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Summary Background Connective tissue growth factor (CTGF) is a secreted glycoprotein that has a central role in the process of fibrosis. This study was designed to assess the safety, tolerability, and efficacy of pamrevlumab (FG-3019), a fully recombinant human monoclonal antibody against CTGF, in idiopathic pulmonary fibrosis. The aim was to establish whether pamrevlumab could slow, stop, or reverse progression of idiopathic pulmonary fibrosis. Methods The phase 2, randomised, double-blind, placebo-controlled PRAISE trial was done at 39 medical centres in seven countries (Australia, Bulgaria, Canada, India, New Zealand, South Africa, and the USA). Patients with idiopathic pulmonary fibrosis and percentage of predicted forced vital capacity (FVC) of 55% or greater were enrolled and randomly assigned (1:1) by use of interactive responsive technology to intravenous infusion of pamrevlumab 30 mg/kg or placebo every 3 weeks over 48 weeks (16 infusions). The primary efficacy outcome was change from baseline in percentage of predicted FVC at week 48. Disease progression (defined as a decline from baseline in percentage of predicted FVC of ≥10%, or death) at week 48 was a key secondary efficacy outcome. All patients in the pamrevlumab group received at least one dose of the study drug and were analysed for safety. Two patients in the placebo group were excluded from the intention-to-treat population for the efficacy analyses because of enrolment error. This trial is registered with ClinicalTrials.gov, NCT01890265. Findings Between Aug 17, 2013, and July 21, 2017, 103 patients were randomly assigned (50 to pamrevlumab and 53 to placebo). Pamrevlumab reduced the decline in percentage of predicted FVC by 60·3% at week 48 (mean change from baseline −2·9% with pamrevlumab vs −7·2% with placebo; between-group difference 4·3% [95% CI 0·4–8·3]; p=0·033). The proportion of patients with disease progression was lower in the pamrevlumab group than in the placebo group at week 48 (10·0% vs 31·4%; p=0·013). Pamrevlumab was well tolerated, with a safety profile similar to that of placebo. Treatment-emergent serious adverse events were observed in 12 (24%) patients in the pamrevlumab group and eight (15%) in the placebo group, with three patients on pamrevlumab and seven on placebo discontinuing treatment. Of the three (6%) deaths in the pamrevlumab group and six (11%) in the placebo group, none was considered treatment related. Interpretation Pamrevlumab attenuated progression of idiopathic pulmonary fibrosis and was well tolerated. Now in phase 3 development, pamrevlumab shows promise as a novel, safe, and effective treatment for idiopathic pulmonary fibrosis. Funding FibroGen.

Integrins αVβ6 and αVβ1 are cell surface proteins that bind to and activate latent TGF-β, resulting in SMAD phosphorylation and pro-fibrotic gene expression. In IPF, both integrins are upregulated in the lung and are thought to play a role in the development and propagation of fibrosis. We have identified an orally available small molecule inhibitor with equal potency towards αVβ6 and αVβ1 that prevents integrin-mediated activation of TGF-β. PLN-74809 has a ligand binding IC50 Inhibition of αVβ6-mediated TGF-β activation in the lung by can be detected through measurement of SMAD phosphorylation in alveolar macrophages. We administered inhibitors of αVβ6 to healthy and bleomycin-injured mice, healthy cynomolgus monkeys, and healthy volunteers to establish their pharmacokinetic/pharmacodynamic relationship. In healthy and fibrotic animals, oral dosing with PLN-74809 resulted in a time- and dose-dependent inhibition of SMAD phosphorylation in alveolar macrophages and lung tissue reflecting a reduction in TGF-β signaling. In healthy volunteers administered PLN-74809 40 mg QD for 7 days, BAL macrophage SMAD phosphorylation was suppressed by approximately half, demonstrative of in vivo pharmacological activity. These clinical pharmacodynamic data inform planned Phase 2a studies of PLN-74809 in IPF patients.

