Safety and efficacy of navitoclax, a BCL-2 and BCL-X_L inhibitor, in patients with relapsed or refractory lymphoid malignancies: results from a phase 2a study

Abstract

Navitoclax, a novel BCL-2 and BCL-X_L inhibitor, demonstrated promising antitumor activity in the dose-escalation part of a phase 1/2a study (NCT00406809) in lymphoid tumors. Herein, we report the continued safety and efficacy results of the phase 2a portion. Twenty-six adult patients with relapsed/refractory follicular lymphoma (n = 11, Arm A) and other relapsed/refractory lymphoid malignancies (n = 15, Arm B) were enrolled. Navitoclax administration schedule consisted of a 150-mg 7-day lead-in dose followed by 250-mg daily dosing with the option to further increase to 325 mg after 14 days if the 250-mg dose was tolerated. All patients experienced at least 1 treatment-related adverse event (TRAE). Seventeen (65.4%) patients reported grade 3/4 TRAEs; thrombocytopenia (38.5%) and neutropenia (30.8%) were the most common. Two patients reported serious AEs; none were fatal (no deaths occurred within 30 days of last dose of study drug). The objective response rate (complete and partial) was 23.1% (6/26; Arm A: 9.1%, Arm B: 33.3%). Median progression-free survival and time to progression were identical: 4.9 months (95% CI: 3.0, 8.2); median overall survival: 24.8 months (95% CI could not be computed). Navitoclax monotherapy has an acceptable safety profile and meaningful clinical activity in a minority of patients with relapsed/refractory lymphoid malignancies.

Keywords:

• BCL-2
• navitoclax
• lymphoid malignancies
• phase 2
• safety
• efficacy

Introduction

Apoptosis is determined by prosurvival proteins and proapoptosis proteins of the B-cell lymphoma 2 (BCL-2) family. The antiapoptotic proteins of the BCL-2 family such as BCL-2 and BCL-X_L prevent the activation of proapoptotic proteins BAX/BAK that are necessary to initiate the mitochondrial apoptosis pathway, subsequently leading to enhanced cancer cell survival [1–4]. Overexpression of antiapoptotic BCL-2 family members frequently occurs in lymphoid malignancies via a variety of mechanisms [5–8] and is associated with chemotherapy resistance and disease progression [9–12]. Several lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) are highly dependent on BCL-2 family members for cancer cell survival [10,13,14]. Therefore, targeting antiapoptotic BCL-2 family proteins represents a rational therapeutic approach in patients with lymphoid malignancies.

Navitoclax is an orally bioavailable, novel small-molecule inhibitor that targets and binds with high affinity (Ki ≤1 nM) to multiple antiapoptotic BCL-2 family proteins including BCL-X_L, BCL-2, BCL-w, and BCL-B, with the exceptions of MCL-1 or BFL-1, resulting in cancer cell death via apoptosis [15]. Preclinical studies have demonstrated potent cytotoxic activity (half-maximal effective concentration ≤1 μM) of navitoclax in human tumor cell lines derived from T- and B-cell lymphoid malignancies that overexpress BCL-2, and showed rapid and complete tumor regression in xenograft models, with durable responses lasting for several weeks in some models [15]. Clinical antitumor activity of navitoclax has been observed in lymphoid malignancies believed to be dependent on BCL-2 for survival [16,17].

The phase 1 results of this study in 55 patients with lymphoid malignancies have been previously reported [16]. With the intermittent 14/21-day dosing schedule, the dose-limiting toxicities (DLTs) were hospital admissions for bronchitis (n = 1) and pleural effusion (n = 1), grade 3 increase in aminotransferases (n = 1), grade 4 thrombocytopenia (n = 1), and grade 3 cardiac arrhythmia (n = 1). Clinical responses were seen across the range of doses and histologies. Ten of 46 patients with assessable disease had a partial response (PR), with median progression-free survival (PFS) of 15.0 months. A 150-mg 7-day lead-in dose followed by a 325-mg dose administered on a continuous 21/21-day dosing schedule was selected for the phase 2a study. Herein, we report the continued safety and efficacy results of the phase 2a portion of this study.

