THER­A­PY with ra­di­a­tion ther­a­py needs to be im­proved. Over­all, our ex­pe­ri­ence with pre-op ra­di­a­tion in sar­co­mas is that we de­pend up­on the ex­per­tise of the best sur­geons to do the very best they can. We gen­er­al­ly have great re­sults with surgery alone for pa­tients with lo­cal­ized dis­ease – but it re­al­ly is key whether these pa­tients were the very small sub­set of pa­tients where even the best sur­geons could not re­move the tu­mor with good out­comes.

Pr. Sylvie Bon­va­l­ot, MD, Head of Sar­co­ma and Com­plex Tu­mor Surgery Unit at In­sti­tut Curie, Paris, France and Glob­al Prin­ci­pal In­ves­ti­ga­tor of the PII/III study.

GD: She is an out­stand­ing sar­co­ma sur­gi­cal spe­cial­ist, and she un­der­stands this dis­ease VERY well, so this is very re­as­sur­ing ex­per­tise in these in­ves­ti­ga­tors.

NBTXR3 is a first-in-class prod­uct with a new mode of ac­tion phys­i­cal­ly de­stroy­ing can­cer cells when ac­ti­vat­ed by ra­di­a­tion ther­a­py. NBTXR3 is de­signed to di­rect­ly de­stroy tu­mors and ac­ti­vate the im­mune sys­tem for both lo­cal con­trol and sys­temic dis­ease treat­ment.

GD: It is a very in­no­v­a­tive tech­nol­o­gy and pro­posed mech­a­nism of ac­tion.

The Phase II/III study was a prospec­tive, ran­dom­ized (1:1), multi­na­tion­al, open la­bel and ac­tive con­trolled two-armed study of 180 pa­tients with lo­cal­ly ad­vanced STS.

GD: The key here is the ac­tu­al de­tails of these 180 pa­tients. “Lo­cal­ly ad­vanced” is a term that en­com­pass­es a very broad group of sar­co­ma pa­tients with vary­ing out­comes, es­pe­cial­ly con­sid­er­ing where the tu­mor is lo­cat­ed (trunk, ex­trem­i­ty, else­where) on the body.

The ob­jec­tive of the Phase II/III tri­al was to eval­u­ate the ef­fi­ca­cy and the safe­ty of NBTXR3 ac­ti­vat­ed by ra­dio­ther­a­py com­pared to the stan­dard of care (ra­dio­ther­a­py alone). Pa­tients have been treat­ed with the stan­dard dose of ra­di­a­tion (25×2 Gy) and ef­fi­ca­cy end­points have been mea­sured on sur­gi­cal­ly re­sect­ed tu­mors.

Pri­ma­ry end­point achieved in the in­tend-to-treat pop­u­la­tion (ITT)

The pri­ma­ry end­point is the patho­log­i­cal Com­plete Re­sponse Rate (pCRR) de­fined as the rate of pa­tients show­ing less than 5% …

GD: not 0%??? <5%? Why that cut­off? Just a mi­nor com­ment, but it shows some ques­tion about the pre-de­fined end­point.

… of resid­ual vi­able can­cer cells in the tu­mor post treat­ment. This pri­ma­ry end­point is re­lat­ed to NBTXR3’s mode of ac­tion and prod­uct ef­fi­ca­cy. Twice as many pa­tients (16.1% vs 7.9%) achieved a patho­log­i­cal Com­plete Re­sponse (pCR) with NBTXR3 com­pared to the con­trol arm (p = 0.0448).

GD: Just made it (whew) un­der the mag­i­cal p<0.05. Would have liked to have seen even high­er, but clear­ly there ap­pears to be a dif­fer­ence.

The sig­nif­i­cant dif­fer­ence ob­served be­tween both arms val­i­dates the su­pe­ri­or­i­ty of the treat­ment with NBTXR3 ver­sus ra­di­a­tion alone.

