Delving into the Latest Updates on BHQ-880 with Synapse

Overview

Basic Info

Drug Type

Monoclonal antibody

Synonyms

Anti-DKK1 mAb, Anti-DKKK-1 neutralising antibody

+ [1]

Target

DKK1

Action

inhibitors

Mechanism

DKK1 inhibitors(Dickkopf-related protein 1 inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication-

Inactive Indication

Multiple MyelomaRefractory Multiple MyelomaSmoldering Multiple Myeloma

Originator Organization

MorphoSys AG

Active Organization-

Inactive Organization

Novartis Pharmaceuticals Corp.

License Organization-

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Sequence Code 179955L

Sequence Code 179861H

The study will evaluate the effects of BHQ880 in patients with previously untreated multiple myeloma and renal insufficiency who are not considered candidates for bisphosphonate therapy. The primary objective of the study will be to evaluate the effect of BHQ880 in combination with bortezomib and dexamethasone, compared to placebo administered with the combination on the time to first Skeletal Related Event (SRE) on study.

Start Date01 Jan 2012

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

NCT01302886

/ CompletedPhase 2

A Single-arm, Open-label, Phase 2 Clinical Trial Evaluating Disease Response Following Treatment With Intravenous BHQ880, a Fully Human, Anti-Dickkopf1 (DKK1) Neutralizing Antibody in Previously Untreated Patients With High-risk, Smoldering Multiple Myeloma

This study will assess the antimyeloma effects of BHQ880A in patients with smoldering multiple myeloma with high risk of progression to active multiple myeloma. BHQ880 will be administered every 28 days in previously untreated patients. Disease assessments will be performed monthly and effects on bone metabolism will be assessed by measurement of serum and urine bone biomarkers, changes in BMD , and QCT with FEA. Additionally, the PK profile of BHQ880 as a single agent and following multiple doses will be obtained.

Start Date01 May 2011

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

NCT00741377

/ CompletedPhase 1

A Phase Ib/II Multicenter Dose-determination Study, With an Adaptive, Randomized, Placebo-controlled, Double-blind Phase II, Using Various Repeated IV Doses of BHQ880 in Combination With Zoledronic Acid in Relapsed or Refractory Myeloma Patients With Prior Skeletal-related Event

This study has two portions, a phase I portion and a phase II portion. The purpose of the phase I portion is to assess the maximum-tolerated dose (MTD) and to characterize dose limiting toxicity (DLT) of escalating doses of BHQ880 (up to a maximum dose of 20 mg/kg) in combination with standard chemotherapy and zoledronic acid in relapsed or refractory multiple myeloma patients.
The phase II portion of the study will also be conducted in relapsed or refractory multiple myeloma patients. Patients will be treated with various doses of BHQ880 or placebo in combination standard chemotherapy. In the phase II portion of the study zoledronic acid will be added after the first 28 days of therapy with BHQ880 or placebo and standard chemotherapy. This will allow any BHQ880-related changes in bone biomarkers to be detected in a zoledronic acid-free environment. The purpose of the phase II portion of the study, is to determine one or more doses of BHQ880 for further development based on dose-efficacy modeling. Efficacy is defined as time to first skeletal-related event and change in bone markers for bone resorption and formation relative to placebo. A skeletal-related event is defined as:
Pathologic fracture
Spinal cord compression
Requirement for either radiation or surgery to bone due to:
Pain
Prevention of imminent fracture
Stabilization of a fracture Biomarker and imaging endpoints will be assessed in both phases of the study. The pharmacodynamic effects of BHQ880 will be assessed by measuring biochemical markers of bone formation, resorption, and metabolism in serum and urine. Charges in serum DKK1 levels will be characterized. The size and number of lytic bone lesions as measured by bone survey (X-ray) or MRI will be assessed. In addition, bone mineral density (BMD) will be measured by DEXA scan and at selected sites with QCT scans.

Start Date01 Jan 2009

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with BHQ-880

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100 Translational Medicine associated with BHQ-880

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100 Patents (Medical) associated with BHQ-880

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12

Literatures (Medical) associated with BHQ-880

01 Jul 2024·Biomedicine & Pharmacotherapy

Enhancing motor functional recovery in spinal cord injury through pharmacological inhibition of Dickkopf-1 with BHQ880 antibody

Article

Author: González-Fernández, Carlos ; Maqueda, Alfredo ; Pérez, Virginia ; Rodríguez, Francisco Javier ; González, Pau