Patients and methods

Patients

Patients were enrolled across multiple sites between 01 November 2006 and 25 October 2010. Patients (≥18 years of age) were eligible if they met the following criteria: relapsed/refractory follicular lymphoma (FL; Arm A) or mantle cell lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma including mycosis fungoides or Sézary syndrome, and other indolent B-cell lymphomas such as marginal zone lymphoma (Arm B); measurable disease per International Working Group (IWG) criteria (patients with CLL and/or small lymphocytic lymphoma [SLL] had measurable disease by the 1996 National Cancer Institute Working Group [NCI-WG] criteria with computed tomography imaging); Eastern Cooperative Oncology Group (ECOG) performance status ≤1; adequate coagulation, hepatic, and renal function, and adequate bone marrow function (absolute neutrophil count [ANC] ≥ 1000/μL; platelets ≥100,000/mm³ [entry platelet count independent of transfusion within 14 days of screening]; hemoglobin ≥9.0 g/dL) independent of any growth factor support (except for patients with heavily infiltrated bone marrow [80% or more], who could use growth factor support to achieve ANC eligibility criteria). Patients who had a history of autologous stem cell transplant had to be >6 months post-transplant with adequate bone marrow independent of growth factor support at screening (ANC ≥1500/μL; platelets ≥125,000/mm³ [entry platelet count independent of transfusion within 14 days of screening]; hemoglobin ≥10.0 g/dL). Patients were excluded if they had a history of or were clinically suspicious for central nervous system disease (lymphoid or nonlymphoid) or had undergone an allogeneic stem cell transplantation.

Study design

The trial was registered with ClinicalTrials.gov registry (NCT00406809) and was approved by an independent ethics committee/institutional review board prior to initiation. The study was performed in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki; written informed consent was obtained from all patients prior to any study-related procedures.

The objectives of this open-label study were to assess the safety and efficacy of navitoclax in the phase 2a portion of the phase 1/2a trial. The data cutoff was May 2018.

The navitoclax recommended phase 2 dose and schedule determined in phase 1 was used [16].

The previous intermittent 14/21-day schedule had been found to be associated with fluctuations in platelet counts, and therefore navitoclax was administered orally on a continuous dosing schedule with an intermediate step-up dosing regimen. A 7-day lead-in navitoclax dose-titration period was implemented to mitigate the severity of navitoclax-induced thrombocytopenia. Patients started navitoclax dosing at 150 mg orally daily on lead-in days 1 through 7, and proceeded to 250 mg daily on cycle 1, day 1 if the pre-dose platelet count was 50,000/mm³ (50 × 10⁹/L) and was stable or increasing. If the 250-mg dose level was tolerated through cycle 1, the dose was titrated to the 325-mg dose level at the discretion of the investigator in consultation with the sponsor. A cycle was defined as 21 days. The study schematic is shown in Figure 1.

Figure 1. Dosing schematic for the phase 2a portion of the phase 1/2a study. C: cycle; D: day.

Safety and efficacy assessments

Safety evaluations were performed throughout the study and included adverse event (AE) monitoring, physical examination, and laboratory assessments including complete blood counts.

Efficacy endpoints included tumor response, PFS, time to tumor progression (TTP), overall survival (OS), and duration of overall response (DOR). Tumor responses were determined using IWG criteria [18] and NCI-WG criteria [19].

Statistical analyses

Descriptive statistics were computed for categoric variables and used to summarize numeric variables. The number and percentage of patients experiencing treatment-emergent AEs (TEAEs) were tabulated by Medical Dictionary for Regulatory Activities system organ class and preferred term. TEAEs were graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

The proportion of patients with a complete response (CR), unconfirmed CR (CRu), or PR on the basis of IWG criteria was estimated and the corresponding 95% CI for the proportion was calculated using the exact binomial distribution. The distribution of PFS, TTP, OS, and DOR was estimated using the Kaplan–Meier method; median time and the corresponding 95% CI were estimated for each endpoint.

The sample size was primarily based on clinical convention for a safety expansion, and designed to provide a certain degree of precision around the estimate for the true PR rate; the sample size of 20 patients provides 90% confidence that the true PR rate at 3 months is within ∼20% of the observed PR rate.