Sec­ondary End­point achieved in the ITT – Re­sec­tion mar­gins sta­tus and op­er­abil­i­ty

The main sec­ondary end­point is the re­sec­tion mar­gin sta­tus eval­u­at­ing the qual­i­ty of surgery. The main ob­jec­tive is to achieve com­part­men­tal clean mar­gins (neg­a­tive mar­gin de­fined as R0) i.e. no more can­cer cells found with­in the sur­gi­cal mar­gins. NBTXR3 demon­strat­ed a sta­tis­ti­cal­ly sig­nif­i­cant in­crease in R0 sur­gi­cal mar­gin rate com­pared to ra­dio­ther­a­py alone (rel­a­tive in­crease of 20%, p = 0.042).

GD: Just made it (whew) un­der the mag­i­cal p<0.05. Again, would have liked to have seen this even high­er as a dif­fer­ence, but there ap­pears to be a dif­fer­ence. This would be a re­view is­sue in the con­text of tox­i­c­i­ty de­scrip­tions, too.

The re­sec­tion with neg­a­tive mar­gins is a val­i­dat­ed sur­ro­gate end­point for sys­temic and long-term ben­e­fit for pa­tients such as lo­cal pro­gres­sion free sur­vival (PFS) and dis­tant PFS.

GD: Cer­tain­ly an as­so­cia­tive re­la­tion, if not causative.

Pr Jean-Yves Blay, MD, Di­rec­tor of the Cen­tre Léon Bérard, Ly­on, France, com­ment­ed, “I am amazed by the dif­fer­ence of Re­sponse Rate, it is ex­treme­ly un­com­mon to dou­ble the Rate of Com­plete his­to­log­i­cal Re­sponse and I do not see any oth­er strat­e­gy able to ac­com­plish that. Even more im­pres­sive is the R0 rate, which is in­creased by more than 20% com­pared to an av­er­age rate of 64%. This dif­fer­ence is re­al­ly im­pres­sive, con­sid­er­ing that R0 im­pacts pa­tients re­laps­es and sur­vival.”

GD: I have great pos­i­tive re­gard for my es­teemed col­league, Dr. Blay.

Safe­ty and fea­si­bil­i­ty

NBTXR3 demon­strat­ed a good lo­cal tol­er­ance among this pa­tient’s pop­u­la­tion. Find­ings showed a very sim­i­lar ra­di­a­tion-re­lat­ed safe­ty in both arms. The pa­tients in both the con­trol and test­ed arms of the study re­ceived the planned ra­dio­ther­a­py (dose and sched­ule).

GD: This is good news..

No­tably, fea­si­bil­i­ty and fol­low-up of surgery were al­so equiv­a­lent. Acute im­mune ad­verse events of short du­ra­tion ob­served in 7.9% of pa­tients.

GD: Was this dif­fer­ent across the ex­per­i­men­tal and con­trol arms? Need a tad more da­ta. Might be in­ter­est­ing (no, it WILL be in­ter­est­ing!) to com­bine this new strat­e­gy with im­muno-on­col­o­gy strate­gies, for sure.

The In­jec­tion site caused pain in 13.5% of pa­tients. In ad­di­tion, 6.7% of pa­tients ex­pe­ri­enced grade 1 in­jec­tion site hematoma / ec­chy­mo­sis.

Re­gard­ing long-term tox­i­c­i­ty, less se­ri­ous ad­verse events were re­port­ed for NBTXR3 arm.

GD: Re­al­ly in­ter­est­ing here. Small num­bers, but good news.

Reg­u­la­to­ry strat­e­gy and CE mark

The pos­i­tive re­sults from this study sup­port and fur­ther val­i­date the Eu­ro­pean reg­u­la­to­ry strat­e­gy of the pre­vi­ous­ly sub­mit­ted CE mark­ing ap­pli­ca­tion in STS. The com­pa­ny will sub­mit the new da­ta as a sup­ple­ment to the Eu­ro­pean No­ti­fied Body in a time­ly man­ner.

