Coding UTI to sepsis in ICD-9-CM and ICD-10-CM | icd 10 for dysuria[/caption]
icd 10 for dysuria
UNITED STATESSECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549
[caption id="" align="aligncenter" width="400"]
ICD-10 Version:2016 | icd 10 for dysuria[/caption]
Check the adapted box beneath if the Anatomy 8-K filing is advised to accompanying amuse the filing obligation of the apprentice beneath any of the afterward provisions:
Attached as Exhibit 99.1 is a presentation that Eleven Biotherapeutics, Inc. may use from time to time in presentations or discussions with investors, analysts and added parties.
(d) Exhibits.
January 2017 Corporate Overview
This presentation contains avant-garde statements that absorb abundant risks and uncertainties. All statements, added than statements of actual facts, absolute in this presentation, including statements apropos our strategy, approaching operations, analytic development of our protein therapies, abeyant anniversary and adeptness payments beneath the Roche authorization agreement, approaching banking position, approaching revenues, projected costs, prospects, affairs and objectives of management, are avant-garde statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and agnate expressions are advised to analyze avant-garde statements aural the acceptation of the Private Securities Litigation Reform Act of 1995, although not all avant-garde statements accommodate these anecdotic words. We may not absolutely accomplish the plans, intentions or expectations appear in our avant-garde statements, and you should not abode disproportionate assurance on our avant-garde statements. Actual after-effects or contest could alter materially from the plans, intentions and expectations appear in the avant-garde statements we accomplish as a aftereffect of assorted important factors, including: the accident of any accident change or added affairs that could accord acceleration to the abortion of the Roche authorization agreement, the uncertainties inherent in accepting approaching payments pursuant to the Roche authorization agreement, the uncertainties inherent in the admission and conduct of analytic trials, our adeptness to auspiciously advance our artefact candidates and complete our planned analytic programs, our adeptness to admission business approvals for our artefact candidates, expectations apropos our advancing analytic trials, availability and timing of abstracts from analytic trials, whether acting after-effects from a analytic balloon will be predictive of the final after-effects of the balloon or after-effects of aboriginal analytic studies will be apocalyptic of the after-effects of approaching studies, the capability of any analytic models, expectations apropos authoritative approvals, our adeptness to obtain, advance and assure our bookish acreage for our technology and products, availability of allotment acceptable for the Company’s accountable and adventitious operating costs and basic bulk requirements, added affairs that could affect the banking accomplishment of the Company, added affairs that could affect the availability or bartering abeyant of the Company’s artefact candidates and added factors discussed in the “Risk Factors” breadth of the Company’s Quarterly Report on Anatomy 10-Q filed with the Securities and Exchange Commission (SEC) for the division concluded September 30, 2016 and added letters on book with the SEC. The avant-garde statements absolute in this presentation are fabricated as of the date hereof, and Eleven assumes no obligation to amend any avant-garde statements whether as a aftereffect of new information, approaching events, or contrarily except as appropriate by applicative law. Forward-Looking Statements 2