Integrin αVβ6 (epithelial cell) and αVβ1 (fibroblast)-mediated activation of TGF-β have been shown to promote fibrosis in the bleomycin lung injury model, and elevated levels of αVβ6 have been found in human IPF lung tissue. Through the development of novel immuno- and cell adhesion assays, we confirmed significantly elevated levels of αVβ1 in IPF lung tissue and demonstrated αVβ1-specific binding of human lung fibroblasts to latent TGF-β. We then compared a dual-specific small molecule inhibitor of αVβ6/αVβ1 (PLN-74809) to a pan-αV inhibitor and specific inhibitors of αVβ6 and αVβ1 in the bleomycin mouse model or precision cut lung slices (PCLS; bleomycin-injured mouse/human IPF tissue) to assess which integrin inhibition strategy was most effective at blocking fibrogenesis. Characterization of inhibitor potency, selectivity, and functional activity was performed by ligand-binding and TGF-β reporter cell-based assays. Prophylactic dosing of PLN-74809 and a pan-αV inhibitor via minipump had similar plateau effects in the bleomycin model, reducing total lung hydroxyproline (OHP) and collagen gene expression by 40%. Oral therapeutic dosing of PLN-74809 also resulted in dose-dependent inhibition of OHP levels. Comparison of single and dual inhibitors in murine PCLS showed an additive effect of dual αVβ6/αVβ1 inhibition vs αVβ6 or αVβ1 inhibition alone, and PLN-74809 potency was higher than that of nintedanib or pirfenidone. PLN-74809 was also confirmed to inhibit collagen gene expression in PCLS from IPF patient tissue (p

The approval of nintedanib and pirfenidone for treatment of idiopathic pulmonary fibrosis has introduced complexity into the design of clinical trials for new drugs on many levels. Placebo-controlled trials excluding background therapy may have issues with feasibility. Those that allow background therapy must consider the possibility of drug-drug interactions with existing therapies, as well as the narrower therapeutic window available to demonstrate incremental slowing of lung function decline with a new agent. While many trial participants will already be on background therapy, a significant number will not, complicating the study design and analysis. Various approaches to improve the efficiency of IPF clinical trials include attempts to validate new endpoints and biomarkers that reflect functional status or quality of life as well as the use of pragmatic and adaptive trial designs.

Objective.Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc.Methods.All patients received pirfenidone and were randomized 1:1 to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day. Patients received pirfenidone for 16 weeks in total. Assessments included treatment-emergent AE (TEAE) and exploratory disease outcomes.Results.Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients reported TEAE during the titration versus the maintenance period. The most commonly reported TEAE were consistent with those observed for pirfenidone in IPF (nausea, headache, fatigue) and were similar regardless of titration schedule. More patients discontinued treatment because of TEAE in the 2- versus 4-week titration group (5 vs 1, respectively); all discontinuation events occurred > 3 weeks after reaching the full dose of pirfenidone. Mycophenolate mofetil (MMF), taken by 63.5% of patients in addition to pirfenidone, did not appear to affect tolerability. Exploratory disease outcomes remained largely unchanged.Conclusion.Pirfenidone showed an acceptable tolerability profile in SSc-ILD, although a longer titration may be associated with better tolerability. Tolerability was not affected by concomitant MMF. The present findings support further investigation of pirfenidone in future clinical trials in patients with SSc-ILD. Trial registration: ClinicalTrials.gov; www.clinicaltrials.govNCT01933334.

