Janssen Pharmaceutica NV Research Articles

Single-Agent Ibrutinib vs Real-World (RW) Treatments for Patients with Chronic Lymphocytic Leukemia (CLL) and del11q: Adjusted Comparison of RESONATE-2TM and RESONATETM with RW Databases

IntroductionIbrutinib, a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase, is approved in many countries for treatment-naïve (TN) and previously treated CLL, supported by improved response rates, progression-free survival (PFS), and overall survival (OS) vs chlorambucil in RESONATE-2™ (NCT01722487; Burger JA, et al. N Engl J Med. 2015;373:2425-2437) and ofatumumab in RESONATE™ (NCT01578707; Byrd JC, et al. N Engl J Med. 2014;371:213-223). We analyzed survival outcomes for ibrutinib vs RW treatments for TN and relapsed/refractory (R/R) CLL by del11q status, an adverse prognostic factor linked with poor patient outcomes despite conventional chemoimmunotherapy. An adjusted comparison restricted to patients with confirmed del11q status was conducted using patient-level data from RESONATE-2™ and RESONATE™ and RW databases from 2 countries.MethodsThe Lyon-Sud RW database holds medical records for CLL patients diagnosed between 1980 and 2017 from the Centre Hospitalier Lyon-Sud, France; the Chronic Lymphocytic Leukemia Registry (CLLEAR) RW database holds medical records for CLL patients diagnosed between 1988 and 2017 from 7 academic centers in the Czech Republic. TN CLL database patients were selected using RESONATE-2™ criteria (which excluded those aged < 65 years or del17p positive). For the R/R group, patients ≥ 18 years of age or those with del17p were allowed per RESONATE™ inclusion criteria. PFS and OS outcomes by del11q status were compared between the ibrutinib arms of RESONATE-2™/RESONATE™ and physicians' choice (PC) treatment in the pooled RW databases (excluding ibrutinib). A multivariate Cox proportional hazards model was fitted on pooled RCT/RW data to estimate adjusted hazard ratios (HRs) for effect of ibrutinib vs RW PC treatment using age, sex, and treatment line as covariates. The unit of observation for the RW databases was the treatment line (rather than patient) number; RW patients receiving multiple lines of therapy contributed to multiple observations, and baseline was defined as the line-specific treatment start date.ResultsFor the RW TN cohort, 466 treatment lines were analyzed; 134 (28.8%) patients were del11q positive. In RESONATE-2™, 29/136 (21.3%) TN patients were del11q positive. The table below shows adjusted HRs for PFS and OS for patients with/without del11q. For the del11q-positive subgroup, adjusted HRs for ibrutinib vs RW PC first-line (1L) therapy were 0.02 (95% confidence interval [CI], 0.00-0.17; p = 0.0002) for PFS and not estimable for OS (no deaths on ibrutinib). For the del11q-negative subgroup, adjusted HRs were 0.34 (95% CI, 0.2-0.57; p < 0.0001) for PFS and 0.74 (95% CI, 0.37-1.49; p = 0.3957) for OS. For second-line (2L) PC treatment in the RW R/R cohort, 385 treatment lines were analyzed; 135 (35.1%) were from del11q positive patients. In RESONATE™, 13 (37.1%) 2L patients were del11q positive. For the del11q-positive subgroup, adjusted HRs for ibrutinib vs RW PC of 2L therapy were 0.03 (0.00-0.21; p = 0.0003) for PFS and 0.08 (0.01-0.46; p = 0.0050) for OS. For the del11q-negative subgroup, adjusted HRs were 0.27 (0.14-0.51; p < 0.0001) for PFS and 0.50 (0.24-1.05; p = 0.0670) for OS. For 2L and beyond (2L+) treatment in the RW R/R cohort, 727 treatment lines were analyzed; 291 (40.0%) were from del11q positive patients. In RESONATE™, 63/195 (32.3%) 2L+ patients were del11q positive. For the del11q-positive subgroup, adjusted HRs (95% CIs) for ibrutinib vs RW PC of 2L+ therapy were 0.13 (0.08-0.20; p < 0.0001) for PFS and 0.15 (0.08-0.26; p < 0.0001) for OS. For the del11q-negative subgroup, adjusted HRs were 0.20 (0.14-0.29; p < 0.0001) for PFS and 0.33 (0.21-0.52; p < 0.0001) for OS.ConclusionsAdjusted comparisons of the registration trial (RESONATE-2™/RESONATE™) and RW patient-level data suggest that OS and PFS improvements with ibrutinib vs PC therapies are pronounced for patients with CLL harboring del11q compared with those who are del11q negative. The findings inform physicians of the comparative effectiveness of ibrutinib in the RW for patients with this high-risk cytogenetic abnormality.Funding Source:This project was sponsored by Janssen Pharmaceutica NV, and Pharmacyclics LLC, an AbbVie Company. The real-world databases are independently owned. Writing assistance was provided by Emma Fulkes of PAREXEL and funded by Janssen Pharmaceutica NV. [Display omitted] DisclosuresSalles:Takeda: Honoraria; Acerta: Honoraria; Epizyme: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Gilead: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Servier: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria. Besson:Janssen Pharmaceutica NV: Employment. Doyle:Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Spacek:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Doubek:Novartis: Consultancy; AbbVie: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Affimed: Research Funding; Gilead: Consultancy, Honoraria, Research Funding.

Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies

Lifelong HIV antiretroviral therapy (ART) has prompted an interest in two-drug regimens to minimise cumulative drug exposure and toxicities. The safety, tolerability, and efficacy of dolutegravir and rilpivirine suggest potential compatibility and effectiveness as a two-drug regimen. We aimed to investigate this two-drug regimen in a phase 3 study. We identically designed SWORD-1 and SWORD-2, which were open-label, parallel-group, multicentre, phase 3, randomised, non-inferiority studies in 12 countries evaluating efficacy and safety of once-daily dolutegravir 50 mg plus rilpivirine 25 mg versus current ART regimen (CAR). We included participants aged 18 years or older who were on first or second ART with stable plasma HIV-1 RNA (viral load <50 copies per mL) for 6 months or longer at screening. We randomly assigned participants (1:1) with stratification by third-agent class, age, and planned participation in a bone mineral density substudy. The primary endpoint was proportion of participants with viral load lower than 50 copies per mL at week 48 among those individuals who received one or more doses of study medication. Investigators monitored adverse events to assess safety. These trials are registered with ClinicalTrials.gov, numbers NCT02429791 (SWORD-1) and NCT02422797 (SWORD-2). We screened for participants from April 14, 2015, to Oct 15, 2015, for SWORD-1 and from April 21, 2015, to Sept 25, 2015, for SWORD-2. We randomly assigned 516 participants to dolutegravir-rilpivirine and 512 to continue with CAR. At week 48 (last patient visit was Nov 22, 2016), in the pooled analysis of the intention-to-treat population, 95% of participants had viral loads lower than 50 copies per mL in each group (486 of 513 in the dolutegravir-rilpivirine group vs 485 of 511 in the CAR group), with an adjusted treatment difference of -0·2% (95% CI -3·0 to 2·5) and showed non-inferiority with a predefined margin of -8%. 395 (77%) of 513 participants in the dolutegravir-rilpivirine group and 364 (71%) of 511 participants in the CAR group reported adverse events. The most common adverse events were nasopharyngitis (49 [10%] for dolutegravir-rilpivirine vs 50 [10%] for CAR) and headache (41 [8%] vs 23 [5%]). More participants taking dolutegravir-rilpivirine (17 [3%]) reported adverse events leading to withdrawal than did participants taking CAR (three [<1%]). Dolutegravir-rilpivirine was non-inferior to CAR over 48 weeks in participants with HIV suppression and showed a safety profile consistent with its components. Results support the use of this two-drug regimen to maintain HIV suppression. ViiV Healthcare and Janssen Pharmaceutica NV.

Tiered Approach: from Plan Into Practice

Tiered Approach: from Plan Into Practice

A Unique Industrial – Academic Collaboration Towards the Next Generation of Schizophrenia Therapeutics

This article describes the unique industrial-academic collaboration that has been running for four years between Janssen Pharmaceutica NV and the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) towards identifying the next generation of schizophrenia therapeutics. This was a true collaboration, with both entities engaged in chemistry, In vitro pharmacology, DMPK and In vivo behavioral pharmacology, and aligned to deliver a first-in-class clinical candidate (NME) and additional back-up molecules. Notably, a first NME was delivered in a rapid timeframe and targeted the novel mechanism of mGlu5 positive allosteric modulation. As with any true collaboration, both sides brought unique skills to the table--Janssen leveraged deep drug discovery expertise and infrastructure, while Vanderbilt brought deep knowledge of the chemistry and pharmacology of the target in addition to the ability to provide deep scientific insight into the mechanism behind target modulation. In this article, we will discuss the science which drove our collaboration as well as some key lessons learned.