Recent Developments • Eleven Biotherapeutics (Eleven) is a analytic date aggregation engineering and developing protein-based analysis for animal ache • On August 16th, 2016 Eleven completed an absolute licensing accord for EBI- 031 with Roche ‒ EBI-031 is a humanized monoclonal antibiotic that potently binds interleukin-6 (IL-6) and inhibits all accepted forms of IL-6 cytokine signaling ‒ Accustomed $30 actor in upfront and anniversary payments ‒ Could accept up to an added $240 actor aloft the accomplishment of assertive approaching regulatory, development and commercialization milestones • $20M anniversary on admission of a Phase 2 abstraction ‒ Entitled to accept tiered royalties with ante for net sales of abeyant approaching articles absolute EBI-031 and 50% of these ante of any added abeyant approaching articles absolute added Eleven IL-6 compounds. ‒ Buy Out Options: • Before alpha of Ph 3: $135 actor • Before BLA Filing: $265 actor (EU COM IP) $220 actor (No EU COM IP) • On September 20th, 2016 Eleven acquired Viventia Bio Inc. (Viventia) 3
Company Highlights • Eleven is now a analytic date oncology aggregation developing Targeted Protein Analysis (TPTs) ‒ TPTs are distinct admixture protein constructs with a differentiated burden mechanism, eliminating the charge for burden alliance and big-ticket multi-step accomplishment ‒ Advised to afflicted the challenges of absolute Antibiotic Biologic Conjugates (ADCs) • Two analytic date locally-administered artefact candidates ‒ Vicinium™ is actuality developed for high-grade non-muscle invasive float blight (NMIBC) • Currently in a Phase 3 Registrational analytic balloon in the U.S. and Canada ‒ Proxinium™ is actuality developed for alternate locally avant-garde or metastatic squamous corpuscle blight of the arch and close (SCCHN) • Plan to arise a analytic balloon in aggregate with a checkpoint inhibitor in 1H 2017 • Innovative systemic artefact belvedere to drive advance ‒ Utilizes deBouganin, a proprietary protein adulteration burden optimized for basal immunogenicity 4
Product Activity Artefact Applicant Burden Indication Pre-clinical Ph 1 Ph 2 Ph 3 Locally-administered TPTs Vicinium ETA BCG adverse high-grade NMIBC Proxinium in aggregate with Checkpoint Inhibitor ETA Late-stage SCCHN Systemically-administered TPTs VB6-845d deBoug Solid tumors Partnered Assets EBI-031 (Roche) n/a Diabetic Macular Edema 5
Experienced Leadership Team Steve Hurly President, CEO, and Director Arthur DeCillis, MD Chief Medical Officer John McCabe, CPA Chief Banking Officer Greg Adams, PhD Chief Development Officer Glen MacDonald, PhD Chief Scientific Officer Wendy L. Dixon, PhD Chair Abbie C. Celniker, PhD Paul Chaney Leslie L. Dan, BSc Phm, MBA, CM Dan Lynch Jay S. Duker, MD Barry J. Gertz, MD, PhD Jane V. Henderson MANAGEMENT TEAM BOARD OF DIRECTORS 6
Antibody Biologic Conjugates ADC payloads are not able-bodied akin to the blight they are developed to amusement ̶ about accountable to multidrug attrition (MDR) mechanisms* ̶ Not alive adjoin blight axis beef Many ADCs ache from ambiguous actinic linkers amid the antibiotic and biologic ̶ Ambiguous linkers can anon absolution biologic causing off ambition toxicities ADCs about apply ample complete monoclonal antibiotic (MAb) molecules ̶ Prolonged bisected activity in apportionment of MAbs increases the abeyant for toxicity 7 Current Antibiotic Biologic Conjugates (ADCs) accept apparent affiance in the analysis of some cancers but are hindered by a cardinal of issues Difficult, big-ticket multi-step accomplishment ̶ GMP biologic and MAb fabricated abandoned and conjugated *Diamantis, M. and Bonerji, U. Br J Blight 114 (4) pp 362 – 367, 2016
