New developments in dialysis membranes for chronic HD patients. What will bring the near future?

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1 New developments in dialysis membranes for chronic HD patients. What will bring the near future? Pr L. JUILLARD Département de Néphrologie, H. E. Herriot, Hospices Civils de Lyon, Lyon. INSERM U1060, Carmen, Université de Lyon, Lyon. COMEDIMS HCL

2 THE CURRENT SITUATION IN DIALYSIS CARE

probability 0,9 0,8 0,7 0,6 0,5 0,4 0,3 1991-1995 0,2 1996-2000 0,1 2001-2005 2006-2010 0 0 1 2 3 4 5 Years since

3 UNMET NEEDS Patient Survival: Incident Dialysis Patients 1 Mortality in HD remains high with current dialytic therapies, in particular due to cardiovascular events with inflammation as a strong risk factor Survival probability 0,9 0,8 0,7 0,6 0,5 0,4 0, , , Years since start of dialysis 2104 ERA-EDTA Annual Report Available at:

4 Dialysis 5-year survival is comparable to a selected range of malignancies year survival of incident European dialysis and renal transplant compared with selected malignancies 87,9 5-year survival (%) ,3 72,4 69,7 21,9 49,0 48, ,5 0 All sites Breast cancer Prostate cancer Stomach cancer Lung cancer Colon cancer Dialysis Transplant (deceased donor) The EUROCARE-5 database on cancer survival in Europe 1 ERA-EDTA 2014 registry 2 Available at: table B.6.5.6b & table A.5.1

5 Cardiovascular events remain a significant cause of dialysis mortality (A) All-cause and (B) cardiovascular (CV) mortality rates in the Australian (Aus), European (Euro), and US dialysis and general populations (Gen Pop). Roberts October et 3, al, 2017 AJKD 2011;58(1):64-72 Baxter Internal Use Only 5

6 VASCULAR CALCIFICATION AND ATHEROSCLEROSIS Specific vascular lesions in CKD Mathew et al. Kidney International 2017; 91:

7 Inflammation is a significant factor leading to progression of cardiovascular disease and poor outcomes Co-morbidities Retention of uremic solutes Infectious complications Inflammation Oxidative stress Reduced appetite Increased catabolism Endothelial dysfunction Vascular calcification Protein-energy wasting Progression of cardiovascular disease Adapted from: Yilmaz et al. Clin Nephrol 2007: 68: 1-9; Stenvinkel P. Sem Dialysis 2012;26_16-9; Akchurin OM and Kaskel F. Blood Purif 2015;39:

8 Clinical significance of Large Middle Molecules (LMM) QOL Survival CVD Immunodefiency Chronic Inflammation Percent of Molecules Involved C Hutchison-manuscript in preparation 8

9 Common categorization of uremic solutes Molecules Small water-soluble compounds Protein-bound solutes Middle molecules Molecular weight < 500 Da Variable > 500 Da Example assymetric dimethylarginine, guanidine, uric acid, oxalate, ethylamine, methylguanidine, neopterin, phenylacetic acid p-cresylsulfate, indoxyl sulfate, phenol, indol-3-acetic acid, hippuric acid, homocystein, carboxymethyllysine, acrolein β 2 -microglobulin, adiponectin, α 1 - acid glycoprotein, cystatin C, prolactin, osteocalcin, vascular endothelial growth factor IDENTIFIED MOLECULES Duranton, J Am Soc Nephrol 2012

10 Common categorization of uremic solutes Duranton, J Am Soc Nephrol 2012 IDENTIFIED MOLECULES

11 Several middle molecule uremic solutes are potentially involved in the systemic inflammation seen in HD patients solute MW [kda] relevance cytokines / interleukins free light chains 22.5 / 45 generally seen as pro-inflammatory, but the group excerts a mix of pro- and anti-inflammatory effects kappa and lambda; pro-inflammatory; plasma levels correlate with outcome in CKD patients complement factor D (adipsin) 24 rate-limiting factor in alternative complement pathway α1-acid glycoprotein 43 acute phase reactant pentraxin-3 40 chitinase-like protein (YKL-40) 40 advanced glycation end products Lisowska-Myjak, Nephron Clin Pract 2014 Chmielewski et al, Sem Nephrol 2014 Okyay et al, Ther Apheresis Dial 2013 acute phase reactant; implicated as inducer of endothelial damage novel marker; up-regulated in inflammation-associated diseases; associated with outcome associated with inflammation, malnutrition, atherosclerosis, CV disease, and survival IDENTIFIED IMPACT