Results

Patient characteristics and study drug exposure

Twenty-six patients were enrolled in the phase 2a portion of the phase 1/2a study: 11 patients in Arm A had FL and 15 patients in Arm B had CLL (n = 7), SLL (n = 2), lymphoplasmacytic lymphoma (n = 2), mantle cell lymphoma (n = 2), low-grade B-cell lymphoma (n = 1), or marginal zone B-cell lymphoma (n = 1). Key patient demographics and clinical characteristics are shown in Table 1. The median age was 62 years (range, 42–77) in Arm A and 62 years (range, 44–86) in Arm B. Demographics were generally comparable to the previously reported phase 1 portion of the study [16]. The median and mean time on treatment was 2.9 and 9.7 months (range, 0.4–71.8); in Arm A, 2.1 and 7.4 months (range, 1.2–52.8); and in Arm B, 4.9 and 11.4 months (range, 0.4–71.8). The mean dose of navitoclax administered during the first year of treatment ranged from 263 mg to 325 mg.

Table 1. Patient demographics and baseline characteristics.

	Arm A	Arm B	Total
	(n = 11)	(n = 15)	(N = 26)
Age, years
Median (range)	62.0 (42–77)	62.0 (44–86)	62.0 (42–86)
<65, n (%)	8 (72.7)	10 (66.7)	18 (69.2)
≥65, n (%)	3 (27.3)	5 (33.3)	8 (30.8)
Sex, n (%)
Female	3 (27.3)	5 (33.3)	8 (30.8)
Male	8 (72.7)	10 (66.7)	18 (69.2)
Race, n (%)
White	8 (72.7)	11 (73.3)	19 (73.1)
Black	1 (9.1)	3 (20.0)	4 (15.4)
Asian	2 (18.2)	0	2 (7.7)
Mixed	0	1 (6.7)	1 (3.8)
Ethnicity, n (%)
Hispanic	1 (9.1)	0	1 (3.8)
No ethnicity stated	10 (90.9)	15 (100)	25 (96.2)
Baseline ECOG performance status^a
0	8 (80.0)	10 (66.7)	18 (72.0)
1	2 (20.0)	5 (33.3)	7 (28.0)
Baseline LDH
High	1 (9.1)	3 (20.0)	4 (15.4)
Normal or low	10 (90.9)	12 (80.0)	22 (84.6)
Median no. of prior therapies (range)	5 (1–7)	2 (1–11)	3.5 (1–11)
Stage III/IV^b, n (%)	5 (50.0)	9 (69.2)	14 (60.9)
	n = 10	n = 13	n = 23
Cancer type, n (%)
Follicular lymphoma	11 (100)	/	11 (42.3)
Chronic lymphocytic leukemia	/	7 (46.7)	7 (26.9)
Small lymphocytic lymphoma	/	2 (13.3)	2 (7.7)
Lymphoplasmacytic lymphoma	/	2 (13.3)	2 (7.7)
Mantle cell lymphoma	/	2 (13.3)	2 (7.7)
Low-grade B-cell lymphoma	/	1 (6.7)	1 (3.8)
Marginal zone B-cell lymphoma	/	1 (6.7)	1 (3.8)
Cutaneous T-cell lymphoma	/	/	/
Peripheral T-cell lymphoma	/	/	/

ECOG: Eastern Cooperative Oncology Group; LDH: lactate dehydrogenase.

^aData missing for 1 patient in Arm A.

^bData not available for all patients.

Safety

All patients have discontinued navitoclax (Supplemental Table S1). The most common reasons for discontinuation were AEs and radiologic progressive disease (n = 10 [38.5% each]).

All-grade TEAEs and serious TEAEs that led to navitoclax dose interruption, delayed dosing, dose reduction, or discontinuation are summarized in Table 2. AEs leading to navitoclax discontinuation were reported for 2 (18.2%) patients in Arm A and 8 (53.3%) patients in Arm B.

Table 2. Summary of treatment-emergent adverse events related to navitoclax.