Background: This Phase 2 study evaluated the safety, tolerability, and efficacy of pamrevlumab (FG-3019), a human monoclonal antibody against connective tissue growth factor, in idiopathic pulmonary fibrosis (IPF). The study was designed to evaluate if pamrevlumab could slow, stop, or reverse IPF progression and to measure average magnitude of effect. Methods: In this double-blind, placebo-controlled study (NCT01890265), patients at 39 sites (7 countries) were randomized 1:1 using interactive responsive technology to pamrevlumab 30mg/kg or placebo IV infusion, every 3 weeks over 48 weeks (total of 16 infusions). Primary efficacy endpoint was change from baseline in forced vital capacity (FVC) %-predicted at Week 48. Findings: Between August 2013 and July 2017, 103 patients were randomized to pamrevlumab 30mg/kg (n=50) or placebo (n=53). All patients received at least one dose and were analyzed for safety. For the efficacy analyses, two placebo patients in the intention-to-treat population were excluded due to enrollment error. Pamrevlumab reduced FVC %-predicted decline by 60.3% at Week 48 (-2.9% pamrevlumab vs. 7.2% placebo; a difference of 4.3%; 95% CI 0.35-8.30; P=0.033). The proportion of pamrevlumab patients with FVC %-predicted decline ≥10% or death was lower at all visits (10.0% vs. 31.4% at Week 48; P=0.010). Quantitative Lung Fibrosis/High Resolution Computer Tomography score was significantly lower in pamrevlumab group vs. placebo at Weeks 24 (24.8 vs. 86.4mL; P=0.009) and 48 (75.4 vs. 151.5mL; P=0.038). Pamrevlumab was well tolerated with a safety profile comparable to placebo. Treatment-emergent SAEs were observed in 12 (24.0%) and 8 (15.1%) patients in pamrevlumab and placebo arms with 3 and 7 patients discontinuing, respectively. Of three (6.0%) deaths in the pamrevlumab arm and six (11.3%) on placebo, none were considered treatment-related. Interpretation: In this Phase 2 trial, pamrevlumab attenuated IPF progression and was well tolerated. Trial Registration Number: NCT01890265. Funding: Sponsored and funded by FibroGen, Inc., San Francisco, CA, USA. Declaration of Interest: LR reports grants from Boehringer Ingelheim and Roche outside of the submitted, personal fees from FibroGen during the conduct of the study, personal fees from Biogen, personal fees from Sanofi-Aventis, personal fees from Roche, personal fees from Boehringer Ingelheim, personal fees from Pliant Therapeutics, personal fees from Promedior, personal fees from Asahi Kasei, personal fees from RespiVant, personal fees from Nitto, personal fees from Celgene, personal fees from Prometic, personal fees from Zambon, personal fees from Veracyte, personal fees from Toray, outside the submitted work; EFP reports grants from Genentech, grants from Boehringer Ingelheim, outside the submitted work; UC reports personal fees and non-financial support from Boehringer, personal fees and non-financial support from Roche, personal fees and non-financial support from Bayer, personal fees from GSK, personal fees from UCB Celltech, personal fees from Biogen, personal fees from FibroGen, personal fees from Global Blood Therapeutics, personal fees from Astra Zeneca, outside the submitted work; CA reports personal fees from ROCHE , personal fees from Boehringer Ingelheim, personal fees from FibroGen, personal fees from GSK, personal fees from Bayer, grants from Boehringer Ingelheim, grants from Roche, personal fees from MSD, outside the submitted work; DJL reports grants and personal fees from FibroGen, during the conduct of the study; personal fees from Galapagos, personal fees from Roche, personal fees from Sanofi Genzyme, personal fees from Philips Respironics, grants and personal fees from Global Blood Therapeutics, other from Galecto, personal fees from Veracyte, other from Pulmonary Fibrosis Foundation, from Boehringer-Ingelheim, outside the submitted work; DJL no longer accepts fees for industry consulting work as of May 2018; KRF reports personal fees from Veracyte, grants and personal fees from Roche/Genentech, grants and personal fees from Boehringer Ingelheim, personal fees from Sanofi Genzyme, outside the submitted work; NE has nothing to disclose; RP has nothing to disclose; MBS reports other from Boehringer Ingelheim, other from Genentech, has a patent Apparatus, Compositions and Methods for Assessment of Chronic Obstructive Pulmonary Disease Progression among Rapid and Slow Decline Conditions issued; JG has nothing to disclose; KPY is employed by FibroGen; TN is employed by FibroGen; SP has two patents US9,480,449 and EP 2844291 issued, and was an employee of FibroGen at the time of the study; MZ is employed by FibroGen; EG reports personal fees from FibroGen during the conduct of the study, and was an employee of FibroGen at the time of the study; EK is employed by FibroGen; GR reports other from FibroGen, during the conduct of the study; other from Avalyn, personal fees and other from Boehringer Ingelheim, other from BMS, other from Bellerophan, other from Gilead, other from Promedior, other from RocheGenentech, other from Respivant, and other from Sanofi, personal fees and other from Veracyte, grants from NIH, outside the submitted work. Ethical Approval: The clinical study protocol, its amendments, and the informed consent form were approved by Independent Ethics Committees, Institutional Review Boards, and/or Research Ethics Boards, and the study was conducted in accordance with the ethical principles of Good Clinical Practice and the Declaration of Helsinki.