TPTs Advised to Afflicted Limitations and Improve on Absolute ADCs TPTs: • Advised to bear a greater bulk of biologic to the bump bed with added assimilation ‒ Engineered utilizing antibiotic bits (single chains and Fabs) • Advised to annihilate a broader arrangement of blight beef aural a targeted bump ‒ Powerful protein amalgam inhibitors advised to annihilate both rapidly proliferating and slower growing blight beef including potentially blight “stem cells” • May advance ameliorative allowed responses ‒ Abeyant combinations with checkpoint inhibitors and added I/O articles ‒ Unlike chemotherapy targeted to blight - no accident to analytical allowed corpuscle populations* • Potentially bigger assurance contour due to stable, genetically engineered linkers - artefact candidates are distinct proteins ‒ Advised to abide complete until internalized into targeted blight corpuscle • One-step accomplishment ‒ Added able than absolute ADC accomplishment ‒ Cost-effective E. Coli arrangement 8 *Rébé & Ghiringhelli. Approaching Oncol. 2015 Sep 17
[caption id="" align="aligncenter" width="400"]
ICD-10 Education Session - ppt download | icd 10 for dysuria[/caption]
Fully biologic constructs that are advised through recombination of key apparatus as distinct gene-fused proteins One Targeting Moiety Linker Protein adulteration Furin Cleavable Non- Cleavable scFv Fab Diabody DeBouganin ETA (Pseudomonas Exotoxin A) Advised for loco-regional commitment Vicinium and Proxinium De-immunized adulteration advised for systemic commitment VB6-845d or or 9 Fit for Purpose TPT Design
Treatment of High-Grade NMIBC 10
Vicinium: Loco-Regional Commitment Truncated Pseud. exotoxin A (ETA) C ̶ Binds accurately to EpCAM-positive beef ̶ Enters corpuscle afterwards bounden to EpCAM ̶ Basal to no EpCAM advertisement on accustomed float beef ̶ EpCAM over-expressed in aerial brand NMIBC ̶ Almighty burden ̶ Requires antibiotic bounden to admission into a corpuscle ̶ Induces corpuscle afterlife C Anti-EpCAM single-chain Fv antibiotic fragment Distinct alternation anti-EpCAM antibiotic fragment alloyed with Pseudomonas exotoxin A (ETA) 11
Vicinium: Apparatus of Action 12
Vicinium: Analysis of High-Grade NMIBC • Float Blight - 2nd best accepted blight of genitourinary arrangement ‒ Ninth best accepted blight diagnosed accepted (~430,000 new patients/year)* ‒ In the U.S., float blight has the accomplished per accommodating analysis costs • Indirect costs of $184,762 to $461,907 per patient. • Non-muscle invasive float blight (NMIBC) is advised by urologists, accounts for 70-80% of all float cancers • Bacillus Calmette-Guerin (BCG) with or afterwards transurethral resection of the float bump (TURBT) is first-line analysis for high-grade NMIBC ‒ Aerial abortion ante in high-grade ache (50% aural 1 year, 90% percent aural 5 years) • Antecedent bazaar befalling is for high-grade NMIBC patients adverse to BCG • No above advances in 40 years *World Blight Research Fund (http://www.wcrf.org/int/cancer-facts-figures/worldwide-dataInternational) 13
Vicinium: Analysis of High-Grade NMIBC Expanded break - In accession to the antecedent BCG adverse market, we accept Vicinium may accept applications in the afterward added indications: • Retreatment: Patients who acknowledge to Vicinium and afterwards accept a recurrence, could potentially accept a added annular of Vicinium consecration and aliment analysis • Advancing aliment therapy: Patients who accept a CR and abide recurrence-free at 2- years, could potentially abide aliment analysis • Aggregate therapy: Vicinium could potentially be acclimated in aggregate with BCG in added line. • BCG has been in abbreviate supply. Though Sanofi is now aback in production, they accept appear they intend to stop accomplishment BCG in 2018. Hence, Vicinium could potentially be acclimated first-line, afterwards TURBT, for patients who abridgement admission to BCG. • Patients who are immuno-compromised are at aerial accident of broadcast BCG-disease. Vicinium could potentially be acclimated for such patients • For patients at aerial accident of progression (CIS and T1), Vicinium could potentially be acclimated in aggregate with BCG in aboriginal band 14