12 Major uremic solutes belong to the class of middle molecules Chmielewski Sem Nephrol 2014 Half of which are 20 kda

13 Current therapies limitation in removal of whole spectrum of uremic toxins 13

14 Pooled data analysis of mortality using four RCTs comparing post-dilution HDF to HD Mortality Cause HD Events/ 100PY HDF Events/ 100PY Hazard Ratio (95%CI) for HDF vs HD All-cause (0.75;0.99) Greater effect in older Cardiovascular disease (0.61;0.97) Infections No difference patients, age >65y Sudden death No difference Data from CONTRAST, Turkish HDF, ESHOL, and French HDF studies used for analysis CI = confidence interval; PY = person-years Peters et al., Nephrol Dial Transplant 2016;31:978-84

15 Post-hoc analysis of effect of convective volume in HDF on mortality, using pooled data from four RCTs Mortality Cause HR (95%CI) for HDF vs HD Convective volume per session, per 1.73 m 2 BSA <19 L L >23 L All-cause 0.83 (0.66;1.03) 0.93 (0.75;1.16) 0.78 (0.62;0.98) Cardiovascular disease 0.92 (0.65;1.30) 0.71 (0.49;1.03) 0.69 (0.47;1.00) Data from CONTRAST, Turkish HDF, ESHOL, and French HDF studies used for analysis Data adjusted for age, sex, albumin, creatinine, history of cardiovascular diseases and history of diabetes HR = hazard ratio; CI = confidence interval; BSA = body surface area Peters et al., Nephrol Dial Transplant 2016;31:978-84

16 THE EXPANDED HEMODIALYSIS (HDX) CONCEPT

17 THE GOAL Through efficient removal of large middle molecules achieve attenuation of patients inflammatory state and reduced progression of cardiovascular disease, leading to improved outcome and quality of life

Expanded Hemodialysis, HDx A renal replacement therapy that! expands blood purification to include more of large uremic toxins (large middle molecules)!

19 Expanded Hemodialysis, HDx A renal replacement therapy that! expands blood purification to include more of large uremic toxins (large middle molecules)! enabled by a dialysis membrane with increased permeability that promotes effective diffusive and convective transport! without the need for external infusion fluid

20 Expanded hemodialysis: Step closer to native kidney HDx

21 MEMBRANE INNOVATION ENABLES HDX THERAPY TO BE ACHIEVED

22 Membrane pore size distribution determined in the spinning processs Phase inversion process non-uniform pore sizes pore size distribution Spinning set up for porous hollow fiber Kim HJ. Jpn J Appl Phys 2016;55 06GH06 fract. number of pores pore size

23 Characterization of Membrane Permeability Retention Onset MWRO (Molecular Weight Retention Onset): Molecular weight at which the sieving coefficient is 0.9 MWCO (Molecular Weight Cut-Off): Molecular weight at which the sieving coefficient is 0.1 Cut Off Boschetti-de-Fierro et al. IJAO 2013;36:455-63

24 MCO membranes with permeability profile closer to the native kidney Sieving coefficient 1,0 0,8 0,6 0,4 0,2 Glomerular membrane (Natural Kidney) High flux membrane MCO membranes High cut-off membrane 0, b2microglobulin Myoglobin k-flc IL-6 l-flc Albumin Dextran molecular weight [g/mol] Boschetti de Fierro et al. Scientific Reports 2015, 16;5:18448

25 MCO membrane characteristics support internal convection Inner fiber diameter 215 µm 185 µm Conventional MCO " Smaller fiber diameter to enhance internal filtration quantitatively

coli O55:B5 UF rate: 16 % of QB " Dialysis membrane pore size does not determine endotoxin

26 Bacterial Endotoxins : Log reduction value Pore size and in vitro retention properties of LPS In vitro LPS from E.coli O55:B5 UF rate: 16 % of QB " Dialysis membrane pore size does not determine endotoxin diffusion " Requirements on dialysis fluid quality for conventional high-flux membranes also apply for MCO membranes Hulko et al. ERA-EDTA 2015 abstract FP516