Background Idiopathic pulmonary fibrosis (IPF) is chronic fibrosing pneumonia with an unpredictable natural disease history. Functional respiratory imaging (FRI) has potential to better characterize this disease. The aim of this study was to identify FRI parameters, which predict FVC decline in patients with IPF. Methods An IPF-cohort (treated with pamrevlumab for 48 weeks) was retrospectively studied using FRI. Serial CT’s were compared from 66 subjects. Post-hoc analysis was performed using FRI, FVC and mixed effects models. Results Lung volumes, determined by FRI, correlated with FVC (lower lung volumes with lower FVC) (R2 = 0.61, p

Dyspnea is a meaningful outcome to patients with IPF. Pamrevlumab, a mAb against connective tissue growth factor, has shown favorable safety, efficacy and QoL (SGRQ) results in PRAISE, a Phase 2, placebo-controlled trial. The UCSD-SOBQ is a respiratory questionnaire used in IPF trials, and in a subset of patients in PRAISE. The UCSD-SOBQ assesses dyspnea associated with activities of daily living (ADL). Subjects indicate severity of SOB on a 6-point scale in 21 ADL. Three additional questions ask about fear of harm from overexertion, limitations and fear caused by SOB. A total score ranges from 0 to 120, with higher scores indicating greater impairment. In a subset (N=42) of patients in PRAISE the UCSD-SOBQ was administered at baseline and every 12 weeks. Data were analyzed using ANCOVA, with missing data imputed using the predicted value from a random coefficient linear regression model. Baseline mean values for pamrevlumab and placebo were: age 68.6 and 65.9 years; FVC%-predicted 74.5 and 73.1%; GAP Score 3.5 and 3.2 and similar GAP Stage distribution. The mean baseline UCSD-SOBQ total score was 39.1 and 31.8 points. The between-groups absolute difference from baseline to Week 48 was statistically significant. These UCSD-SOBQ results suggest that pamrevlumab attenuates dyspnea progression in IPF patients in comparison to placebo.

Background: There is increasing interest in determining treatment efficacy early in the setting of patients with IPF. This is important in design of clinical trials in which decline in FVC is used to assess PFS as an endpoint. Aim: This study explores whether change in Quantitative Lung Fibrosis (QLF) score or FVC at 24 weeks is more sensitive in predicting PFS (where progression is defined as a decline in of > 10%) . Methods: In an open-label phase 2 trial in patients with idiopathic pulmonary fibrosis subjects underwent standardized HRCT scans (QLF) and spirometry (FVC) at baseline and and every 24 and 12 weeks respectively. Cox regression models and Kaplan-Meier (KM) Progression-Free-Survival plots was were performed to evaluate 24 week change in QLF of 4%, 3%, and 2% and FVC of 5% as a predictor of PFS. Harrell’s C index test was performed to assess the validity of the models. Results: The nNumber of subjects with both QLF scores and FVC at baseline, weeks 24, 48, 72 and 96 were 73, 66, 32, and 24 respectively. For the whole lung the hazard ratios for change in QLF of 4, 3, and 2% wereas 3.65, 3.6 and 3.7 respectively (all p Conclusion: A 24 week change in QLF > 2 % (worst lobe) rather change in FVC is a stronger predictor of PFS defined by FVC decline defined PFS in clinical trials.

Aims and objectives To identify baseline FRI parameters that predict changes in FVC and fibrosis after 48w of treatment with FG3019 Methods: In this open label study, 66 IPF patients (67.9±7.0 years) completed 48 weeks of treatment with an anti-CTGF monoclonal antibody. Pulmonary function was assessed every 12 weeks and HRCT scans (TLC and RV) were taken at baseline and after 24 and 48w. Machine learning algorithms were used on the baseline FRI parameters to obtain accurate predictions of changes in FVC and fibrosis after treatment (responder phenotyping). Results: FVC responders, as defined by stable or improving FVC, could be predicted with an accuracy of 87% by assessing lobe volumes and specific airway radii (siraw) of all zones measured at TLC together with siraw in the lower lobes measured at RV (Figure 1). Fibrosis responder, as defined by stable or improving fibrosis, could be predicted with an accuracy of 76,2% by combining the specific image based airway volumes (siVaw) and the specific image based surface area (siSaw) of the lower lobes measured at TLC. Figure 1: Change in FVC predicting features Conclusion: IPF is a highly heterogeneous disease with a heterogeneous response to treatment. Quantitative imaging can adequately describe the heterogeneity and has the potential to provide accurate responder phenotyping.