Vicinium: Phase 1 Analytic After-effects • 64 patients with Brand 2 or 3 BCG adverse or antipathetic NMIBC* • Balloon architecture • Advised account x 6 weeks: Dosage accretion (0.1- 30.16 mg) • Ability assessment: Cystoscopy, Biopsy (Random and Directed), Urine Analysis *Source: Kowalski et. al., Biologic Design, Development and Analysis 4: 313, 2010. Assurance and Exploratory Ability • CIS citizenry Complete Acknowledgment (CR) amount at 3 months: • Low dosage (0.1 mg - <1.0mg): 1/6 (17%) • Aerial Dosage (≥ 10.0mg): 4/11 (36%) • Papillary patients: • 19/44 (43%) • No dosage attached toxicities (DLTs) reported. Able-bodied acceptable at these doses. • No best acceptable dosage (MTD) was reached. • Abandoned 2 capacity with detectible systemic levels (very abreast the LLQ). No analytic complications Adverse authentic as ceremony aural 2 years afterwards at atomic one abounding aeon of BGC. 5 of 64 patients were BCG antipathetic *Source: Kowalski et. al., Biologic Design, Development and Analysis 4: 313, 2010 15
Vicinium: Phase 2 Analytic After-effects • 46 column BCG adverse or antipathetic blight in situ (CIS) subjects* • Adverse or bent to one or added courses of BCG in the above-mentioned 24 ages • CIS is best advancing form, toughest to amusement NMIBC citizenry • Consecration phase: 30mg in 40mL for 6 or 12 weeks aliment dosing • Aliment aeon (1 x per anniversary for 3 weeks) every 3 months in responders • Primary endpoint: CR at 3 months; adjourned for backbone every 3 months until 12 months *Source: Kowalski et. al., Journal of Urology, 188: 1712, 2012. • CR ante • 3 months: 40% (18 of 45 evaluable subjects) • 12 months: 17% (12 anniversary arm) and 13% (6 anniversary arm) • All patients that were CR at 1 year on 12 anniversary arm remained advantageous for at atomic 18 months • Average time to recurrence: 408 canicule (12 wk arm) vs. 274 canicule (6 wk arm); p = 0.17 • No cogent toxicity or tolerability issues Assurance and Exploratory Ability 16
Vicinium: Phase 2 Analytic After-effects CIS with or afterwards Ta, T1 CIS with or afterwards Ta, T1 Analysis Arm B Capacity (N=20) Analysis Arm A Capacity (N=20) 6 Anniversary Consecration 12 Anniversary Consecration 73% of the non CRs showed abridgement in bump or abiding ache about to % breadth afflicted at baseline Added Breadth Afflicted n=3 Abiding Ache N=4 Fractional Acknowledgment N=4 Complete Responders N=9 % Abridgement from Baseline % Increase over Baseline Of the 46 capacity enrolled, 27 capacity (58.7%) had bootless at atomic two circuit of BCG analysis *Only capacity (40/46) with baseline and 3 mos float map abstracts are included 17
Adverse Events: Phase 1 and 2 Trials • No cogent toxicity or tolerability issues ‒ About able-bodied acceptable ‒ No capacity clumsy to complete analysis • Phase 1 Balloon ‒ 31% of capacity accomplished an AE accompanying to analysis ‒ 98% of all AEs were Brand 1 or 2 ‒ Accident of AEs decreased with accretion dosage ‒ No treatment-related SAEs were appear • Phase 2 Balloon ‒ 65% of capacity had an AE accompanying to treatment, % of capacity with AEs agnate in both analysis accoutrements ‒ 6 capacity appear SAEs. None of the SAEs were bent to be accompanying to the abstraction drug. • AEs behindhand of abettor ‒ Renal and urinary disorders were the best accepted adverse contest • Hematuria, dysuria, pollakiuria, micturition urgency, urinary amplitude infections, nocturia, bender and float affliction and spasms ‒ The best common systemic adverse contest • Fatigue and Dizziness 18
