Cmmercialisatin f nanmaterials: prcess, issues, and management June 7, 2017 Taking a nan-based medical prduct t the internatinal market
The Unmet Need The glbal incidence f breast cancer is 1.7m annually and is the leading cause f cancer death in wmen Breast cancer incidence is prjected t reach 3.2m by 2030 due t cntinued demgraphic changes* When cancer is cnfirmed, it s stage must be established t decide nextsteps fr treatment T 1-4 N 0-3 M 0-1 system (Tumur, Ndes, Metastasis) Sentinel lymph nde bipsy (SLNB) is the best methd fr staging ndes Hwever, nly 1 in 6 patients glbally receives the gld-standard f care *Ginsburg, O. et al. The glbal burden f wmen s cancers. The Lancet (2016). di:10.1016/s0140-6736(16)31392-7
Breast Cancer and Lymphatics When a tumur spreads, its cells are carried away by the interstitial fluid f the lymphatic system Axillary lymph nde dissectin (ALND) was the riginal surgical methd fr determining whether cancer had spread Arund 30 lymph ndes were surgically remved fr histlgical examinatin
NSABP B-32 Trial (May 1999 t Feb 2004) A sentinel lymph nde bipsy (SLNB) is where nly 1-2 lymph ndes are remved and analysed The Lancet, Octber 2010: Results frm 5,611 wmen acrss 80 Nrth American institutins Cnfirmed equivalent survivability at 5 years between patients with SLNB and thse with ALND established SLNB as the gldstandard f care
SLNB is superir fr patients Surgical cmplicatins Lymphedema at 5 years (subjective assessment) Lymphedema at 5 years (bjective assessment) Decreased range f mtin at 5 years Axillary paresthesia at 5 years Incidence 0% 20% 40% 60% 80% 100% Axillary clearance Sentinel nde bipsy Surgical cmplicatins including wund infectins and sermas greatly reduced with SLNB versus axillary clearance 1 Key measures f mrbidity five years after surgery als all significantly lwer fr SLNB 2 1. Lucci, A, et al. Surgical Cmplicatins Assciated With Sentinel Lymph Nde Dissectin (SLND) Plus Axillary Lymph Nde Dissectin Cmpared With SLND Alne in the American Cllege f Surgens Onclgy Grup Trial Z0011, JCO August 20, 2007 vl. 25 n. 24 3657-3663 2. Teshme M, Ballman KV, McCall LM, et al: Lng-term incidence f lymphedema after sentinel lymph nde dissectin fr early stage breast cancer: ACOSOG Z0010 (Alliance). 2014 SSO Cancer Sympsium.
The Availability Issue The traditinal technique injects a radiistpe that is filtered ut by the nde, and then lcated using a gammaray detecting prbe Hwever, radiistpes limit availability: Unreliable supply chain Shrt 6-hur half-life Subptimal wrkflw
Radiistpe Shrtage Apr 2014 OECD Reprt n the supply f medical radiistpes In Eurpe, prcessing capacity is particularly limited Glbal prcessing capacity is insufficient t ensure secure supply f 99 M/ 99m Tc in the perid thrugh 2020
Endmag s Plan Replace the radiistpe-labelled cllid with a magnetic nanparticle f similar dimensins Remves a material with a half-life, imprving availability and wrkflw Reduces radiactivity frm the OR and hspital waste stream Prvides the ptential fr a reliable and rbust supply chain Replace the gamma-ray detectin prbe with a magnetic prbe t lcate the magnetic nanparticles taken by the sentinel lymph ndes
System Requirements Our target: T meet the clinical need, we needed t detect 100 µg f a nanparticulate magnetic tracer at a distance f 20 mm frm the tip f a handheld prbe Our calculatins: We required a stimulated respnse (susceptmetry), and the ability t discern a 60 pt change n tp f a magnetising field f 50 µt a 1 ppm challenge
Sentimag Sentimag s handheld prbe is directinal, and indicates prximity by an increase in signal value and audi pitch Received CE mark apprval in Dec 2010
Early Develpment Crisis Irn xide MRI cntrast agents varied frm market t market acrss the wrld Mre cncerning was that irn xide agents started disappearing frm the market due t cmpetitin with gadlinium and, by Jan 2011, the nly agent available in the EU was discntinued Endmag needed t develp smething quickly! Bnus challenge: all MRI cntrast enhancement agents are regulated as drugs