Background: Patients with IPF experience varying degrees of decline in lung function over time. The rate of decline can vary between patients and across over time and at present there is no reliable way to predict which subjects will decline faster. Aim: This study explores whether short term change in QLF score can predict fast from vs slow FVC decline. Methods: In an open-label phase 2 trial in patients with IPF subjects underwent standardized HRCT scans (QLF) and spirometry (FVC) performed at baseline and every 24 and 12 weeks, respectively. QLF was measured whore for the whole lung and worst lobe. Mixed effect models were used to estimate and compare against the reduction in FVC over repeated measurements with linear or quadratic growth models. Results: The aAnnual rate of reduction in mean FVC was 3.5% for the Week 24week QLF changes of Conclusion: Change in QLF of 4 percent at 6 months isn predictive of rapid FVC decline within 12 to 15 months

Drugs currently approved for treatment of idiopathic pulmonary fibrosis (IPF) (pirfenidone or nintedanib) slow the decline of FVC (forced vital capacity) over time. Nonetheless, there is still a medical need for effective and better tolerated therapies. Pamrevlumab (FG-3019) is a human monoclonal antibody against connective tissue growth factor (CTGF) that is well tolerated by IPF patients. Preliminary data from an open-label Phase 2 trial in IPF suggest that pamrevlumab may have stabilized or improved FVC as well as lung fibrosis assessed by quantitative HRCT (qHRCT) in about one third of patients. Based on these positive findings, PRAISE was initiated. 103 patients with IPF per current guidelines, with FVC ≥55% predicted, DLCO ≥30% predicted and between 10% and 50% lung fibrosis by HRCT, were randomized to receive 16 doses of pamrevlumab (30 mg/kg IV q3w) or placebo for 48 weeks. Two additional cohorts on stable dosing with pirfenidone (n=36) or nintedanib (n=21) were also enrolled for 24 weeks. Patients were assessed for FVC, patient reported outcomes and biomarkers every 12 weeks. Lung fibrosis was assessed by qHRCT centralized reading every 24 weeks. Safety was assessed continuously throughout the study. At baseline, randomized patients were male (71.9%), white (88.8%) and former smoker (64.4%). Mean age was 68.3 years, median % predicted FVC and DLCO were 70.3% and 51.5% respectively and the median GAP score was 4. Last enrolled subject will complete participation in June 2017, at which time data will be unblinded. Safety and efficacy results of pamrevlumab in monotherapy and in combination with current IPF standard of care will be presented.

This post hoc analysis examined the differences in idiopathic pulmonary fibrosis disease progression and the effects of pirfenidone in patients stratified by more preserved versus less preserved baseline lung function status using forced vital capacity (FVC) or GAP (gender, age and physiology) index stage.Efficacy outcomes, i.e. FVC, 6-min walking distance (6MWD) and dyspnoea (University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)), were analysed at 12 months in patients randomised to pirfenidone 2403 mg·day−1 or placebo in the pooled phase 3 CAPACITY/ASCEND population (n=1247), with subgroups stratified by baseline FVC ≥80% versus versus II–III. Treatment-by-subgroup interaction was tested based on a rank ANCOVA model; factors in the model included study, region, treatment, subgroup and treatment-by-subgroup interaction term.Patients with both more preserved (FVC ≥80% or GAP stage I) and less preserved (FVC These findings support the initiation of treatment with pirfenidone, irrespective of stage of baseline lung function in this patient population.