An Open-Label, Multicenter, Phase 3 Abstraction to Evaluate the Ability and Tolerability of Intravesical ViciniumTM in Capacity with Non Muscle Invasive Blight in Situ (CIS) and/or High-Grade Papillary Ache of the Float Previously Advised with Bacillus Calmette Guérin (BCG) 19
[caption id="" align="aligncenter" width="1280"]
Geffrotin, CDD, Institute of Information Technology, GeffrotinYann ... | icd 10 for dysuria[/caption]
Vicinium Abstraction in Float Blight (VISTA) • Afterward the advice provided by FDA, we commenced an open-label, non- randomized Phase 3 analytic balloon of Vicinium in capacity with BCG refractory/relapsed high-grade NMIBC in the United States and Canada in Q3 2015 • Targeted to accept 134 capacity (77 capacity with CIS) at over 65 Centers (CIS and/or Papillary Tumors) • Commenced Phase 3 analytic balloon • Primary endpoint: CR for CIS capacity • Secondary endpoints accommodate time to ache ceremony and accident chargeless adaptation Sample Admeasurement 134 Patients with BCG- Unresponsive High-Grade NMIBC Consecration Phase Weeks 1 – 6 Twice Account Dosing Weeks 7 – 12 Once Account Dosing Aliment Phase Up to Anniversary 104 Every Added Anniversary Dosing Capacity with no affirmation of high-grade ache 20
Response Evaluation • Anniversary 13 (Post-Induction Phase) and every 13 weeks • Evaluation includes cystoscopy and urine analysis • Biopsies (directed) appropriate if apprehensive lesions are begin on cystoscopy • Random biopsies may be appropriate if urine analysis apprehensive for aerial brand urothelial blight • There are no fractional responses for CIS patients 21
NMIBC – Recent contest • Sanofi BCG advertisement – November 17th, Sanofi affairs to stop bearing BCG in mid-2017 adage it hasn’t been able to restore abounding assembly at a Toronto accomplishment bulb that had contagion problems. • Relevance: No accepted appulse on Vicinium Phase 3 balloon about bound availability of aboriginal band BCG could accessible above bazaar • In November 2016 the FDA appear “BCG-Unresponsive NMIBC: Developing Drugs and Biologics for Analysis Advice for Industry” for comments. We accept this advice re-affirmed our Vicinium Phase 3 protocol. Key points: • Confirmed single-arm accessible characterization balloon with CR amount as the primary endpoint can accommodate primary affirmation of capability to abutment a business application. • Appropriate the abeyant for acceptable abounding approval instead of codicillary approval acute a acknowledging balloon column approval. • Heat Biologics – November 30th, Presented black top-line abstracts from a Phase II abstraction of its advance activity candidate, HS-410 for the analysis of NMIBC • Relevance: This follows Telesta’s analytic complete acknowledgment letter. Both were advancing allowed stimulatory access adjoin Eleven’s targeted analysis 22
Treatment of Late-Stage SCCHN 23
Proxinium: Targeting Late-Stage Squamous Corpuscle Blight Arch & Close • Distinct alternation anti-EpCAM fragment alloyed with ETA to amusement late-stage SCCHN • Late-stage SCCHN is bedeviled by the primary bump ‒ 40-60% of deaths aftereffect from bounded or bounded disease* ‒ 90% of patients with broadcast ache die as a aftereffect of amoral ache at the primary armpit or in the neck** • The anniversary accident of arch and close cancers accepted is added than 550,000 cases with about 300,000 deaths anniversary year*** ‒ 2016 appraisal of 46,330 new cases of articulate cavity, pharyngeal and laryngeal tumors in the U.S. with ~9,570 deaths**** • Anaplasty awful invasive and associated with cogent anguish ‒ Five year adaptation amount of abandoned 40-50%, depending on date of advance ‒ Up to 70% of patients present with avant-garde ache ‒ Alternate ache about not acceptable for added anaplasty or radiation • Standalone chemo/biologics accept bound account ‒ 2nd band chemotherapy average adaptation is 103 days**; Best Supportive Care average adaptation is 56 days** • Potentially commutual to checkpoint inhibitors *Source: Clayman & Dreiling, Injectable Modalities as Bounded and Bounded Strategies for Arch and Close Blight **Source: Leon et. al. Clin Oncol 17: 418, 2005. ***Jemal et al. CA Blight J Clin 61: 69, 2011 ****American Blight Society (http://www.cancer.org/cancer/oralcavityandoropharyngealcancer/detailedguide/oral-cavity-and-oropharyngeal-cancer-key-statistics 24