27 Bacterial Endotoxins : Clinical simulation model Results: Cell response values expressed as IL-1β concentrations in the THP-1 cell culture supernatant Medium Negative Control LPS Positive Control Dialysate Challenge Blood side pre Blood side post Statistics Pre vs Post Polyflux 17L 11 ± 4 54 ± ± ± 4 11 ± 4 Revaclear ± 3 62 ± ± ± 3 11 ± 3 Theranova ± 4 53 ± ± ± 4 11 ± 3 No significance No significance No significance Theralite ± 4 60 ± ± ± 4 11 ± 3 No significance Using the THP-1 assay, none of the PVP solutions induced IL-1β compared to culture medium per se. Rounded numbers taken from FINAL REPORT: ENDOTOXIN PERMEABILITY STUDY PERFORMED AT GHENT UNIVERSITY HOSPITAL FOR BAXTER

28 THE NOVEL THERANOVA DIALYZER WITH PERFORMANCE DESIGNED FOR HDX THERAPY

29 Kirsch, Nephrol Dial Transplant 2016

30 Baxter Confidential Highly Restricted: Do not distribute without prior approval HDx : theranova in HD: THERANOVA Removal dialyzer of middle in HD molecules and HDF versus regular high-flux HD and HDF N = 19 Q B = 400 ml/min T = 4.4 ±0.3 h V CONV = 24 L $, Measures in dialysate # p<0.001 vs high-flux HD and HDF $ p<0.001 vs high-flux HD p<0.01 vs HDF # Note: YKL-40 was not measurable in dialysate # # # # high-flux HD = HD by FX Cordiax 80 dialyzer; HDF = high volume HDF by FX Cordiax 800 dialyzer Bars indicate mean and SD Statistics by a mixed model with fixed effects of period and study dialyzer type, and the random effect of subject. Kirsch et al. Nephrol Dial Transplant, Sep Advance Access Krieter et al. Abstract to ERA-EDTA 2016: MP464 Baxter Clinical Study Report:

HDx : theranova in HD: Removal of middle molecules versus regular high-flux HD and HDF N = 19 Q B = 400 ml/min T = 4.4 ±0.3 h V CONV = 24 L $ # $ # # # p<0.001 vs high-flux HD and HDF $ p<0.

31 HDx : theranova in HD: Removal of middle molecules versus regular high-flux HD and HDF N = 19 Q B = 400 ml/min T = 4.4 ±0.3 h V CONV = 24 L $ # $ # # # p<0.001 vs high-flux HD and HDF $ p<0.001 vs high-flux HD p<0.01 vs HDF # high-flux HD = HD by FX Cordiax 80 dialyzer; HDF = high volume HDF by FX Cordiax 800 dialyzer Bars indicate mean and SD Post-dialysis data are corrected for hemoconcentration Statistics by a mixed model with fixed effects of period and study dialyzer type, and the random effect of subject. Kirsch et al. Nephrol Dial Transplant, Sep Advance Access Krieter et al. Abstract to ERA-EDTA 2016: MP464 Baxter Clinical Study Report: Baxter Confidential Highly Restricted: Do not distribute without prior approval

32 Albumin loss during 4h dialysis PerCom 1 study Q B = 302 ±22 ml/min, T = 4.0 h PerCom 2 study Q B = 400 ml/min, T = 4.4 ±0.2 h Bars indicate mean and SD. Kirsch et al. Nephrol Dial Transpl 2017;32(1):165-72

33 Reported albumin removal in HDF and HDx treatments Albumin removal, g/treatment HDF HDx HDF data are obtained in different studies using a variety of high-flux dialyzers, different dilution modes (post-, pre-, mid-), and different convective flow rates

34 Useful compounds : Serum albumin Pre- and post-dialysis levels of Creatinine, ß2m and albumin N = 10 NO DECREASE IN SERUM ALBUMIN after 5weeks 5 weeks treatment with Theranova Teatini et al. ERA-EDTA 2017 abstract MP527