TEAEs	Total
	(N = 26)
Any AE (≥20% patients), n (%)	26 (100)
Diarrhea	23 (88.5)
Nausea	16 (61.5)
Thrombocytopenia	14 (53.8)
Fatigue	11 (42.3)
Vomiting	10 (38.5)
Neutropenia	8 (30.8)
Grade 3 or 4 AEs (≥5% patients), n (%)	17 (65.4)
Thrombocytopenia	10 (38.5)
Neutropenia	8 (30.8)
Increased alanine aminotransferase	2 (7.7)
Lymphopenia	2 (7.7)
Serious AEs	2 (7.7)
Bacterial sepsis	1 (3.8)
Increased white blood cell count	1 (3.8)
Overview of TEAE	Total	Arm A	Arm B
	(N = 26)	(n = 11)	(n = 15)
Any AE leading to navitoclax
Discontinuation	10 (38.5)	2 (18.2)	8 (53.3)
Dose reduction	9 (34.6)	3 (27.3)	6 (40.0)
Dose interruption	13 (50.0)	3 (27.3)	10 (66.7)
Dose delay	2 (7.7)	0	2 (13.3)
Any serious AE leading to navitoclax
Discontinuation	2 (7.7)	0	2 (13.3)
Dose reduction	0	0	0
Dose interruption	2 (7.7)	0	2 (13.3)
Dose delay	0	0	0

AE: adverse event; TEAE: treatment-emergent adverse event.

TEAEs related to navitoclax are summarized in Table 2. All patients experienced at least 1 navitoclax-related TEAE, mainly of low-grade gastrointestinal or hematologic type; most common were diarrhea (88.5%), nausea (61.5%), and thrombocytopenia (53.8%). Seventeen patients (65.4%) experienced grade 3/4 AEs related to navitoclax, with thrombocytopenia (38.5%) and neutropenia (30.8%) being most common. Serious related AEs were reported in 2 patients (bacterial sepsis and increased white blood cell count [n = 1 each]); none were fatal. Overall, no deaths occurred within 30 days of the last dose of study drug.

Hematologic AEs of NCI CTCAE grade 3/4 during the study recovered to grade 2 or better by the final visit, with the exception of 3 patients (11.5%) who did not have recovery of grade 4 thrombocytopenia to grade 2 or better.

Efficacy

The objective response rate (ORR) was 23.1% (95% CI: 9.0, 43.6) in all treated patients: 9.1% (95% CI: 0.2, 41.3) in Arm A, and 33.3% (95% CI: 11.8, 61.6) in Arm B (Table 3). One patient with FL achieved a CR (Supplemental Figure S1). Five patients achieved a PR: 3/7 patients with CLL, 1/2 patients with lymphoplasmacytic lymphoma, and 1/1 patients with low-grade B-cell lymphoma (Table 3). Best percentage change in tumor size from baseline in all patients is illustrated in Supplemental Figure S2.

Table 3. Tumor response rate.

Response, n/N (%) [95% CI]^a	Arm A (FL) (n = 11)	Arm B							Total (N = 26)
		All	CLL	SLL	LPL	MCL	Low-grade B-cell lymphoma	Marginal zone B-cell lymphoma
		(n = 15)	(n = 7)^c	(n = 2)	(n = 2)	(n = 2)	(n = 1)	(n = 1)
Objective response^b
CR	1/11 (9.1)	0/15	0	0	0	0	0	0	1/26 (3.8)
nPR	0/11	0/15	0	0	0	0	0	0	0/26
PR	0/11	5/15 (33.3)	3/7 (42.9)	0	1/2 (50.0)	0	1/1 (100)	0	5/26 (19.2)
CR + nPR + PR	1/11 (9.1) [0.2, 41.3]	5/15 (33.3) [11.8, 61.6]	3/7 (42.9) [9.9, 81.6]	0	1/2 (50.0) [1.3, 98.7]	0	1/1 (100)	0	6/26 (23.1) [9.0, 43.6]

CLL: chronic lymphocytic leukemia, CR: complete response; FL: follicular lymphoma; LPL: lymphoplasmacytic lymphoma; MCL: mantle cell lymphoma; nPR: nodular partial response; PD: progressive disease; PR: partial response; SLL: small lymphocytic lymphoma.

^a95% CI determined from the exact binomial distribution.

^bComplete or partial responses needed to be confirmed >4 weeks (28 days) apart for an objective response.

^cOne patient with CLL was not evaluable.

