In February 2004, Avastin became the first anti-angiogenesis drug to gain FDA approval and has rapidly become a blockbuster. During 2006, the drug gained regulatory approval for two additional indications and Genentech reported $1.33 billion in Avastin sales for the first three quarters. Yet as rosy as that picture is, the future of angiogenesis inhibitors — and promoters — is likely to be even rosier and much richer.
Avastin’s own value is projected to climb, with sales topping $7.5 billion in 2010, according to Shiv Kapoor, an analyst for Montgomery & Co. A majority of that increase will be driven by two new markets, non-small cell lung cancer and breast cancer. The lung cancer indication, for which Avastin (bevacizumab) was approved in October 2006, is worth $4.3 billion, while the breast cancer indication, for which the drug is currently under review, is worth $3.7 billion. And the company doesn’t plan to stop there. There are at least 130 clinical trials underway in 25 different types of cancers.
Oncology: The First Market
Following Avastin’s success, several other angiogenesis inhibitors have entered the oncology market. Nexavar (sorafenib, Bayer/Onyx) is approved for use in kidney cancer, while Sutent (sunitinib, Pfizer) targets both kidney cancer and Gleevec (imatinib mesylate, Novartis)-resistant gastrointestinal stromal tumor. Both agents block major angiogenesis pathways, including vascular endothelial growth factor (VEGF) signaling, which is Avastin’s molecular target as well. By contrast, Tarceva (erlotinib, Genentech/
OSIP), which is approved for use in non-small cell lung cancer and pancreatic cancer, takes a slightly different route to blocking angiogenesis. The drug inhibits the epidermal growth factor receptor (EGFR) signaling pathway, slowing proliferation directly and inhibiting angiogenesis indirectly. (See Table for approved angiogenesis-inhibitor agents and their indications.)
Of course, not all agents and indications have been so successful. Avastin itself has had problems with rare but serious toxicities, including gastrointestinal perforations, and failed to show improvement in patients with advanced pancreatic cancer. Similarly, Onyx Pharmaceuticals announced in December that Nexavar failed to improve progression-free survival in melanoma patients.
Additionally, Novartis and Schering AG suffered a setback when their lead anti-angiogenesis drug PTK/ZK (also known as PTK787) failed to delay disease progression in colorectal cancer (CRC), despite the fact that Avastin is known to work in this disease. An exploratory analysis of the Phase III trial data suggests that CRC patients with high lactate dehydrogenase may derive more benefit from PTK/ZK than the average patient. Thus the companies plan to initiate further trials focusing on this patient subgroup. They are also testing the drug in other malignancies, including glioblastoma and non-small cell lung cancer.
Such hiccups, however, haven’t dampened the community’s enthusiasm for angiogenesis inhibitors, and there are numerous new inhibitors in early and late-stage development. Many of the companies are trying to distinguish their agent from the pack in one way or another. For example, EntreMed’s Panzem (2-methoxyestradiol or 2ME2) is a small molecule that disrupts microtubules, blocking cell division and down regulating VEGF via the HIF1a pathway. “It is not just an anti-angiogenic agent — it also directly kills tumor cells in culture. For that reason alone, it is somewhat different than Avastin,” says Carolyn Sidor, EntreMed’s vice president and chief medical officer.
Although EntreMed hasn’t yet generated enough clinical data to know whether the small molecule will work in settings where monoclonal antibodies, like Avastin, do not, the two-pronged hit of limiting proliferation and angiogenesis might reduce the risk of tissue perforations seen with Avastin, says Sidor. Additionally, Panzem’s inhibition of HIF1a makes it likely to work in cancers where overexpression of the protein is a driving force for both tumor growth and VEGF expression, as in clear cell ovarian cancer.
Ophthalmology and Inflammation
But cancer is not the only target for angiogenesis inhibitors. Already, such agents have been approved for use in eye diseases, and several agents are being developed for inflammatory disorders.
Macugen (pegaptanib sodium injection, Pfizer/Eyetech Pharmaceuticals), a small-molecule inhibitor of VEGF, was the first of the agents to gain approval for the treatment of wet age-related macular degeneration (AMD). Wet AMD accounts for only about 10% of all AMD cases, but that still includes approximately 200,000 new cases per year and a market worth as much as $1 billion annually, according to some analysts.
Genentech’s Lucentis (ranibizumab injection) has also been approved for wet AMD and the company has ongoing trials testing the agent in diabetic macular edema. Future trials are planned to test the drug in retinal vein occlusion, says Charles Semba, senior group director, ophthalmology and vascular medicine. “Technology companies don’t want to have a one-hit wonder, with one agent approved for one indication,” Semba says. “Investors want to know what you can do for them lately.” With that in mind, Genentech is trying to “work smarter” and build on their success with Lucentis — and Avastin — and ask how they can make each drug better.
