Targeting Cutaneous Venous and Lymphatic Malformations at Their Source.
Targeting cutaneous venous and lymphatic malformations at their source.
PATIENTS
Venous and lymphatic malformations (VM and LM respectively) are types of congenital vascular anomalies, which are present at birth. These malformations can cause a number of clinical complications including pain, bleeding and impairment of the function of the affected area. Many people living with either VMs or LMs have disfigurement, which can have a meaningful psychological and social impact.
Cutaneous VMs are characterized by overgrown, disorganized veins near the skin, and they may look like a blue discoloration of the skin.
Cutaneous LMs are fluid-filled sacs that do not drain properly due to abnormalities in the lymphatic system, and they tend to become infected and may require repeated antibiotic treatments. Cutaneous LMs often lie just under the skin or involve other tissues close to the skin.
Both VM and LM channels have little to no flow and are susceptible to the formation of clots, also known as coagulopathy.
Current treatment options are limited to surgery, sclerotherapy, laser treatments, and compressive garments. There are no pharmacological therapies currently approved for people with cutaneous VM and LM.
SCIENCE
The majority of VMs and LMs are caused by somatic mutations in either the TEK or PIK3CA gene. These genes encode the proteins Tie2 and PI3Kα respectively, both of which are key proteins in the PI3Kα/AKT signaling pathway. This signaling pathway plays a central role in the development and maintenance of healthy venous and lymphatic channels. TEK and PIK3CA mutations result in the abnormal activation of the PI3Kα/AKT signaling pathway, which in turn drives increased growth and survival of the endothelial cells that line venous and lymphatic channels. The increased signaling results in overgrown and malformed venous and lymphatic channels.
VM or LM are often considered “mosaic” because only a fraction of cells in a person contain the mutation. The number of the cells that contain the mutation determines the extent of the VM or LM, which can sometimes be associated with overgrowth. Because the mutation arises during fetal development, it is only present in subsequently dividing cells, and these cells ultimately comprise the VM or LM.
OUR APPROACH
Our approach to treating VMs and LMs focuses on getting the right medicine to the right tissue.
Right drug: PI3K inhibition targets VM and LM at their genetic source
No Mutation
PIK3CA Mutation
Treated with PI3K Inhibitor
Activation of the Tie2 receptor stimulates the PI3K pathway, leading to healthy cell proliferation.
Increased activation of the PI3K pathway leads to the underlying cellular changes in VM and LM.
VT10 reduces PI3K signaling.
Right drug: PI3K inhibition targets VM and LM at their genetic source
No Mutation
TEK Mutation
Treated with PI3K Inhibitor
Activation of the Tie2 receptor stimulates the PI3K pathway, leading to healthy cell proliferation.
Increased activation of the PI3K pathway leads to the underlying cellular changes in VM and LM.
VT10 reduces PI3K signaling.
Targeting the PI3K pathway emerged as a promising clinical approach in a 2016 paper from Castel, et al., that demonstrated activating mutations of the PIK3CA gene in mice gives rise to venous malformations and that treating those mice with topical PI3K inhibitors achieved a rapid and sustained regression of skin lesions.1 Human data from a compassionate use study (Venot, 2018) has demonstrated that oral administration of a PI3K inhibitor quickly and markedly improves VMs and LMs in PIK3CA-related overgrowth spectrum (PROS) patients – indicating that PI3K inhibition is a potentially effective therapeutic approach.2 Based on these encouraging earlier results, we believe that delivering a PI3K inhibitor to the skin and structures close beneath has the potential to be an effective way of managing VMs/LMs.
VT10 targets VMs and LMs at their genetic source, suppressing the PI3K signaling pathway that drives growth of these lesions. Our in vitro and in vivo experiments have shown that VT10 can suppress PI3K signaling and reduce the viability of VM cells.
References
1. Castel, P., et al. “Somatic PIK3CA mutations as a driver of sporadic venous malformations.” Sci Transl Med. (2016).
2. Venot, Q., et al. “Targeted therapy in patients with PIK3CA-related overgrowth syndrome.” Nature. (2018).
Right tissue: VT30 topical gel is designed for direct delivery to cutaneous lesions
Our lead product, VT30 topical gel, is designed to target the right tissue – the network of malformed vasculature lying just underneath the skin. It is a gel formulation optimized for skin permeation. Once VT30 crosses the skin, it is cleaved by naturally occurring enzymes to produce VT10, a potent inhibitor of PI3Kα. Our local transdermal approach is designed to deliver the drug directly to the cutaneous lesion, bypassing the need for systemic administration.
ABOUT US
Venthera, an affiliate of BridgeBio Pharma, is a biotechnology company focused on developing therapeutics for the treatment of venous and lymphatic malformations, congenital conditions that are driven by activating mutations of the PI3K signaling pathway. We aim to develop a safe and effective treatment for these painful disorders as quickly and safely as possible.
LEADERSHIP
Thomas Rossi, PhD
Chief Executive Officer
Ken Truitt, MD
Chief Medical Officer
Kahlil D’Souza
VP of Business Development and Operations
Lisa Pugliese
VP of Clinical Operations
CLINICAL ADVISORY BOARD
Dra. Eulalia Baselga (Co-founder)
SJD Barcelona Children’s Hospital
Dr. Ilona Frieden
University of California, San Francisco
Dr. Laurence Boon
Cliniques Universitaires Saint-Luc
Dr. Beth Drolet
University of Wisconsin Madison
Dr. Denise Adams
Boston Children’s Hospital
Dr. Guillaume Canaud
Necker Hospital, Paris
Our work continues in memory of our co-founder, Dr. José Baselga. A pioneer in targeted oncology and beyond, his work has impacted countless patients.
SCIENTIFIC ADVISORY BOARD
Pau Castel, PhD (Co-founder)
University of California, San Francisco
Kevan Shokat, PhD
University of California, San Francisco
Miikka Vikkula, MD, PhD
Université Catholique de Louvain
Bart Vanhaesenbroeck, PhD
University College London
VENTHERA IS A MEMBER OF
THE BRIDGEBIO FAMILY
BridgeBio is a team of experienced drug discoverers, developers and innovators working to create life-altering medicines that target well-characterized genetic diseases at their source. BridgeBio was founded in 2015 to identify and advance transformative medicines to treat patients who suffer from Mendelian diseases, which are diseases that arise from defects in a single gene, and cancers with clear genetic drivers. BridgeBio’s pipeline of over 20 development programs includes product candidates ranging from early discovery to late-stage development.
SCIENTIFIC PUBLICATIONS
CONTACT
421 Kipling Street
Palo Alto, California 94301
To receive updates or get in touch, contact us at:
info@venthera.com