Next steps

The Com­pa­ny will present the re­sults at an up­com­ing in­ter­na­tion­al med­ical con­fer­ence.

The clin­i­cal val­i­da­tion of NBTXR3’s phys­i­cal mode of ac­tion in a very het­ero­ge­neous and hard-to-treat dis­ease strength­ens the uni­ver­sal pro­file of the prod­uct and con­firms the de­vel­op­ment strat­e­gy in mul­ti­ple in­di­ca­tions.

Cur­rent­ly, the com­pa­ny is eval­u­at­ing NBTXR3 in sev­en clin­i­cal tri­als with a fo­cus on head and neck can­cers and Im­muno-On­col­o­gy pro­grams.

GD: There it is.

David Raben MD, Pro­fes­sor of Ra­di­a­tion On­col­o­gy, Uni­ver­si­ty of Col­orado Can­cer Cen­ter, CO, USA, com­ment­ed, “These re­sults from a Phase III study are im­pres­sive in a no­to­ri­ous­ly dif­fi­cult dis­ease like Soft Tis­sue Sar­co­ma. These can­cers are gen­er­al­ly less sen­si­tive to ra­di­a­tion and pre­vi­ous at­tempts to im­prove lo­cal con­trol with chemo-ra­di­a­tion reg­i­mens were con­sid­ered too tox­ic. This study sub­stan­ti­ates the med­ical ben­e­fit of safe­ly en­hanc­ing the ef­fect of ra­di­a­tion ther­a­py with nov­el physics-based ap­proach­es de­liv­ered lo­cal­ly with­in the can­cer. In ad­di­tion, this prod­uct may po­ten­ti­ate a pro-in­flam­ma­to­ry en­vi­ron­ment suit­able for im­mune en­abling or DNA dam­age in­hibitor drugs. These find­ings set the foun­da­tion for ad­di­tion­al stud­ies in ar­eas such as head and neck can­cer and per­haps in ar­eas such as high-risk prostate, blad­der or pan­creas can­cer.”

GD sum­ma­ry: Cer­tain­ly will be a re­view is­sue, but over­all very fa­vor­able re­sults with an in­no­v­a­tive new tech­nol­o­gy that will be rel­e­vant for a sub­set of soft tis­sue sar­co­ma pa­tients. Look­ing for­ward to see­ing all the da­ta. 

Im­age: George Demetri. PHAR­MA­MAR via YOUTUBE

Eli Lil­ly’s first PhI­II show­down for their $1.6B can­cer drug just flopped — what now?

When Eli Lilly plunked down $1.6 billion in cash to acquire Armo Biosciences a little more than a year ago, the stars seemed aligned in its favor. The jewel in the crown they were buying was pegilodecakin, which had cleared the proof-of-concept stage and was already in a Phase III trial for pancreatic cancer.

And that study just failed.

Lilly reported this morning that their cancer drug flopped on overall survival when added to FOLFOX (folinic acid, 5-FU, oxaliplatin), compared to FOLFOX alone among patients suffering from advanced pancreatic cancer.

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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.
The biotech started by putting together an “arsenal” of technologies aimed at making cell therapies for cancer much, much better than the rather crude first-generation drugs that hit the market from Novartis and Kite.
Their drugs have become the baseline against which all others are being measured.
“The technology set we’re developing is independent of the chassis,” Drazan tells me. “It doesn’t have to be autologous (extracted from the patient) or allogeneic (off the shelf). It doesn’t have to be a T cell, it could be a B cell.” But they are starting out on the autologous side, where they have the most knowledge and insight into manufacturing techniques.
It also doesn’t have to be close to the clinic.
Drazan expects the biotech will be working its way through preclinical operations for “a few years,” with enough money from the $85 million launch round to get into humans.
By today’s superheated fundraising standards, that’s not a huge amount of cash. Lyell, another cell therapy 2.0 startup we featured last week, raised $600 million in a year, including a big chunk of cash from GlaxoSmithKline. Drazan is interested in dealmaking as well, but he also knows he has the cash necessary to support the company for a good run — a key part of what it takes to bring together a stellar team of top players.