Background: ILD is a serious complication of SSc. Objectives: The LOTUSS study assessed the safety and tolerability of PFD in patients with SSc-ILD. Methods: In this open-label, 16-week study, 63 patients were randomized to a 2- or 4-week titration of PFD up to 2403 mg/day. Stable mycophenolate mofetil (MMF) was allowed. Adverse events (AEs), vital signs, ECGs, laboratory data and disease-related indicators were collected. Results: Mean±SD age was 50.6±12.3 yrs; 82.5% female; 76.2% white. Mean±SD SSc duration was 38.3±26.0 months. 63.5% received MMF. Mean±SD %FVC, %DLco and mRSS at baseline were 76.0±14.2, 59.7±16.5 and 11.4±9.6, respectively. Mean duration PFD was 3.5 months. At week 16, median change from baseline in %FVC was -0.5% (range -42%-12%); %DLco was +1.5% (range -24.0% to 40.0%). Minor changes were observed in mRSS and Mahler TDI. 61 patients (96.8%) had AEs; 19% severe AEs and 4.8%serious AEs. Most AEs were mild or moderate and resolved without sequelae. Common (≥10%) reported AEs were observed in PFD IPF studies (Table). AE profiles were generally similar between titration arms. No clinically meaningful changes occurred in vital signs, ECGs, lab tests or GI symptoms by UCLA SCTC GIT2.0, including Reflux scores. ![Figure][1] Conclusions: PFD was generally well-tolerated in SSc-ILD patients. AEs were similar to previously observed ones in IPF studies. [1]: pending:yes

In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis ; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. RESULTS: In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died ; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P

SummaryThe safety of full-length sucrose-formulated recombinant factor VIII (rFVIII-FS; KOGENATE® FS) for up to 24 months of use was evaluated in a postmarketing observational study in Europe. Long-term safety and efficacy data were available for 212 patients with severe haemophilia A, including 13 previously untreated patients (PUPs) and 12 patients with 1–19 exposure days (EDs). Patients accumulated a mean (± SD) of 187 (121) EDs to rFVIII-FS and received a total of 39,627 infusions, mainly for prophylaxis and for the treatment of 4,283 spontaneous or trauma-related bleeds during an average observation time of 710 (136) days. Of these bleeding episodes, 85.4% were successfully treated with one or two infusions of rFVIII-FS. Haemostasis was also evaluated during 46 minor to major surgical pro- cedures, and the response to infusion was “excellent” or “good” in all cases. FVIII inhibitor formation was observed in six patients (two de novo; four persistent or recurrent). The de novo cases represent 8.0% (2 of 25) of patients who reported 0–19 previous EDs at study entry. Four of the five patients who reported possible drug-related adverse effects developed inhibitors. The results of this observational study demonstrate the efficacy and safety of rFVIII-FS during normal clinical use in the treatment of patients with severe haemophilia A. Furthermore, these findings are consistent with those of previous phase III clinical studies with rFVIII-FS, particularly with regard to its efficacy and low incidence of inhibitor formation.