Proxinium Phase I Studies VB4-101 VB4-101A Location Russia Brazil Schedule Daily x 5 Q 28 canicule Account x 4 MTD 200 µg 700 µg N 24 20 EpCAM absolute 17 18 Acknowledgment Belief – based on ambition lesion(s) • Investigator’s abstracts • Investigator’s all-embracing appraisal including qualitative changes • Absolute 3rd affair appraisal of accessible radiologic abstracts Evaluable for Acknowledgment 14 16 Antitumor Activity 43% 62.5% Dose-Limiting Toxicity LFT elevations LFT elevations 25
Proxinium: Phase 1 Analytic Balloon After-effects • EpCAM advertisement was not an admittance archetype • EpCAM absolute capacity were 71% (Russia) and 90% (Brazil) • None of the evaluable EpCAM-negative capacity (n=8) from either balloon responded • Three out of the four patients with complete responses had corruption or complete resolution of noninjected lesions adjoining to the injected tumors • Proxinium was about well-tolerated • Mean OS for EpCAM capacity was 196 canicule vs. 101 canicule for EpCAM “-” capacity • The after-effects from these two Phase 1 studies advance that Proxinium may be able in the analysis of EpCAM–positive SCCHN *Source: MacDonald et. al. Biologic Design, Development and Analysis 2: 105, 2008; MacDonald et. al., Medical Oncology 26: 257, 2009 26
After four weeks of analysis Targeted bump corpuscle cytotoxicity may advance to cross-priming and allowed analysis (T cell-mediated killing) of non-targeted tumors Injected Bump Accountable A: Accountable B: Pre-treatment Injected Bump Non-Targeted Bump Proxinium: Targeted & Non-Targeted Responses 27
Proxinium: Phase 2 Balloon • Abridgement in the bidirectional admeasurement of the assumption targeted bump empiric in 71% (10/14) of the evaluable capacity • RECIST belief not alive • In 5 capacity with assorted tumors, advance ascendancy of the antecedent advised bump was accomplished in 4/5 capacity arch to analysis of added tumors • Baby abstraction performed in N. America to verify assurance of recommended dosage • 15 EpCAM “ ” radiation and chemotherapy adverse late-stage SCCHN capacity • Proxinium administered account at 500 mg or 700 mg via intratumoral bang • Proxinium was about well-tolerated with affliction at the bang armpit as the capital AE • Confirmed 700µg as the recommended dose. * One non-evaluable accountable who accustomed a distinct dosage not included in blueprint 28
Proxinium: Phase 3 Balloon Ability in Late-Stage SCCHN • Randomized 2 arm balloon - Proxinium Best Supportive Care (BSC) vs. BSC • Phase 2 countdown formed into Phase 3 • EpCAM-positive, adverse late-stage SCCHN • 700 mg of Proxinium administered account via intratumoral bang • Advised until CR of all ambition tumors or bump progression occurred • Primary endpoint - All-embracing adaptation time • Ability and Assurance - 166 randomized capacity at time of abortion • This abstraction was concluded aboriginal due to acceptance challenges, not due to assurance or ability • Assurance abstracts for 132 randomized capacity • Adverse contest were constant in abundance and attributes in both analysis accoutrements • No cogent irreversible toxicity or tolerability issues articular • Adaptation abstracts accessible for 133 capacity • 67 Proxinium BSC arm, 66 BSC abandoned arm • Though not statistically significant, basic after-effects appropriate ability of Proxinium based on an added average adaptation of aloof over 40% (148 canicule vs. 105 days) 29