35 ERA-EDTA 2017 Poster on Theranova clinical use in France NO DECREASE IN SERUM ALBUMIN after 6 months

36 ONGOING TRIALS

37 Baxter HDx / Theranova IIRs : Partnership with clinicians IIR / HCP Key endpoints Comparator Study duration per subject # Subjects Expected key publications REMOVAL-HD PI: Hutchinson, multi-center, ANZ Changes in S-albumin and FLC levels over 6 months, Several exploratory measures Standard of care high-flux HD 8 months 85 Abstract: ASN 2018 Article: Q1 / 2019 PI: Koball, Rostock, Germany Albumin-binding capacity HDF (FX) 4 weeks 30 Abstract: ASN 2017 Article: Q1 / CEC Program REMOC Change in FLCs and S-albumin, various MMs and PI: Rosenkranz, Graz, Austria cytokines, calcification propensity, symptoms PI: Bridoux, Poitiers, France ModuVas PI: Zickler, Berlin, Germany PI: Cozzolino, Milan, Italy MMs and inflammatory markers, several secondary measures Vascular calcification in human cell culture model, PWV and calcification propensity test Vascular calcification and oxidative stress in rat cell culture model HDF 6 months 30 HD (Elisio) 6 months 40 HD (Revaclear) 7 months 48 Regular HD 6 months 20 Abstract: ASN 2018 Article: 2019 Abstract: ASN 2018 Article: 2019 Abstract: ERA-EDTA 2019 Article: 2019 Abstract: ASN 2018 Article: 2019 PI: Juillard, Lyon, France I: Proteome of depuration, inflammatory markers II: Effect on albumin isoforms I:HD (FX) II: HD/HDF (FX) I: 16 weeks II: 24 weeks I: 20 II: 20 Abstract: ERA-EDTA 2019 Article: 2019 PI: Schmaderer, Munich, Gerrmany Wide range of inflamamtory markers and MMs, Immunophenotype change, +more HD 8 months 34 Abstract: ERA-EDTA 2019 Article: 2019 PI: S.Mitra, Manchester, UK Vascular health (endothelial microparticles), vascular endothelial markers, CV events, QoL HDF 9 months 40 Abstract: ERA-EDTA 2019 Article: CEC Program PI: M.Canziani, Sao Paolo, Brazil PI: U.Teatini, Multi-center, Italy PI: K-W Joo, multi-center, Korea PI: R.Perez, Multi-center, Endothelial function (FMD%, PWV), endothelial dysfunction markers ESA resistance, plasma levels of FLCs, hepcidin, inflammatory markers CV surrogate markers (PWV, CT coronary Ca, Echo), biomarkers (BNP, troponins, CRP, IL-6), PROMs Observational study: Survival, hospitalization, HD 6 months 32 HD 48 weeks 55 Abstract: ERA-EDTA 2019 Article: 2019 Abstract: ASN 2019 Article: 2019 HDF 12 months HDF 3 years

38 2016 CEC Program Baxter HDx / Theranova IIRs : Partnership with clinicians Study duration IIR / HCP Key endpoints HDx physiologic Comparator # Subjects per : subject REMOVAL-HD Changes in S-albumin and FLC levels over 6 PI: Hutchinson, multi-center, Standard of care months, 8 months 85 high-flux HD ANZ Several exploratory Inflammation measures PI: Koball, Rostock, Germany Albumin-binding capacity HDF (FX) 4 weeks 30 REMOC Change in FLCs and S-albumin, various MMs and PI: Rosenkranz, Graz, Austria cytokines, calcification propensity, symptoms PI: Bridoux, Poitiers, France ModuVas PI: Zickler, Berlin, Germany PI: Cozzolino, Milan, Italy PI: Juillard, Lyon, France PI: Schmaderer, Munich, Gerrmany Calcifications HDF 6 months 30 MMs and inflammatory markers, several secondary Impact measures on CV Heath Vascular calcification in human cell culture model, PWV and calcification propensity test Vascular calcification and oxidative stress in rat cell culture model Quality of I:HD life (FX) II: HD/HDF (FX) I: Proteome of depuration, inflammatory markers II: Effect on albumin isoforms Wide range of inflamamtory markers and MMs, Immunophenotype change, +more HD (Elisio) 6 months 40 HD (Revaclear) 7 months 48 Regular HD 6 months 20 I: 16 weeks II: 24 weeks I: 20 II: 20 HD 8 months 34 Expected key publications Abstract: ASN 2018 Article: Q1 / 2019 Abstract: ASN 2017 Article: Q1 / 2018 Abstract: ASN 2018 Article: 2019 Abstract: ASN 2018 Article: 2019 Abstract: ERA-EDTA 2019 Article: 2019 Abstract: ASN 2018 Article: 2019 Abstract: ERA-EDTA 2019 Article: 2019 Abstract: ERA-EDTA 2019 Article: CEC Program PI: S.Mitra, Manchester, UK PI: M.Canziani, Sao Paolo, Brazil PI: U.Teatini, Multi-center, Italy PI: K-W Joo, multi-center, Korea PI: R.Perez, Multi-center, Vascular health (endothelial microparticles), vascular endothelial markers, CV events, QoL HDF 9 months 40 Abstract: ERA-EDTA 2019 Article: 2019 Global Endothelial function RCT (FMD%, PWV), endothelial and registry in Abstract: ERA-EDTA 2019 dysfunction markers HD 6 months 32 Article: 2019 ESA resistance, plasma levels of FLCs, hepcidin, Abstract: ASN 2019 HD 48 weeks 55 inflammatory markers planning Article: 2019 CV surrogate markers (PWV, CT coronary Ca, HDF 12 months Echo), biomarkers (BNP, troponins, CRP, IL-6), PROMs Observational study: Survival, hospitalization, HDF 3 years