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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?

UCB tries to win some re­spect in the crowd­ed pso­ri­a­sis mar­ket with a dual IL-17 ap­proach — and it won't be easy

For a pharma company with about $5 billion in revenue, a couple of respectably sized blockbuster drugs on the market and some high-profile partners like Amgen, Belgium’s UCB has kept an unusually low profile on the pipeline side of things over the years.
Until now.
Just days after striking a $2.1 billion deal to buy Ra Pharmaceuticals and its C5 rival to Soliris, UCB is posting positive top-line Phase III results for a dual IL-17 inhibitor that it’s steering into one of the most competitive commercial spaces in the industry. And despite plenty of obvious challenges as they struggle to roll out Evenity with Amgen and patent expirations loom on its franchise drugs, including Cimzia, the company just may be ready to tackle some of the biggest players on the planet.
In their first of 3 Phase III studies for bimekizumab, researchers touted top-line wins on statistically significant results on clearing plaque psoriasis, including a victory over J&J’s IL-23 contender Stelara on key endpoints. The drug targets both IL-17A and IL-17F, a modification on the IL-17A strategy laid out for Taltz (Eli Lilly) and Cosentyx (Novartis). And the new group also includes J&J’s Tremfya and AbbVie’s Skyrizi.
We don’t know the PASI90 and IGA scores — but UCB knows that with the kind of heavyweight competition it faces with Novartis and others, marginal gains for patients won’t stack up. So we’ll be watching for the hard numbers. And there’s another head-to-head with Cosentyx that will play a big role in pushing up analysts’ projections on peak sales, which currently fall well short of blockbuster status.
UCB hasn’t exactly been in the spotlight for the last few years, but it’s in a position now that the company has to win some respect in R&D, with blockbuster projects that can keep investors’ attention at a time the industry is experiencing booming R&D development efforts around the planet.
It hasn’t been easy. There was a setback on a lupus drug partnered with Biogen. But there have been some advances, with a deal to buy Proximagen’s NDA-ready nasal spray therapy USL261, designed as a rescue therapy for acute repetitive seizures, for $150 million in cash and another $220 million in sales and regulatory milestones. There was even a report that the company was kicking the deflated tires at Acorda, though nothing came of that.
Late last year UCB also committed to spend up to £200 million on a new R&D hub in the UK.
That may not translate into a lot of excitement right now, but they’re trying. And there’s a subtle promise that more deals may be in the works.

Swamy Vijayan. Plexium

San Diego up­start de­buts dis­cov­ery en­gine that puts a twist to pro­tein degra­da­tion

For years, the idea of protein degradation — utilizing the cell’s natural garbage disposal system to mark problematic proteins for destruction — remained an elegant but technically difficult concept. But now established as a promising clinical strategy, with major biopharma players such as Bayer, Gilead and Vertex trying to grab a foothold via partnership deals, a San Diego startup is looking to exploit it and push its limits.

CSL ac­cus­es ri­val Pharm­ing of par­tic­i­pat­ing in a scheme to rip off IP on HAE while re­cruit­ing se­nior R&D staffer

Pharming has landed in the middle of a legal donnybrook after recruiting a senior executive from a rival R&D team at CSL. The Australian pharma giant slapped Pharming with a lawsuit alleging that the Dutch biotech’s new employee, Joseph Chiao, looted a large cache of proprietary documents as he hit the exit. And they want it all back.
Federal Judge Juan Sanchez in the Eastern District Pennsylvania court issued an injunction on Tuesday prohibiting Chiao from doing any work on HAE or primary immune deficiency in his new job and demanding that he return any material from CSL that he may have in his possession. And he wants Pharming to tell its employees not to ask for any information on the forbidden topics.
For its part, Pharming fired off an indignant response this morning denying any involvement in extracting any kind of IP from CSL, adding that it’s cooperating in the internal probe that CSL has underway.

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