Reapplication of Known Efficacious Compounds
Another problem pharma seeks to address is the treatment sustainability bottleneck. Currently, the treatments available consist of injections of Lucentis (ranibizumab injection) or off-label use of Avastin (bevacizumab). “It’s not surprising that given the antiproliferative properties of many anticancer drugs they would be explored for inhibiting cell proliferation and neovascularization that comes with wet AMD,” says Richard M. Soll, vp of research and development at TargeGen (www.targen.com).
MacuSight (www.macusight.com) is reapplying known efficacious compounds for use in the eye. Its proprietary formulation of sirolimus (rapamycin) for serious ocular diseases is being advanced. Currently, rapamycin is used as an immunosuppressant to prevent organ rejection in transplant patients, as well as in drug-coated stents for patients with coronary artery disease.
However, according to David A. Weber, president and CEO of MacuSight, there are some potentially rewarding alternative applications of the drug. “Sirolimus is a broad-acting small molecule that provides critical efficacy advantages for minimally invasive local delivery to the eye,” he says. “Studies have shown that sirolimus inhibits the activity of all forms of VEGF as well as other pro-angiogenic factors and has been shown to inhibit proliferation, inflammation, and fibrosis—so really, it makes sense that this compound could be an attractive therapy option for AMD and other ocular diseases.”
MacuSight says that its sirolimus product candidate has already yielded promising results across several animal models of choroidal neovascularization and retinal angiogenesis and has also demonstrated that it exerts a direct inhibitory effect on VEGF-induced microvascular hyperpermeability. “And because of its broad mechanisms of action, this compound could provide a unique opportunity to mimic combination therapy using a single compound,” Weber says.
New discoveries are often made when research in several labs converge. “In 2005, a number of important papers were published that specifically linked complement factor H polymorphisms to age-related macular degeneration,” says Pascal Deschatelets, Ph.D., cofounder and COO of Potentia Pharmaceuticals (www.potentiapharma.com)“We had already been working on developing complement inhibitors to treat AMD, but these studies indicated that we were on the right track.”
Nobody knows what triggers macular degeneration. “One thing we do know is that the main complication of late-stage AMD is angiogenesis—so anti-angiogenic approaches similar to those being developed to treat cancer have provided the first real breakthrough in the treatment of wet AMD,” notes Dr. Deschatelets. “We want to act earlier in the progression of the disease, hopefully interfering before any vision is lost. We focus on that development.”
For Potentia, the confirmation that complement activation plays an important role in the pathogenesis of AMD led it to looking at complement inhibition as a therapeutic approach to AMD.
“Numerous other studies confirmed the initial correlation. And if you look at the literature, the correlation was expanded to include a number of other complement proteins such as the complement component C2 and complement factor B. It’s reasonable to conclude that excessive complement activation is a crucial factor in the initiation and progression of AMD.”
Reasonable enough of a conclusion that the first few complement inhibitors for this indication are currently making their way through the drug pipeline. Potentia is among this first wave with POT-4, a peptide inhibitor of complement component C3 derived from Compstatin. “POT-4 is able to interfere with all three major pathways of complement activation,” says Dr. Deschatelets.
Ultimately, Potentia hopes to treat AMD in its entirety, not just one specific aspect of it. “Our hope is to target the disease before it gets to the angiogenesis stage,” says Dr. Deschatelets. “In 2007, we are looking to launch the first clinical trial using complement inhibition to treat AMD.”