Background Interstitial lung disease (ILD) is a common and serious complication of systemic sclerosis (SSc). Pirfenidone, a novel antifibrotic agent, has been shown to be safe and effective in the treatment of idiopathic pulmonary fibrosis (IPF). Objectives The LOTUSS study was designed to assess the safety and tolerability of pirfenidone in patients with SSc-ILD. Methods This is an open-label, 16-week study. Patients were randomized to a 2- or 4-week titration of pirfenidone to the target dose of 2403 mg/day. Eligibility required a diagnosis of SSc ≤7 years from first non-Raynaud9s symptom, HRCT-confirmed ILD, FVC ≥50% and DLco ≥40%, absence of clinically significant pulmonary hypertension or severe GERD. Stable background treatment with mycophenolate mofetil (MMF) or oral cyclophosphamide was permitted. Safety assessments included collection of treatment emergent adverse events (TEAEs), vital signs, ECGs and laboratory tests. Though the study was not designed or powered to evaluate efficacy, FVC % predicted, DLco % predicted, modified Rodnan skin score (mRSS), Mahler BDI/TDI, and UCLA SCTC GIT 2.0 were recorded at baseline and 4 months. Results Of the 63 patients enrolled, the mean (SD) age was 50.6 (12.3) years; the majority were female (82.5%) and white (76.2%). The mean (SD) SSc duration was 38.3 (26.0) months. Forty patients (63.5%) were on MMF and the rest (36.5%) were not receiving any immunosuppressants. The mean (SD) mRSS, %FVC and %DLco at baseline were 11.4 (9.6), 76.0 (14.2) and 59.7 (16.5), respectively. The frequency and type of TEAEs were similar for both titration groups. The safety results are summarized below. No clinically significant changes in vital signs, ECGs, or laboratory tests were observed. At week 16 (end of treatment), the median change from baseline in %FVC was -0.5% (range -42% to 12%); 10 patients (16.7%) had an increase ≥5% whereas 5 (8.3%) had a decrease >5% at week 16. Median change from baseline in %DLco was +1.5% (range -24.0% to 40.0%); 19 subjects (31.7%) had an increase ≥5% vs. 10 (16.7%) had a decrease >5% at week 16. Minor changes (mean ± SD) were observed in Mahler TDI (1.0±3.41) and mRSS (-0.4±3.71). No change was noted in the GI symptoms on UCLA SCTC GIT 2.0; the change was not clinically meaningful from baseline to week 16 (mean ± SD) in the UCLA Reflux scores (0.0330±0.29). Conclusions In the 16-week, open label trial of pirfenidone in SSc-ILD, pirfenidone was generally well-tolerated in SSc-ILD patients, despite pre-existing co-morbidities, including underlying GI disease, and concomitant use of MMF. The observed AEs were expected and consistent with those previously seen with pirfenidone treatment in IPF trials. The data support further investigation of pirfenidone in SSc-ILD. Disclosure of Interest D. Khanna Grant/research support from: Actelion, Astra-Zeneca, EMD Serono, Bristol Myers Squibb, Bayer, InterMune, Consultant for: Takeda, Sanofi-Aventis/Genzyme, EMD Serono, InterMune, Glaxo SmithKline, Genentech/ Roche, Bristol Myers Squibb, Actelion, Astra-Zeneca, Bayer, Biogen Idec, C. Albera Consultant for: InterMune, A. Fischer Grant/research support from: InterMune, J. Seibold Consultant for: InterMune, G. Raghu: None declared, N. Khalidi: None declared, L. Chung Grant/research support from: InterMune, E. Schiopu Grant/research support from: InterMune, D. Chen Shareholder of: InterMune, Genentech/Roche, Employee of: Genentech, E. Gorina Shareholder of: InterMune, Genentech/Roche, Employee of: Genentech

SummaryThe safety and efficacy of a full-length sucrose-formulated recombinant factor VIII product (rFVIII-FS; KogenateFS; Kogenate Bayer) was evaluated in previously untreated (PUPs) and minimally treated (MTP) patients with severe haemophilia A (FVIII < 2%). Patients (37 PUPs; 24 MTPs) aged 0.1–25.7 months were treated with rFVIII-FS for a cumulative of 9,141 exposure days (EDs), median 114 EDs (range 4–478), on prophylactic or on-demand therapy. Eighty-nine percent of all treated bleeding episodes were successfully treated with 1 (74%) or 2 (15%) infusions. Clinical response to first infusion for each bleeding episode was rated as ‘excellent’ in 58%, or ‘good’ in 33%, of all cases. Recombinant FVIII-FS was used in 27 surgical procedures, mainly catheter implantations, which were all conducted without bleeding complications. FVIII recovery mean values (~2%/kg/ IU) were as expected for any licensed FVIII concentrate. FVIII neutralizing antibody formation was 15% (9/60). Aside from inhibitor formation, three adverse events were rated as ‘at least possibly drug-related’ for a total drug-related adverse event rate of 0.14%. No viral seroconversions were observed. Overall, excellent safety and efficacy were demonstrated with rFVIII-FS for therapy of young children with severe haemophilia A.

