Bion-1301, a First-in-Class APRIL Neutralizing Antibody for the Treatment of Multiple Myeloma: Preclinical Safety, and Analysis of Pharmacokinetics — Pharmacodynamics Relationship

BION-1301 is a first-in-class humanized antibody targeting APRIL (TNFSF13). We demonstrated that BION-1301 inhibits proliferation and survival of tumor cells and alleviates both APRIL-mediated drug resistance and immune suppression in preclinical multiple myeloma (MM) models¹. BION-1301 inhibits ligand dependent activation of both receptors TACI and BCMA, and as such differentiates from BCMA (TNFSF17) targeting cytotoxic approaches. Here, we report on the preclinical safety, Pharmacokinetics (PK)/ Pharmacodynamics (PD) relationship and pharmacometric analysis of BION-1301.

A single-dose non-human primate study administering intravenous BION-1301 at 0.3, 3 and 30 mg/kg dose levels, yielded PK parameters typical for IgG4 class antibodies and absence of tolerability issues. PD analysis showed a statistically significant reduction in total IgA and IgM in a dose-dependent fashion. Another measure of target modulation by BION-1301 was provided by co-injection of the hapten TNP-Ficoll (T-cell independent antigen) in different dose groups. Consistent with our observations in hAPRIL transgenic mice and in a dose-dependent fashion, BION-1301 reduced TNP-specific IgA and IgM². Using a weekly dosing regimen, a 4-week repeat-dose toxicity study was executed at 10, 30 and 100 mg/kg, demonstrating that BION-1301 had no effect on vital organs, ECG's, blood pressure, neurobehavioral examinations, and other factors examined, at any dose level at up to 100mg/kg. Chronic exposure to BION-1301 led to significantly reduced levels of IgA, IgG and IgM observed at all dose levels.

To determine target engagement of BION-1301, quantitative assays were developed to detect free APRIL and BION-1301. BION-1301 reduced free APRIL levels in serum in a dose-dependent manner following single and multiple dose administrations. Using a MABEL approach, PK/PD pharmacometric modeling informed a proposed human starting dose of 50 mg.

We anticipate initiation of a clinical trial to characterize safety and PK/PD relationship of BION-1301 in heavily pretreated patients with MM. Eligible patients need to have received at least 3 prior treatment lines, including IMiDs, PIs, and monoclonal antibodies. Following identification of a recommended Phase 2 dose, an expanded cohort will investigate clinical activity of single-agent BION-1301. The clinical activity of BION-1301 in combination with other MM therapies as informed by our preclinical experiments will be investigated in additional clinical trials.

In summary, BION-1301 was well tolerated and binding of APRIL in non-human primates resulted in decreased IgA, IgG and IgM production. PK and target engagement biomarkers predict the first in human dose using PK/PD modeling. BION-1301, which was shown preclinically to inhibit MM proliferation, survival, drug resistance and reversed an immune suppressive phenotype¹, is expected to enter clinical trials in 2017.

References:

1) Tai YT, Acharya C, An G, Moschetta M, Zhong MY, Feng X, Cea M, Cagnetta A, Wen K, van Eenennaam H, van Elsas A, Qiu L, Richardson P, Munshi N, Anderson KC. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood. 2016 Jun 23;127(25):3225-36

2) Guadagnoli M, Kimberley FC, Phan U, Cameron K, Vink PM, Rodermond H, Eldering E, Kater AP, van Eenennaam H, Medema JP. Development and characterization of APRIL antagonistic monoclonal antibodies for treatment of B-cell lymphomas. Blood. 2011 Jun 23;117(25):6856-65