39 Membrane characteristics Limited to spent dialysate analysis Albumin loss : role of adsorption? Limited to few molecules Opportunity for a global approach?

40 Proteomic ALBUMIN Baudin, Revue Francophone des Laboratoires 2011

41 Depict the variability of Membrane / proteins interaction Urbani, Blood Transfusion 2012

42 Ishikawa, Am J Nephrol 2006 Provide a global approach

43 Ishikawa, Am J Nephrol 2006 Dialysate

44 Ishikawa, Am J Nephrol 2006 Membrane

45 Proteomic summary Overall interest of proteomic for characterizing dialysis membranes Provide access to all implicated depuration mecanisms Absorption Constant Extremely variable among membranes Our contribution to the HDx program

46 Limits in albumin quantitation Michaelis, J bbrc 2010

47 Limits in albumin quantitation Michaelis, J bbrc 2010

48 Useful compounds : Albumin Albumin concentration are they false in dialysis? Is it mandatorily detrimental to remove altered albumin? Does all membranes remove altered albumin similarly? Florens, Juillard, Contrib Nephrol 2017

49 MY EXPERIENCE WITH HDX / THERANOVA

50 HD unit University Hosp Lyon 24 positions, 3 shifts, 60 dialysis/day Ultrapure water, 2 Gambro heat treatment 100 % 5008 Fresenius, 95 % of patients treated by HDF (1992) HDx with Theranova : 3rd generation dialyser

51 Limited Controlled Distribution 1 out 12 sites in Europe 5000 treatments performed Ease of use : Priming, rinse back and anticoagulation, monitor compatibility No adverse events and positive feedback

52 Theranova experience Available since 2 months in the unit Very well accepted Overall positive comments 2 clinical cases : old vintage patients, spontaneous reports

53 Miss Bou. 48 yo, start dialysis at 16 yo Interstitial nephritis Very high sensitization after two Tx Extensive and destructive β2 amyloidosis, joints pain HDF dependent

54 Miss Bou. Very positive after switch to HDx No recurrence of joint pain Decreased recovery time Increase appetite the day of HDx dialysis by theranova

55 Mr Bou. 50 yo, start dialysis 1994 Cysto ureteral reflux Paranoiac psychosis Refuse HDF, reluctant to change

56 Mr Bou. Positive after switch to HDx Significant improvement in recovery time after dialysis Doesn t the usual deep weakness after dialysis Feel that the treatment is less aggressive than HDF

57 Nurses point of view Overall positive feedback : Use is easy Easy to remove bubbles and rinse Quick and complete restitution Probably link to dialyzer geometry Reduced inner diameter size

58 Conclusion Strong perception that HDx by theranova could Provide significant improvement in HD patients care In a very accessible manner

59 BACKUP Baxter Confidential Highly Restricted- Do Not distribute Without Prior Approval 59

60 IS IT SAFE TO USE LARGER PORES?

61 Useful compounds : In vitro retention Clotting factors and medications Factor VII activity (MW 50 kda) during 4 h simulated HD treatments Erythropoietin During 1 h simulated treatments (NeoRecormon, Roche; ~30 kda) " Well preserved activity levels of coagulation factors and inhibitors " No increased removal of drugs during simulated treatments " No loss of heparin Ref: Voigt et al. ERA-EDTA 2016 abstract SP426 Ref: Gebert et al. ESAO 2016 abstract 132