Many of the physical, psychosocial, and financial difficulties associated with severe hemophilia can be attributed to the effects of recurrent joint bleeds and chronic arthropathy. Regimens for clotting factor replacement treatment for hemophilia include prophylactic and on-demand therapy. A study in pediatric male patients with severe hemophilia A showed that prophylactic treatment with sucrose-formulated recombinant factor VIII (rFVIII-FS) resulted in prevention of joint damage and a decrease in the frequency of joint and other bleeds compared with on-demand therapy (Manco-Johnson MJ, et al. N Engl J Med.2007;357:535). A clinical trial was conducted in adult patients with severe hemophilia A and history of frequent bleeding to evaluate the effect of secondary rFVIII-FS prophylaxis on the number of joint bleeds after switching from on-demand rFVIII-FS therapy. Secondary study objectives were to compare these treatment strategies with regard to joint function, number of all bleeds, health-related quality of life, health economics, and safety. Male patients who were aged 30–45 years, had a negative inhibitor status, had a history of FVIII treatment (>100 exposure days), and were using on-demand FVIII treatment before the study were eligible to participate in this prospective 13-month crossover study. During the first 6 months, all patients received on-demand rFVIII-FS treatment. Patients were then switched to prophylactic rFVIII-FS treatment (20–40 IU/kg 3 times per wk at a stable dose as determined by investigators based on the patient’s bleeding history) for the remaining 7 months, with the first month constituting a washout/stabilization run-in period. Patients were monitored throughout the 13 months for bleeds and health-economics parameters and were evaluated by the Gilbert score (joint function) and the Haemo-QoL questionnaire at baseline and at the end of the on-demand (at 6 mo) and prophylactic (at 13 mo) treatment periods. A total of 20 patients from 9 international sites participated in the study. Patients received a mean dose of 31 IU/kg/wk during the on-demand period, which increased to 86 IU/kg/wk during the prophylaxis period. Although 16/20 patients already had 1 to 4 target joints, mean (±SD) numbers of joint and total bleeds per patient significantly decreased during the prophylaxis period (1.5±2.1 and 1.9±3.3, respectively) compared with the on-demand period (18.5±11.6 and 23.7±13.3; P

Continuous infusion of factor VIII (FVIII) is an alternative treatment approach to bolus dosing for providing hemostatic control in patients with hemophilia A undergoing surgery. Continuous infusion maintains consistent circulating FVIII, thus avoiding wastefully high or dangerously low levels. Potential advantages of continuous infusion include improved protection from excessive bleeding, reduced factor consumption, and easier monitoring. Continuous infusion requires FVIII usage parameters that are typically outside of the tested and approved ranges for the product, including extended time in an aqueous state at room temperature and exposure to a large surface area of tubing. Here we present in vitro data on the stability and sterility of a sucrose-formulated recombinant FVIII product (Kogenate® FS/Bayer; rFVIII-FS) under conditions comparable to those that would be experienced during the continuous infusion of patients. Three lots for each of 3 vial sizes (250, 500, and 1000 IU) were tested. Twenty vials of each size were reconstituted in Water for Injection, pooled into a 50 mL volume (100, 200, or 400 IU/mL for the 250, 500, and 1000 IU vial sizes, respectively), and aseptically transferred to pump reservoirs. Two mini-pumps were evaluated (WalkMed 350 Ambulatory Infusion Pump and CADD-Legacy PLUS Ambulatory Infusion Pump Model 6500) using a flow rate of 0.6 mL/hr. Reservoir bags containing reconstituted rFVIII-FS, pumps, and tubing were incubated at 30°C and samples were withdrawn to test coagulation activity via one-stage and chromogenic assays after 0.5, 1, 2, 3, 6, 12, 24, and 48 hours. Sample remaining in the reservoir after 48 hours was tested for sterility. The reservoirs and tubing used in this study were made from polyvinyl chloride (PVC), which has a high FVIII adsorption potential. Results for all 1000 IU lots based on the recoveries obtained at the first time point demonstrated >80% activity at the end of the study using both the one-stage and chromogenic assays on both pumps. Results for all 500 IU lots showed similar recoveries (≥80%) for both pumps at study end using the chromogenic assay. However, the one-stage assay gave higher recovery values for the WalkMed pump (>90%) compared to the CADD pump (>75%). Results for all 250 IU lots demonstrated ≥79% activity at the end of the study using both pumps and both assays. All lots passed the sterility test. These findings indicate that rFVIII-FS is stable in both the WalkMed and CADD pumps and that sterility of rFVIII-FS is maintained for at least 48 hours. This suggests that rFVIII-FS is suitable for use in continuous infusion.