Towards a Better Prediction of Peak Concentration, Volume of Distribution and Half-Life after Oral Drug Administration in Man, Using Allometry

It is imperative that new drugs demonstrate adequate pharmacokinetic properties, allowing an optimal safety margin and convenient dosing regimens in clinical practice, which then lead to better patient compliance. Such pharmacokinetic properties include suitable peak (maximum) plasma drug concentration (C(max)), area under the plasma concentration-time curve (AUC) and a suitable half-life (t(½)). The C(max) and t(½) following oral drug administration are functions of the oral clearance (CL/F) and apparent volume of distribution during the terminal phase by the oral route (V(z)/F), each of which may be predicted and combined to estimate C(max) and t(½). Allometric scaling is a widely used methodology in the pharmaceutical industry to predict human pharmacokinetic parameters such as clearance and volume of distribution. In our previous published work, we have evaluated the use of allometry for prediction of CL/F and AUC. In this paper we describe the evaluation of different allometric scaling approaches for the prediction of C(max), V(z)/F and t(½) after oral drug administration in man. Twenty-nine compounds developed at Janssen Research and Development (a division of Janssen Pharmaceutica NV), covering a wide range of physicochemical and pharmacokinetic properties, were selected. The C(max) following oral dosing of a compound was predicted using (i) simple allometry alone; (ii) simple allometry along with correction factors such as plasma protein binding (PPB), maximum life-span potential or brain weight (reverse rule of exponents, unbound C(max) approach); and (iii) an indirect approach using allometrically predicted CL/F and V(z)/F and absorption rate constant (k(a)). The k(a) was estimated from (i) in vivo pharmacokinetic experiments in preclinical species; and (ii) predicted effective permeability in man (P(eff)), using a Caco-2 permeability assay. The V(z)/F was predicted using allometric scaling with or without PPB correction. The t(½) was estimated from the allometrically predicted parameters CL/F and V(z)/F. Predictions were deemed adequate when errors were within a 2-fold range. C(max) and t(½) could be predicted within a 2-fold error range for 59% and 66% of the tested compounds, respectively, using allometrically predicted CL/F and V(z)/F. The best predictions for C(max) were obtained when k(a) values were calculated from the Caco-2 permeability assay. The V(z)/F was predicted within a 2-fold error range for 72% of compounds when PPB correction was applied as the correction factor for scaling. We conclude that (i) C(max) and t(½) are best predicted by indirect scaling approaches (using allometrically predicted CL/F and V(z)/F and accounting for k(a) derived from permeability assay); and (ii) the PPB is an important correction factor for the prediction of V(z)/F by using allometric scaling. Furthermore, additional work is warranted to understand the mechanisms governing the processes underlying determination of C(max) so that the empirical approaches can be fine-tuned further.

Pure Red-Cell Aplasia “Epidemic”—Mystery Completely Revealed?

Starting in 1998, the number of pure red-cell aplasia (PRCA) cases in patients treated with recombinant human erythropoietin (rHuEPO) increased dramatically. Most cases were observed in patients treated with epoetin alfa produced outside the United States. The peak was observed in 2002; since then, the PRCA incidence has declined. Many factors are likely to have contributed to this up-surge. The molecular structure of the various epoetins and patient characteristics do not seem to play a major role. The route of administration holds some importance, because most PRCA patients received rHuEPO subcutaneously. The peak of PRCA cases overlapped with the removal of human serum albumin from the Eprex formulation (Janssen-Pharmaceutica NV, Beerse, Belgium), for which polysorbate 80 and glycine were substituted. Polysorbate 80 may have increased the immunogenicity of Eprex by eliciting the formation of epoetin-containing micelles or by interacting with leachates released by the uncoated rubber stoppers of prefilled syringes. Compared with the previous formulation, the polysorbate 80 formulation has lower stability, making it more susceptible to stress conditions such as insufficient attention to the cold chain. This situation could facilitate protein denaturation or aggregate formation. Uncoated rubber stoppers were replaced with coated stoppers, and the cold chain was reinforced; the Eprex formulation has remained unchanged. Even though the incidence of PRCA returned to very low levels, discriminating the cause-effect relationship of a single action is difficult, given that all occurred with a similar chronology, and that PRCA develops after a relatively long exposure period. Careful observation of future trends of new PRCA cases is thus mandatory.