By Mike Nagle 05/11/2007- BioInvent and ThromboGenics' new anticancer antibody is poised to enter clinical trials and could prove a serious rival to VEGF-blocking drugs, due to fewer side-effects and less drug resistance.
The overall affect of TB-403 is to starve cancer tumours by cutting off their blood supply. In this way, it is similar to Genentech and Roche's Avastin (bevacizumab), a blockbuster antibody that targets vascular endothelial growth factor (VEGF). However, the pretender to the Avastin throne exerts its effect through a totally different target - placental growth factor (PlGF).
The drug's developers believe this new target gives TB-403 a couple of advantages over VEGF drugs. The first is that VEGF inhibitors act on normal, as well as diseased, tissue causing side-effects such as blood clots, high blood pressure, blood vessel pruning in healthy organs, interruption of pregnancy, and other side effects, according to scientists at the University of Leuven, Belgium, and the Flanders Institute for Biotechnology (VIB).
Writing in the latest edition of the journal Cell, the researchers explain that, by comparison, PlGF levels are virtually undetectable and dispensable in normal, healthy tissue.
"PlGF knockout mice survive and are healthy," said Peter Carmeliet from the University of Leuven.
"With no VEGF, they die before birth."
PlGF is overexpressed in cancer and chronic inflammatory conditions and induces new vessel formation in tissues under stress. This means that, unlike VEGF, PlGF does not seem to affect normal blood vessel growth, according to BioInvent.
"This mode of action, which is different from and complementary to current anti-VEGF inhibitors, makes it attractive as both a stand-alone and combination therapy," said Prof. Desire Collen, CEO of Belgium-based ThromboGenics.
The hope is that PlGF inhibitors could cause limited side-effects yet still provide the desired efficacy.
The second potential advantage to attacking this new target in preference to VEGF paradoxically stems from the fact that PlGF inhibitors don't seem to be as effective as their more established rivals. Avastin and others do their job to such an extent that the body begins to produce other molecules that promote new blood vessel growth (angiogenesis), including PlGF.
This effectively 'rescues' the tumour from the effects of Avastin and can lead to some patients becoming resistant to the therapy. By working less well, TB-403 doesn't induce this rescue attempt and the developers hope patients won't become resistant to it.
The antibody has now been tested in more than 12 mouse models of cancer, including ones resistant to VEGF-inhibiting therapy. TB-403 blocked angiogenesis and the ability of tumour cells to move. It also prevented infiltration of blood vessel-promoting immune cells, called macrophages.
It will be several years before TB-403 makes it anywhere near approval but Svein Mathisen, CEO of BioInvent, is confident enough to have proclaimed that "TB-403 will secure a prominent place in the oncology armoury."
The first step of the process is ready to start, with a humanised form of the antibody having already been created. The two companies say they expect to begin a Phase I clinical trial before the end of this year.
"It needs to stand the test of time and rigorous clinical testing, but the findings in mice look promising," said Carmeliet.
Clinical trials to assess the drug's ability to block blood vessel growth in conditions such as age-related macular degeneration (AMD) and diabetic retinopathy - two of the developed world's leading causes of blindness - are also planned.
ThromboGenics/BioInvent: I’m skeptical of this anticoagulation program for two reasons: the unorthodox MoA—inhibiting FVIII—and the slowness of the clinical progress to date. (The drug finished phase-1 eighteen months ago: #msg-22662024.) Inhibiting FVIII is a normal place to intervene in the coagulation cascade for a coagulant but it is not a normal place to intervene for an anticoagulant. The MoA of inhibiting FVII is tantamount to inducing a mild, artificial state of hemophilia-A while hoping to avert the major-bleeding events typical of more severe manifestations of the disorder. (See #msg-16990872 for additional skeptical musings from rfj1862.)
