Therapeutic Focus - Looking beyond VEGF in diabetic eye disease

Analysis

KalVista Pharmaceuticals’ injection of cash to advance its plasma kallikrein inhibitor into the clinic shows that companies researching novel treatments for diabetic macular edema (DME) are expressing interest beyond the well-trodden VEGF pathway (EP Vantage Interview - New spin-out KalVista testing alternative technique for DME, August 23, 2011).

A review of EvaluatePharmapipeline data shows that while inhibitors of VEGF still dominate phase III along with anti-inflammatory corticosteroids and NSAIDs, newer approaches such as mTOR inhibitors and gene therapy are being assessed in phase I and II. Companies testing the new approaches are betting they can address some treatment gaps left by laser coagulation, antibodies and more invasive treatment methods; however, the small number of candidates adopting an alternative approach suggests that VEGF targeted therapeutics will likely dominate the indication for some time to come (see table below).

Non-VEGF candidates for diabetic macular edema
Status Product Pharmacological Class Company (s) Originator
Phase II FOV2304 Bradykinin B1 receptor antagonist Sanofi Fovea Pharmaceuticals
Optina (danazol) Eye preparation Ampio Pharmaceuticals DMI Life Sciences
DE-109 (sirolimus) Rapamycin analogue (mTOR inhibitor) Santen Pharmaceutical Wyeth
PF-04523655 RTP801 RNAi therapeutic Pfizer/Silence/Quark Atugen
Phase I iCo-007 (ISIS 13650) C-Raf kinase antisense iCo Therapeutics/Isis Pharmaceuticals Isis Pharmaceuticals
DMI-5207 Eye preparation Ampio Pharmaceuticals DMI BioSciences
IVT Plasma Kallikrein Inhibitor * Plasma kallikrein inhibitor KalVista Pharmaceuticals KalVista Pharmaceuticals
* phase I trial to start in 2012

Complication

Macular edema is a complication of diabetic retinopathy, caused by a weakening of the blood vessel walls from prolonged periods of hyperglycaemia. In the eye, the capillaries swell and leak, and in the nerve-rich macula the swelling can result in blurred vision. The risk of developing DME is 10% in diabetics, making it a common cause of blindness in working age people.

Laser coagulation is the main treatment strategy in the US, followed by vitrectomy, removal of the fluid in the eye, if too much blood accumulates there. Earlier this year, European authorities authorised the use of anti-VEGF antibody Lucentis to treat DME, and it is being used off-label in the US along with cancer drug Avastin, also an anti-VEGF antibody but titrated for use in the ophthalmological indication.

Lucentis and Avastin are Roche products, but Novartis has rights to Lucentis outside of North America thanks to a deal with Genentech pre-dating its acquisition by Roche; thus Roche is likely to be anxious to get formal US approval in DME, which affects more people than its first indication of wet age-related macular degeneration (AMD).

Two other notable VEGF inhibitors, Regeneron and Bayer’s Eylea and Molecular Partners' MP0112, are in phase III and II trials, respectively, for macular edema. Eylea faces an FDA approval decision for AMD in November following a unanimous advisory committee vote (Eylea breezes through adcom and looks ahead to approval, June 20, 2011), while Molecular Partners secured an impressive deal with Allergan for further development of its candidate (Allergan sees dosing potential in Molecular Partners' AMD candidate, May 5, 2011).

However, in announcing its $13m in venture funding to advance its plasma kallikrein inhibitor into the clinic, KalVista claims that 40-60% of DME patients do not respond adequately to VEGF based treatment, and with growing numbers of diabetics the unmet need for alternative treatments will be huge.

Product mix

The non-VEGF candidates in development are a mix of compounds that like the VEGF class hinder the growth of blood vessels in the eye or attack inflammatory responses.

The candidate attracting most attention so far is FOV2304, Sanofi’s bradykinin B1 receptor antagonist acquired with the purchase of Fovea Pharmaceuticals in 2009 for up to $530m. Bradykinin is a protein that causes vasodilation and inflammation, and the B1 receptor is expressed only in response to tissue damage; thus an anti-inflammatory approach it is hoped will reduce central retinal thickness, the primary endpoint in its 216-patient phase II trial due to report in 2012.

The other truly novel drug in phase II is PF-04523655, the Quark Pharmaceuticals/Silence Therapeutics RNA interference candidate licensed to Pfizer. Its phase II Degas trial was terminated early following an interim analysis that showed the dosage being tested would not be sufficient to show a therapeutic benefit compared with new VEGF treatments. The Degas trial compared three doses of the compound to laser therapy. Quark is now planning a phase IIb trial against Lucentis.

As with the VEGF therapies, injections of ‘655 are thought to interfere with the vascularisation that results in DME; it does so by turning off the gene RTP801, which becomes more active in response to ischemia, hypoxia or oxidative stress.

Uphill fight

Two repurposed drugs fill out the phase II pipeline. Ampio Pharmaceuticals has repurposed the oral steroid danazol, once used to treat endometriosis, into a low-dose oral version it calls Optina to treat DME. Sirolimus, the anti-organ rejection drug marketed as Rapamune, is being tested as DME drug DE-109 by Santen Pharmaceutical in a dose-ranging study of 120 patients. As an mTOR inhibitor, sirolimus suppresses cell proliferation.

In phase I the antisense treatment iCo-007 also targets neovascularisation processes. Two weeks ago iCo Therapeutics announced plans to advance the RNA-based treatment into a phase II DME trial as a monotherapy or in combination with Lucentis or laser therapy.

With the VEGF class set to dominate the indication for some time, any new drugs will have a big efficacy obstacle to overcome, as demonstrated by Quark’s redesign of its clinical programme for ‘655. The most immediate hope for future success, as expressed by KalVista, is to identify and address patients that do not respond to Lucentis or other drugs in its class.

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