The median PFS and TTP were identical at 4.9 months (95% CI: 3.0, 8.2). The median PFS and TTP for Arm A was 3.1 months (95% CI: 1.4, 3.7), and 6.5 months (95% CI: 4.9, 22.1) for Arm B. In Arm B, 5 patients were observed to have a PFS duration beyond 1 year. Two of those patients eventually had events: 1 CLL patient had PD at month 18 and 1 low-grade B-cell lymphoma patient had PD at month 22. The other 3 patients (CLL, n = 1; lymphoplasmacytic lymphoma, n = 2) concluded the study prior to PD or death. The median OS was 24.8 months (95% CI could not be computed): 17.6 months (95% CI could not be computed) for Arm A and 24.8 months (95% CI could not be computed) for Arm B (Figure 2(A–C)). The median DOR was 20.5 months (95% CI: 4.9, 50.7) on the basis of 6 responders, 4 of whom experienced progressive disease or death events; median DOR was 50.7 months for Arm A and 20.5 months for Arm B.

Figure 2. (A) PFS, (B) TTP, (C) OS for patients by arm (Arm A = solid line, Arm B = dotted line). OS: overall survival; PFS: progression-free survival; TTP: time to tumor progression.

Discussion

These results confirm the preliminary efficacy initially observed during the phase 1b portion of the study and provide extended follow-up with continuing acceptable toxicity data for navitoclax in patients with relapsed/refractory CLL and NHL. Navitoclax was well tolerated for up to 6 years of continuous dosing, one of the longest continuous exposures studied of BCL-2 family inhibitors to date. The most common related AEs were diarrhea, nausea, and thrombocytopenia. Treatment-related lymphopenia and thrombocytopenia were on-target BCL-2 and BCL-X_L effects, respectively. The DLT of navitoclax was thrombocytopenia [16,17] due to inhibition of BCL-X_L, the key prosurvival protein sustaining circulating platelet survival [20,21]. We again observed grade 3 and 4 neutropenia in 30.8% of patients, responsive to dose interruptions and growth factor support, a side effect possibly due to an on-target effect on myeloid progenitors [16,22].

Navitoclax had meaningful clinical activity in patients with relapsed/refractory indolent NHL and CLL/SLL. The ORR was 23.1%, in line with the ORR of 21.7% in the phase 1 trial (Supplemental Table S2) [16], where all patients who responded had PRs [16]. In this phase 2a part of the trial, 1 patient in Arm A achieved a CR (FL) and 5 patients in Arm B had PRs, including 3 patients with CLL, 1 with lymphoplasmacytic lymphoma, and 1 with indolent NHL. These response rates were mainly driven by CLL patients (42.9% ORR), consistent with phase 1 study results of navitoclax in patients with relapsed/refractory CLL demonstrating an ORR of 35% [17]. Comparable response (38% ORR) was also reported in a multicenter international phase 2 study of navitoclax in patients with relapsed/refractory CLL [23].

New effective therapies with favorable safety profiles are needed to improve outcomes for patients with relapsed/refractory lymphoid malignancies. Contrary to the dominant dependency of CLL cells on BCL-2 for survival, pro- and antiapoptotic proteins are expressed at varying levels in other lymphoid malignancies. It is not surprising that single agents with a limited on-target profile demonstrate varying responses in these histologies. Therefore, navitoclax combinations with potentially synergistic agents hold promise to improve the response rates when targeting NHL. Preclinical models have demonstrated synergistic activity of navitoclax with gemcitabine, vincristine, docetaxel, and bendamustine plus rituximab [15,24–26]. The clinical activity of navitoclax in a chemotherapy-free setting in combination with rituximab was investigated in patients with relapsed or refractory CD20-positive lymphoid malignancies and patients with previously untreated B-cell CLL, demonstrating good tolerability and promising synergistic antitumor activity [27,28]. Navitoclax was also tested in combination with bendamustine and rituximab in patients with relapsed diffuse large B-cell lymphoma as part of the NAVIGATE study, but recruitment was terminated in 2011 due to non–safety-related reasons (NCT01423539).

Due to the BCL-X_L–mediated DLT of thrombocytopenia, a next-generation highly potent, orally bioavailable, BCL-X_L–sparing and BCL-2–selective inhibitor, venetoclax, was developed [29]. On the basis of significant activity as monotherapy in CLL, the US Food and Drug Administration (FDA) approved venetoclax for CLL with 17p deletion (April 2016) [30], venetoclax plus rituximab for previously treated CLL (June 2018) [31], and as combination therapy with obinutuzumab for treatment-naive CLL (May 2019) [32]. Further, venetoclax received accelerated approval in combination with either azacitidine, decitabine, or low-dose cytarabine by the FDA for newly diagnosed acute myeloid leukemia patients ineligible for intensive induction chemotherapy (November 2018) [33].