62 Albumin removal by dialysis comparing therapies High-flux HD HD with highperformance membranes in Japan HDF using conventional high-flux membranes Albumin removal by dialysis Negligible, typically well below 1 gram/session Varies between membranes from less than 1 to 8 g/session Depending on dilution mode, degree of flux across the membrane, etc., from <1 to around 10g/session Effect on serum albumin level No Decrease when albumin removal is high (by 7% with albumin loss of 7.7 g/ session) The large RCTs showed no effect of HDF on serum albumin level One observational study indicated 5% lower albumin level by HDF treatment HDx 1-4 g/session No data yet, but no effect expected PD Varies by number of large pores; mean values in the 3.9 to 5.7 g/day range High peritoneal clearance of albumin associated with 10% lower serum albumin level than low albumin clearance Tsuchida K and Minakuchi J. Contr Nephrol 2011;173:76-83, Meert N et al. Nephrol Dial Transplant. 2011;26: , Maduell F, et al. Blood Purif. 2014;37:125-30,Kirsch AH et al. Nephrol Dial Transplant 2016 Sep 1 (Advance access), Yeun JY and Kaysen GA. Am J Kidney Dis 1997;30:923-7, Balafa O et al. Clin J Am Soc Nephrol 2011;6:561-6

63 Useful compounds : Serum albumin Pre- and post-dialysis levels of Creatinine, ß2m and albumin N = 10 NO DECREASE IN SERUM ALBUMIN 5 weeks treatment with Theranova Teatini et al. ERA-EDTA 2017 abstract MP527

64 Useful compounds : Albumin THERANOVA dialyzer in HD: Removal of albumin during treatment Amount of albumin found in spent dialysate (g/session) NCT NCT THERANOVA 400 in HD QB 300 ml/min THERANOVA 400 in HD QB 400 ml/min Mean ±SD 2.7 ± ±0.7 Median Range Albumin removals with regular high-flux membranes were in these studies 0.2 ±0.0 and 0.5 ±0.2 g/session, in high-flux HD and HDF respectively Baxter Clinical Study Reports and Rosenkranz et al. and Krieter et al. to be submitted for publication

65 Useful compounds : Albumin What if albumin is removed by dialysis? the case of HDF " Albumin removal per HDF session is reported to be in the gram range " It depends on dilution mode, UF flux, type of membrane, etc. Krieter DH et al. Kidney Int. 2005;67:349-56, Pedrini LA et al Kidney Int. 2006;69:573-9, Krieter DH et al. Artif Organs. 2008;32:903-9, Joyeux V et al Int J Artif Organs. 2008;31:928-36, Le Roy F et al. Clin Kidney J. 2009;2(suppl 2): Sa402, Krieter DH et al. Nephrol Dial Transplant. 2010;25:212-8, Masakane I. NDT Plus. 2010;3(suppl 1):i28-i35, Meert N et al. Nephrol Dial Transplant. 2011;26: , Pedrini LA et al. Int J Artif Organs. 2011;34: , Baranger T et al. Nephrol Dial Transplant 2012;27(Suppl 2):ii222, Maduell F, et al. Blood Purif. 2014;37:125-30, Fournier A et al Int J Artif Organs. 2015;38:76-82, Kirsch AH et al. Nephrol Dial Transplant 2016 Sep 1 (Advance access)

66 Limits in albumin quantitation Michaelis, J bbrc 2010

67 Limits in albumin quantitation Michaelis, J bbrc 2010

68 Useful compounds : Albumin Albumin concentration are they false in dialysis? Is it mandatorily detrimental to remove altered albumin? Does all membranes remove altered albumin similarly? Florens, Juillard, Contrib Nephrol 2017, In press

HDx THERAPY. Enabled by. Making possible personal.

HDx THERAPY. Enabled by. Making possible personal. HDx THERAPY Enabled by Making possible personal. THE NEXT HORIZON IN DIALYSIS IS CLOSER THAN YOU THINK PHOSPHATE UREA HDx BY THERANOVA EXPANDS YOUR RENAL POSSIBILITIES The new HDx therapy (expanded HD)