Therapy Analysis - AMD
A new hope?
A number of intravitreally injected compounds have also been developed. Novartis Ophthalmics further strengthened its position in the market when it licensed Genentech’s vascular endothelial growth factor (VEGF) antagonist, Lucentis (ranibizumab), a fragment of a recombinant anti-VEGF humanized antibody that binds to VEGF-165, VEGF-121 and VEGF-110. Lucentis was approved in the US in 2006 on the basis of the ANCHOR and MARINA trials. In the Phase III ANCHOR trial in 423
predominantly wet AMD patients, monthly injections of
0.3 and 0.5mg of Lucentis produced mean gains in visual acuity of 8.5 and 11.3 letters, respectively, compared with a loss of visual acuity of 14.9 letters with verteporfin. The MARINA study showed that these effects could be maintained for two years, with 0.3 and 0.5mg monthly injections producing mean gains in visual acuity of 5.4 and 6.6 letters, respectively. The potential of a drug to not only stem the loss of visual function but also restore it in some patients is not to be underestimated.
A number of different pharmacological strategies are being explored for the treatment of wet AMD (Graph 2); however, therapies targeting VEGF, an important signalling protein involved in angiogenesis, seem to be a key area of development. Five of the active compounds in development for wet AMD, as listed on Pharmaprojects, are VEGF antagonists. The first of these to be launched was Macugen (pegatanib octasodium), which, as the first ever aptamer to be launched, holds particular interest. Macugen is a pegylated oligonucleotide aptamer which binds to VEGF 165, and was developed by Eyetech (now OSI Pharmaceuticals) and Pfizer. It received US fast track designation and went on to become the first aptamer to be approved by the US FDA in 2004. Pharmaprojects currently list 12 aptamers in development for various indications. It is yet to be seen how these others shall fare and whether Macugen will herald the emergence of a new class of therapeutics.
As an indication, AMD has also witnessed some pioneering clinical work in the field of small interfering RNA (siRNA). RNA interference (RNAi) was hailed as the "breakthrough of the year" by Science in 2002, and generated a lot of excitement as companies sought to take advantage of its ability to cause potent and selective 'silencing' of genes. Reflecting this, the number of RNAi compounds in development has been on the increase since 2002 (Graph 3). In August of this year, Opko initiated dosing in a Phase III trial (COBALT) of Cand5 (bevasiranib sodium), its anti-VEGF siRNA compound for the treatment of wet AMD. This is the first ever Phase III trial of an RNAi therapeutic. In a Phase II trial (CARE) in 129 wet AMD patients, Cand5 produced dose-dependant decreases in the growth and size of CNV, with higher doses halting CNV growth for at least 12 weeks. Over 30% of patients reported an improvement in visual acuity and it was well tolerated with a good safety profile. Opko anticipates launching Cand5 in 2010.