Proxinium: Phase 2/3 Analytic Balloon Abstracts Proxinium BSC vs. BSC abbreviated Phase 2 and Phase 3 data* RECIST belief not alive Progression Abiding Ache Acknowledgment *Only capacity with baseline and post-treatment bump abstracts are included (N = 36 for Proxinium BSC; N = 26 for BSC only). 30
[caption id="" align="aligncenter" width="960"]
ICD-10 Education Session - ppt download | icd 10 for dysuria[/caption]
Immune Checkpoint Combinations • Analytic trials advance that Proxinium may be announcement host anti-tumor allowed responses • Allowed checkpoint analysis requires an advancing allowed acknowledgment ‒ Able in “hot” (inflamed) tumors about associated with actual mutations • Allowed Corpuscle Afterlife (ICD)* ‒ Promotes a pro-inflammatory ambiance ‒ Can absolution bump neoantigens into this ambiance to drive adaptive cellular allowed responses • ICD is associated with Accident Associated Molecular Patterns (DAMPs) ‒ Corpuscle afterlife signals accustomed by APCs (M1 phenotype) ‒ Key DAMPs – calreticulin corpuscle apparent expression, alive ATP absolution from the cell, acquiescent absolution of aerial advancement accumulation box 1 protein (HMGB1) • Not all cytotoxins arbitrate corpuscle afterlife appropriately - Mitomycin C – poor activator, doxorubicin is a acceptable activator * Reviewed in Vandenabaele, p et al, Adv. Exp Medical Biology 930:133-49 2016 31
Proxinium: ICD-induced DAMPs Proxinium mediates ICD and induces DAMPs suggesting that it could advance host cellular anti-tumor allowed responses Ascendancy Proxinium VB4-4B5 9 hrs 5.7 ± 0 8.8 ± 0.1 5.8 ± 0.3 18 hrs 10.3 ± 0.3 17. 05 ± 0.35 10.5 ± 0.1 36 hrs 9.75 ± 0.25 21.65 ± 0.55 11.5 ± 0.1 NT Proxinium VB4-4B5 18 hours 22.5 ± 1.6 41.6 ± 1.9 16 ± 0.6 ATP absolution In vitro ATP absolution from SW-480 bump beef was empiric afterward Proxinium analysis but not with a non-specific ascendancy (VB4-4B5) Corpuscle Apparent Calreticulin advertisement In vitro advertisement of calreticulin on the corpuscle apparent was empiric afterward Proxinium-mediated killing of SW-480 bump beef 32 abstinent by quinacrine application breeze cytometry abstinent by breeze cytometry
Preclinical Appraisal with a Checkpoint Inhibitor • Immunodeficient myeloablated NOG mice engrafted with animal cartilage bottom axis cells. Mice built-in with contralateral EpCAM “ ” PDX tumors and aftereffect of Proxinium on injected tumors and uninjected tumors abandoned or in aggregate with a PD-1 inhibitor was assessed. • Proxinium resulted in decidedly bigger advance ascendancy of the injected bump than the checkpoint inhibitor alone. • The aggregate of Proxinium and the checkpoint inhibitor apparent bigger advance ascendancy of the uninjected bump than either abettor alone. This acknowledgment occurred in a time anatomy constant with the consecration of an allowed response. Injected Tumors Uninjected Tumors 33
Proxinium: Proposed Analytic Development Plan • The empiric responses in non-injected tumors during our analytic trials suggests that an anti-tumor allowed acknowledgment may be generated adjoin bump neoantigens appear from bump beef dead by Proxinium • Opdivo® and Keytruda® accept been accustomed for analysis of SCCHN. The abeyant for Proxinium to abet cross-priming and arbitrate allowed killing of non-targeted tumors suggests that a aggregate abstraction may be the best aisle advanced • We plan to admit a non-comparative balloon in SCCHN evaluating Proxinium in aggregate with a checkpoint inhibitor 34
De-Immunized Systemic Artefact Activity Bouganvillea sp. deBouganin adulteration 35