In a venetoclax phase 1 monotherapy study, the reported ORR varied across the subtypes of NHL, with an overall ORR of 44% (mantle cell lymphoma, 75%; FL, 38%; diffuse large B-cell lymphoma, 18%) [34]. The lower-than-expected response rate in FL was surprising and exemplified the molecular complexity of this malignancy. Therefore, combination therapy and better understanding of mechanisms of primary and secondary resistance to BCL-2 inhibition are required to improve response rates and durations in lymphoma. Venetoclax has been safely combined with multiagent chemotherapy such as bendamustine-rituximab [35], rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP; CAVALLI trial) [36], or rituximab-etoposide-prednisone-vincristine-cyclophosphamide-doxorubicin (R-EPOCH; NCT03036904).

The role of navitoclax combinations in inducing cancer cell apoptosis is an area of active investigation. Multiple clinical trials using navitoclax are underway, including a study of navitoclax in combination with ruxolitinib for patients with myelofibrosis, and in combination with venetoclax and multiagent chemotherapy for patients with relapsed/refractory acute lymphocytic leukemia (ALL) and lymphoblastic lymphoma. In the pediatric and adult study of ALL evaluating weight-adjusted low doses of navitoclax (25 to 100 mg) with venetoclax and optional low-dose chemotherapy, preliminary data in 9 patients demonstrated 5 CRs and 1 PR, with a tolerable safety profile [37]. Of interest is the observation that optimized dosing levels of navitoclax may provide efficacy without severe thrombocytopenia.

In a preclinical study, the potential role of navitoclax to counteract the upregulation of BCL-X_L as a mechanism of resistance in mantle cell lymphoma to treatment with venetoclax (BCL-2–specific inhibitor) was demonstrated. Functional modeling in mantle cell lymphoma cell lines demonstrated that increased BCL-X_L expression provides a dominant escape mechanism from BCL-2–specific inhibitors, and combination therapy with BCL-2 and BCL-X_L inhibitors was able to overcome this resistance [38]. While navitoclax may have a role in combination with venetoclax, neither drug targets MCL-1, a potential venetoclax-resistance mediator. However, MCL-1 may be targeted with specific MCL-1 inhibitors, phosphoinositide 3-kinase inhibitors, or CDK9 inhibitors that downregulate MCL-1 expression [39]. BCL-2 homology domain 3 profiling [40] may improve our ability to better understand the antiapoptotic makeup of lymphoid malignancies and to select the appropriate targeting agent in the future. Navitoclax could possibly have a role as an effective tool in such a personalized effort targeting the antiapoptotic defense of lymphoid and other hematologic malignancies.

Acknowledgements

Medical writing support was provided by Mary L. Smith, PhD, CMPP, of Aptitude Health, Atlanta, GA, funded by AbbVie. This manuscript is original and not under consideration for publication elsewhere. The phase 1 portion of this study has been previously published in Wilson et al. [16]. Results of this trial have partially been presented at the 16th Congress of the European Hematology Association (EHA).

Disclosure statement

Sven de Vos is in the advisory boards for Incyte, Bayer, and Genentech. John P. Leonard is a consultant for Sutro, Bayer, Gilead, AstraZeneca, Celgene, Roche/Genentech, ADC Therapeutics, Sandoz, Karyopharm, Miltenyi, Epizyme, MEI Pharma, BMS, Regeneron, Genmab, AbbVie, Incyte. Jonathan W. Friedberg is involved in the data and safety monitoring committee activities: Bayer and Ascerta; travel support from Roche. Jasmine Zain reports no conflict of interest. Kieron Dunleavy holds consultant/advisory roles for AbbVie, Adaptive, Amgen, Celgene, Janssen, Seattle Genetics, Pharmacyclics, Kite. John Hayslip and John Pesko are AbbVie employees and may own stock. Rod Humerickhouse is a former employee of AbbVie and may hold AbbVie stock or options. Wyndham Wilson reports no conflict of interest.

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Additional information

Funding

AbbVie Inc. provided financial support for the study and participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review, and approval of the manuscript.