In addition to using Panzem in oncology, EntreMed plans to test it in rheumatoid arthritis. Preclinical tests in animal models showed that the drug reduces both soft tissue inflammation and bone erosion. PCR analysis of tissue from treated animals demonstrated that both VEGF and fibroblast growth factor (FGF-2) were down regulated. “The thing we like about pursuing this as an indication is that [Panzem] has been very well tolerated by the oncology patient population,” says Sidor. “We don’t really see the typical toxicities that you would tolerate very nicely in oncology patients but would be unacceptable for chronic therapy, such as for rheumatoid arthritis patients.”
It’s Not All About Inhibition
In addition to expanding the indications for angiogenesis inhibitors, several companies are working on angiogenesis-promoting agents. Thus far, the results, though mixed, are sufficiently promising to keep researchers and investors interested.
Genentech is currently testing a topical VEGF agent for its ability to stimulate healing of diabetic foot ulcers. Early results show “a robust biological signal,” says Semba. If the late-phase trials go well, the approach could have a large impact, well beyond diabetic foot-ulcer treatment. “I think that opens the doorway to all types of tissue healing,” Semba says. “We’re kind of looking at this as a litmus test.”
The advantage the company has over previous ones that have “crashed and burned on this pathway” is a stronger scientific base. “We think the missing element has been that people really didn’t understand the wound-healing process that well; the road to getting good tissue repair really begins with getting a good blood supply. We don’t know if that hypothesis is correct, but that is what we are currently testing,” he says.
Christopher J. Reinhard, chief executive officer of Tissue Repair Company (TRC) and of Cardium Therapeutics, is making a similar bet. TRC is testing a topical ointment for the treatment of diabetic foot ulcers. The ointment, called Excellarate, is a collagen matrix gel containing the human platelet-derived growth factor-B (PDGF-B) gene in an adenovirus vector. PDGF expression should stimulate blood vessel growth and healing. The idea, he says, is not so far fetched. Already, Johnson & Johnson has a topical treatment for diabetic foot ulcers, called Regranex (becaplermin), which contains PDGF protein. That agent, however, says Reinhard, is cumbersome to use, requiring many reapplications. Excellarate, by contrast, is designed to be used only once or twice and has a sustained release due to its formulation as a DNA-adenovirus moiety.
But when you ask Reinhard about angiogenesis stimulators, the agent you’re most likely to hear about first is Generx, which is being developed by Cardium Therapeutics. Generx is an adenovirus-based therapy that encodes the myocardial-derived FGF-4 (mdFGF-4) growth factor. Although the drug failed to increase exercise treadmill time in angina patients in a Phase III trial, a subset analysis showed that women did derive benefit from the therapy. Following discussions with the FDA, Cardium has designed a new randomized Phase III trial to test the agent in 600 women with severe angina. Enrollment should begin in the first quarter of 2007.
Moreover, perfusion tests performed in previous Phase II trials showed that a single treatment with Generx, which can be delivered by a standard diagnostic catheter, increased microvasculature in the heart muscle of patients. The drug, says Reinhard, “is the next frontier,” following drugs that treat symptoms and mechanical interventions to restore blood flow. This agent, if it works as it currently appears to, will be “disease modifying.”
Reinhard’s enthusiasm for the approach appears to run exactly counter to that of executives at Corautus Genetics. Following disappointing Phase III trials of their VEGF-2 compound for the treatment of angina, Corautus has been reorganized. “We are not going to be working in the angiogenesis field,” says Jack W. Callicutt, vice president, finance and administration and chief accounting officer. “We are more interested in finding the right business opportunity than sticking with any one area, such as angiogenesis.”
When asked about those trial data, Reinhard lays the blame primarily on the delivery mechanism used by Corautus to deliver VEGF plasmid DNA, and emphasizes the ease and safety of the diagnostic catheter approach used for Generx.
Expanding Territory
Thus far, most of the angiogenesis inhibitors and promoters target the VEGF ligand, its receptor, or a closely related tyrosine kinase signaling pathway, but companies have started to reach a bit farther for creative targets. Æterna Zentaris Inc. is developing Neovastat, which works via multiple mechanisms, including blocking VEGF ligand-receptor interaction, up regulating endothelial cell apoptosis, and increasing angiostatin production. Abbott’s ABT-510 inhibits thrombospondin-1 and thus may down regulate pro-angiogenic growth factors, including VEGF, bFGF, and IL-8. Merck KGaA’s Cilengitide inhibits two cell surface integrin receptors that would initiate angiogenesis when stimulated.
“I think at this stage, we have just a very rudimentary understanding of angiogenesis,” says Genentech’s Semba. “We just happened to be fortunate enough to discover one of the key elements. But clearly, as the science is opening up, we are realizing that this is a very complex orchestration of molecular pathways. Once we understand these pathways better, we will be in a position to start blocking things to see what happens.”
|
