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

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

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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).

Daniel O'Day [via AP Images]

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Hal Barron [File photo]

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Monday morning we learned that the pharma giant is snapping up tiny Mavupharma out of Seattle, a Frazier-backed startup that has its own unique take on STING — which is on the threshold of their first clinical trial.

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The pharma giant reported early Monday that the FDA has rejected its blockbuster drug Farxiga for Type 1 diabetes that can’t be controlled by insulin. And while the pharma giant maintained its usual grim silence in the face of a setback, this one should be easy to interpret.