What We Knew Dextran-cated irn xide nanparticles were retained in the lymph nde sinuses Particles didn t appear t transit t higher echeln ndes (~100nm diameter) But, the rate f transit t the first nde was nt ideal fr impatient surgens
Nanparticle Selectin Endmag investigated lymph nde sinus structure and identified an ideal diameter in the range f 40-80nm Missin was t develp r surce a sub-22nm irn xide particle with a bicmpatible cating that increased its diameter t ~60nm Ultimately surced a material that had a lng safety histry, but as an MRI cntrast agent a drug
Regulatry Challenges All MRI cntrast enhancement agents are regulated as drugs Hwever, Article 1(2)(a) f the Medical Device Directive 93/42/EEC (MDD) suggested that Sienna culd be classed as a medical device as it achieves its primary intended actin withut emplying pharmaclgical, immunlgical r metablic means Endmag initiated a pre-clinical investigatin t evaluate the mechanism f transprt and retentin in the lymph nde Magnetic signal at draining lymph nde vs time after injectin f Sienna at the third inguinal papilla in a prcine mdel
Mechanism f Actin Due t its particle size, Sienna+ is taken up int lymphatic vessels with the nrmal flw f lymph and flws t the lymph ndes Pre-clinical and clinical studies shwed transit t the nde in minutes. Only free transprt culd accunt fr this rapid uptake. Cell trafficking experiments shwed peripheral immune cells reaching the ndes nly after a number f hurs at the earliest.
Sienna+ Apprval Eurpe In Jul 2011, the MHRA agreed that Sienna culd prceed fr evaluatin as a Class IIa medical device Successful frmulatin, manufacturing and technical file audit supprted CE apprval in Dec 2011 making Sienna the first marketed nanparticle medical device
Manufacturing Challenges With CE apprvals in hand, clinical trials started in Feb 2012 On Mar 2 nd, the Sienna+ packager stated that the 6-mnth accelerated stability tests had failed visual inspectin due t particulates bserved by tw analysts Trial was halted while the nature and rt cause f the particulates was investigated An independent test huse cnfirmed the particulates were cttn/rayn fibres, and rt cause analysis indicated the likely surce was the packagers prcess The particulates were assessed as lw-risk as they were infrequent, nn-txic and the sterility f Sienna+ was nt cmprmised Ntified bdy accepted inclusin f pre-injectin filtratin needles
Sienna+ Apprval USA In Sep 2013, the FDA als accepted a device primary mde f actin, paving the rute t an Investigatinal Device Exemptin (IDE) and a multi-site pivtal trial that cmpleted in Dec 2015 PMA review is underway, and Sienna+ is likely t be the first apprved nanparticle medical device in the US later in 2017
Sienna+ Designed fr sentinel nde lcalizatin Magnetic nanparticles ptimized fr lymph nde uptake regulated as a device Reslves availability f the standard f care Imprves prcedural cnvenience Puts the surgen in cntrl Over 20,000 breast cancer prcedures perfrmed CE, CMDCAS and ARTG apprved FDA PMA expected late 17* *USA: Sienna+/Sentimag are limited t investigatinal use nly under an FDA-apprved IDE
Clinical Summary Results summary including >1,000 breast cancer patients
Epilgue Headquartered in Cambridge after spinning ut frm UCL and the University f Hustn in 2007 Revenue-stage with multi-digit grwth ver last 4 years, fllwing investments ttaling 9m Nrth America (Jul 2016) 2016 sales at 1.6m via strategic distributin partnerships, with 2017 cmmitted at ~ 4m Treated >20,000 breast cancer patients acrss 30 cuntries since launching in Nv 2012 EMEA (Feb 2013) Expanding internatinal IP prtfli f 15 patent families with 11 patents currently granted
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