›ThromboGenics, BioInvent Start Phase-2 Trial of TB-402 for DVT Prevention ,
- Trial to Assess the Benefits of Partial Factor VIII Inhibition in Patients Undergoing Knee Replacement Surgery -
Monday February 23, 2009, 2:00 am EST
LEUVEN, Belgium and LUND, Sweden, February 23 /PRNewswire/ -- ThromboGenics NV (Euronext Brussels: THR) and co-development partner BioInvent International (OMXS: BINV) announce today that the first patient has been enrolled in the Phase II trial with their long-acting anticoagulant TB-402 for the prophylaxis of Deep Vein Thrombosis (DVT) following orthopaedic surgery. TB-402, which is given as a single injection post surgery, could overcome the major drawbacks such as bleeding and the need for extensive patient monitoring associated with current anti-coagulant therapy.
TB-402 is a recombinant human monoclonal antibody that targets Factor VIII, a key component of the coagulation cascade. TB-402 is a novel anticoagulant agent, which may deliver important clinical benefits due to it only partially inhibiting Factor VIII activity even when given in very high doses. This novel mode of action is expected to reduce the risk of undesirable bleeding events and the need for patient monitoring, the two main drawbacks associated with current anticoagulants. In addition, TB-402 is a long-acting agent which means that patients are expected to receive just one single dose after surgery to prevent the development of DVT, as opposed to all current treatment options which require daily treatment for up to several weeks.
The Phase II trial is an active (enoxaparin)-controlled, dose-escalating, multicenter, prospective, randomised, open label trial evaluating TB-402 for the prophylaxis of DVT after knee surgery. The study will assess three different doses of TB-402 given as a single intravenous bolus injection post knee replacement surgery. The trial will enroll 300 patients across 36 centers mainly in Central Europe. The primary endpoint is the safety and efficacy of the three escalating doses of TB-402. It is anticipated that the study will conclude by the end of 2010.
Patrik De Haes, CEO of ThromboGenics, commented on today's news "We are very excited about the start of the Phase II trial for TB-402. Our work to date suggests that this novel agent could represent a major advance in anti-coagulant therapy, given our expectation that it will cause fewer unwanted bleeding events and will require no monitoring of patients. This combined with its ability to be used as a "one-off" treatment could make TB-402 the anti-coagulant of choice to prevent DVT in patients undergoing surgery. Given the size of the market opportunity for TB-402 and the sales reach that will be needed to engage with the potential prescribers of TB-402, it is our intention to seek a partner to undertake the later stage development and commercialisation of this exciting new agent."
Svein Mathisen, CEO of BioInvent, also commented, "The initiation of this Phase II trial is another successful step forward in the clinical development of our antibody product development portfolio. TB-402 addresses a broad market and has potentially significant advantages over existing anti-coagulants. We are hopeful it will have application in a number of clinical settings."
About ThromboGenics
ThromboGenics is a biotechnology company focused on the discovery and development of biopharmaceuticals for the treatment of eye disease, vascular disease and cancer. The Company's lead product Microplasmin is in Phase III clinical development for the non-surgical treatment of back of the eye diseases. Microplasmin is also being evaluated in Phase II clinical development for additional vitreoretinal indications and as a potential therapy for stroke. ThromboGenics is also developing novel antibody therapeutics in collaboration with BioInvent International; these include TB-402 (Anti-Factor VIII), a long acting anti-coagulant, and TB-403 (anti-PlGF) for cancer.
ThromboGenics has built strong links with the University of Leuven and the Flanders Institute for Biotechnology (VIB) and has exclusive rights to certain therapeutics developed at these institutions. ThromboGenics is headquartered in Leuven, Belgium and has subsidiaries in Dublin, Ireland and New York, U.S. The Company is listed on Eurolist by Euronext Brussels under the symbol THR. More information is available at http://www.thrombogenics.com.
About BioInvent
BioInvent International AB, listed on the OMX Nordic Exchange Stockholm (BINV), is a research-based pharmaceutical company that focuses on developing antibody drugs. The Company is currently running innovative drug projects within the areas of thrombosis, cancer and atherosclerosis. The Company has signed various strategic alliances around these product candidates and is developing them in collaboration with partners including Genentech, Roche and ThromboGenics.
These projects are based around a competitive and in substance patented antibody development platform. The scope and strength of this platform is also utilised by partners, such as ALK-Abello, Bayer HealthCare, ImmunoGen, OrbusNeich, Sanofi-Aventis, UCB and XOMA. More information is available at http://www.bioinvent.com.‹
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