BACKGROUNDMounting experimental evidence has underscored the remarkable role played by the Wnt family of proteins in the spinal cord functioning and therapeutic potential in spinal cord injury (SCI). We aim to provide a therapeutic prospect associated with the modulation of canonical Wnt signaling, examining the spatio-temporal expression pattern of Dickkopf-1 (Dkk1) and its neutralization after SCI. We employ an intraparenchymal injection of the clinically validated Dkk1-blocking antibody, BHQ880, to elucidate its effects in SCI.METHODSA rat model of contusion SCI was used. Histological analyses were performed, wherein Dkk1 protein was sought, and ELISA analyses were employed for Dkk1 detection in cerebrospinal fluid and serum. To ascertain the BHQ880 therapeutic effect, rats were subjected to SCI and then injected with the antibody in the lesion epicenter 24 hours post-injury (hpi). Subsequent evaluation of motor functional recovery extended up to 56 days post-injury (dpi). qRT-PCR and histological analyses were conducted.RESULTSWe demonstrate the presence of Dkk1 in the healthy rat spinal cord, with pronounced alterations observed following injury, primarily concentrated in the epicenter regions. Notably, a significative upregulation of Dkk1 was detected at 24 hpi, peaking at 3 dpi and remaining elevated until 42 dpi. Moreover, we revealed that early administration of BHQ880 considerably improved motor functional recovery, promoted preservation of myelinated tissue, and reduced astroglial and microglia/macrophage reactivity. Furthermore, there was a decrease in the acute expression of different inflammatory genes.CONCLUSIONSCollectively, our findings highlight the therapeutic potential of BHQ880 treatment in the context of SCI.

01 Apr 2021·Molecular Cancer Research

mDKN-01, a Novel Anti-DKK1 mAb, Enhances Innate Immune Responses in the Tumor Microenvironment

Article

Author: Haas, Michael S. ; Newman, Walter ; Kagey, Michael H. ; Schuerpf, Franziska ; Heath, Heidi ; Rottman, James B.

AbstractDickkopf-1 (DKK1), a secreted modulator of Wnt signaling, is overexpressed in many cancers, is often associated with worse clinical outcomes, and has been shown to have immunosuppressive effects. DKN-01 is an IgG4 clinical stage antibody that potently and specifically neutralizes human and murine DKK1 and has recently completed a promising study in combination with pembrolizumab in patients with gastric/gastroesophageal junction cancer. The purpose of this study is to characterize a murine version of DKN-01 (mDKN-01) and to better understand its mechanism of action. We examined the efficacy of mDKN-01 in both melanoma and metastatic breast cancer models. Immune depletion experiments revealed a requirement for natural killer (NK) but not B and T cells for tumor growth inhibition. mDKN-01 treatment promotes the induction of the NK-activating cytokines IL15 and IL33 as well as an enhanced recruitment of CD45+ cells. Other treatment-related changes include a reduction of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSC) in the tumor and spleen and the upregulation of PD-L1 on MDSCs. In addition, mDKN-01 has a marked effect at reducing pulmonary metastases in the mouse 4T1 breast cancer model. Finally, the mDKN-01/anti-PD-1 combination was more effective at inhibiting melanoma growth than mDKN-01 alone. Taken together, our data demonstrate that mDKN-01 has efficacy by blocking the immunosuppressive effects of DKK1 in the tumor microenvironment (TME) and provides insight into the clinical activity observed with DKN-01–based treatment.Implications:mDKN-01 reverses a DKK1-mediated innate immune suppression in the TME and has additive efficacy with a PD-1 inhibitor.

19 Apr 2016·Oncotarget

A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model

Article

Author: Guzman, Wendy Bautista ; Trucco, Matteo ; Loeb, David M. ; Hayashi, Masanori ; Goldstein, Seth D.

The outcome of patients with metastatic osteosarcoma has not improved since the introduction of chemotherapy in the 1970s. Development of therapies targeting the metastatic cascade is a tremendous unmet medical need. The Wnt signaling pathway has been the focus of intense investigation in osteosarcoma because of its role in normal bone development. Although the role of Wnt signaling in the pathogenesis of osteosarcoma is controversial, there are several reports of dickkopf-1 (DKK-1), a Wnt signaling antagonist, possibly playing a pro-tumorigenic role. In this work we investigated the effect of anti-DKK-1 antibodies on the growth and metastasis of patient-derived osteosarcoma xenografts. We were able to detect human DKK-1 in the blood of tumor-bearing mice and found a correlation between DKK-1 level and tumor proliferation. Treatment with the anti-DKK-1 antibody, BHQ880, slowed the growth of orthotopically implanted patient-derived osteosarcoma xenografts and inhibited metastasis. This effect was correlated with increased nuclear beta-catenin staining and increased expression of the bone differentiation marker osteopontin. These findings suggest that Wnt signaling is anti-tumorigenic in osteosarcoma, and support the targeting of DKK-1 as an anti-metastatic strategy for patients with osteosarcoma.

100 Deals associated with BHQ-880

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Myeloma	Phase 2	Spain	Novartis Pharmaceuticals Corp.	01 Jan 2012
Multiple Myeloma	Phase 2	United Kingdom	Novartis Pharmaceuticals Corp.	01 Jan 2012
Multiple Myeloma	Phase 2	United States	Novartis Pharmaceuticals Corp.	01 Jan 2012
Smoldering Multiple Myeloma	Phase 2	Germany	Novartis Pharmaceuticals Corp.	01 May 2011
Smoldering Multiple Myeloma	Phase 2	France	Novartis Pharmaceuticals Corp.	01 May 2011
Smoldering Multiple Myeloma	Phase 2	United States	Novartis Pharmaceuticals Corp.	01 May 2011
Refractory Multiple Myeloma	Phase 2	United Kingdom	Novartis Pharmaceuticals Corp.	01 Jan 2009
Refractory Multiple Myeloma	Phase 2	United States	Novartis Pharmaceuticals Corp.	01 Jan 2009

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Biosimilar

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