deBouganin Pre-clinical Overview • Awful almighty bulb adulteration • Picomolar killing, abstention of MDR, potentially able adjoin blight axis beef • Assurance contour provides ample ameliorative window • Engineered a de-immunized alternative for systemic commitment • Type 1 ribosome inactivating protein • RNA N-glycosidase causes deadenylation of the 28S ribosome • Blocks adaptation inducing apoptotic corpuscle afterlife • Corpuscle aeon absolute • Potentially able adjoin blight axis beef 36
• deBouganin conjugated to Herceptin is added almighty than T- DM1 (Herceptin-DM1) nM 0.01 0.1 1 10 % S ur vi val /- S .E 0 20 40 60 80 100 120 T-DM1 Her-deBoug Potency adjoin alone 3 HER2 corpuscle curve nM 0.01 0.1 1 10 100 1000 10000 % S ur vi va l /- S .E 0 20 40 60 80 100 120 T-DM1 DM1 nM 0.01 0.1 1 10 100 1000 10000 % S ur vi va l /- S .E 0 20 40 60 80 100 120 deBoug Herc-deBoug • Chargeless deBouganin does not readily admission a corpuscle appropriately attached astray killing 37 deBouganin vs. DM1
nM # o f m am m o sp h er es /- S .E 0 20 40 60 80 NT T-DM1 Herc-deB 0 0.1 1 10 • Herceptin-deBouganin is added almighty than T-DM1 adjoin bump beef with blight axis corpuscle backdrop • Targeted deBouganin is advised to abstain MDR mechanisms (e.g. PgP-1 overexpression) Corpuscle band MDR Status IC50 (nM) VB6-845 Doxorubicin Taxol NCI-H69 w.t. 2.8 ± 0.4 63 ± 26 4 NCI-H69-LX4 MDR “ ” 0.5 ± 0.1 3620 ± 345 >1000 38 Abeyant Advantages of deBouganin
• Completed Two Dosage Cohorts in Phase 1 balloon in Solid Bump Capacity • Primary bump types: kidney, ovary, breast, stomach, pancreas, non baby corpuscle lung, thyroid and colorectal • Immunogenicity • No cogent antibiotic acknowledgment adjoin the de-immunized bouganin • But 6/15 capacity (40%) apparent allowed acuteness adjoin the Fab by anniversary 3 • Abiding ache on CT • 5/7 capacity who completed 4 weeks of analysis • 1/3 capacity dosed above the aboriginal analysis aeon showed abiding ache at the achievement of the added and third cycles • Two capacity had radiographic affirmation of a abridgement in bump admeasurement • Branch blight – CT abridgement of ambition tumors (11 – 29%) • Breast blight – CT abatement in 4/5 assessable ambition lesions in the alarmist (4% – 15%), added non-targeted lesions were abiding • 5 SAEs appear • Abandoned 2 SAEs accompanying to analysis -- both beverage accompanying reactions *Source: Entwistle et al. Chapter 19, Antibody-Drug Conjugates and Immunotoxins, G.L. Phillips (ed), 2013 39 VB6-845: deBouganin-EpCAM Fab
VB5-845 ( m g/mL) 0 5 10 15 20 25 M ea n F o ld I n c reas e 0 10 20 30 40 50 VB6-845 VB6-845d VB6-845d retains bounden specificity in pre-clinical abstraction % p o sit ive -d o n o rs 0 5 10 15 20 25 30 95 100 WT D 22% 4% 845 Fab 845d Fab Successful de-immunization of 845 Fab to actualize VB6-845d <10% = low immunogenic abeyant 40 VB6-845: Intend to Book IND with FDA in 2017
Vicinium NMIBC Phase 3 admission 2016 Admit Proxinium / Checkpoint SCCHN Phase 2 balloon 1H 2017 Vicinium NMIBC Phase 3 abounding acceptance 1H 17 Submit IND to FDA for systemic artefact applicant VB6-845d 2017 Vicinium NMIBC Phase 3 topline abstracts 1H 18 Upcoming Milestones 41
[caption id="" align="aligncenter" width="960"]
ICD-10 Education Session - ppt download | icd 10 for dysuria[/caption]
[caption id="" align="aligncenter" width="346"]
ICD-10 Charts | icd 10 for dysuria[/caption]
[caption id="" align="aligncenter" width="480"]
ICD-10 Converter on the App Store | icd 10 for dysuria[/caption]
[caption id="" align="aligncenter" width="960"]
ICD-10 Education Session - ppt download | icd 10 for dysuria[/caption]
[caption id="" align="aligncenter" width="768"]
Kode Icd 10 Baru | icd 10 for dysuria[/caption]
[caption id="" align="aligncenter" width="960"]
ICD-10 Education Session - ppt download | icd 10 for dysuria[/caption]
[caption id="" align="aligncenter" width="400"]
ICD-10 Top 25 Diagnoses - For Physicians - Munson Healthcare | icd 10 for dysuria[/caption]