pSivida--focusing on delivery to the eye

As people live longer, and as global demographics shift toward an older population, age-related eye diseases such as glaucoma and macular degeneration are increasing. The blood-eye barrier is very effective--this is useful in health, protecting such a sensitive organ, but an obstacle in disease as it makes it very hard to get drugs inside the eye. Because of these two factors, it is hardly surprising that companies such as pSivida ($PSDV) are focusing on ocular delivery.

The ocular drug delivery market

According to pSivida's president and CEO, Paul Ashton, there are about 2 million cases of age-related macular degeneration in the U.S., including wet AMD (15%) and dry AMD (85%). There were also about 4 million cases of diabetic retinopathy, 2.5 million to 3 million cases of glaucoma, and 200,000 people with uveitis. All of these can be described as "back of the eye" diseases.

"Last year, the market for Lucentis [ranibizumab] and the newly approved Eylea [aflibercept] for wet AMD was more than $1.7 billion," says Ashton. "This does not include the much larger market for dry AMD. Ocular drug delivery is an opportunity as well as a challenge, and we realized that this was a large commercial prospect, with few other people there."

Most drugs for eye disease are administered as eye drops, but only 2% to 3% of the ingredients actually penetrate to the aqueous humor, the gel-like fluid between the cornea and the iris, and even less enters the back of the eye, into the vitreous humor. Eyedrops are hard to use and compliance is poor. Because of this inefficiency of delivery, an effective eye delivery system would only need to deliver a tiny fraction of the drug delivered by an eyedrop. A long-term delivery system also removes compliance issues.

Some eye drugs, such Roche ($RHHBY) and Genentech's monoclonal antibody fragment Lucentis or Regeneron Pharmaceuticals' ($REGN) fusion compound Eylea, have to be injected every month or two, which is costly, inconvenient and stressful. pSivida's approach is to create long-term erodible or non-erodible implants that are administered through injection or minor surgery and last for between months and years.

Targeting the eye: On the market

Focusing on developing tiny sustained-release drug delivery systems, pSivida has developed three of the only four products approved by either the U.S. or EU for the long-term, sustained-release delivery of drugs to treat chronic eye disease, Ashton explained. Vitrasert, approved for the treatment of AIDS-related cytomegalovirus retinitis, and Retisert, approved for the treatment of uveitis, are both licensed to Bausch & Lomb by pSivida, and are inserted through a small incision. Iluvien, which is based on the Durasert delivery system, is approved in a number of European countries for the treatment of chronic diabetic macular edema (DME) and has been licensed to Alimera Sciences ($ALIM) by pSivida for indications other than uveitis. This is a non-erodible insert delivering the drug for up to three years and is inserted using a needle.

Ashton was involved in the development of Retisert, which was a larger implant that had to be surgically implanted. Retisert delivers the equivalent of half an eye drop's worth of the drug fluocinolone acetonide over three years directly into the vitreous humor, the gel between the lens and the retina at the back of the eye. 

"This was very effective in the treatment of uveitis, a potentially blinding disease that involves inflammation at the back of the eye and can last for years. Although Retisert is associated with significant side effects--around 35% of patients had to have surgery because of increased pressure in the eye, it was approved because for a blinding disease like uveitis, the risk-benefit profile works," says Ashton.

The insert was redesigned to create Durasert, an injectable device intended to overcome many of the issues of Retisert. Its use is associated with fewer side effects with less than 5% of the patients requiring surgery for increased eye pressure. The product was licensed to Alimera as Iluvien for DME.

Alimera has gained approval in 5 of the company's 7 targeted EU countries and is planning to market the product as Iluvien beginning in 2013. In August, the draft recommendation from NICE (the U.K.'s National Institute for Health and Clinical Excellence) did not recommend Iluvien for use in the U.K., but Ashton is calm: "The NICE decision isn't until November, so there is plenty of time for negotiation between Alimera and NICE."

Alimera submitted Iluvien in the U.S., but it was rejected for the second time in November 2011. However, after Alimera's recent discussions with the FDA, the company is going ahead with U.S. resubmission.

Targeting the eye: In development

In its own development program, pSivida is targeting posterior uveitis with Durasert and this is the most advanced product in pSivida's pipeline. It uses the same drug and device as Iluvien.

"We have had a meeting with the FDA to talk about Phase III trials for this project, and it will accept two relatively small 12-month Phase III trials, and we can reference the safety data for Iluvien in DME," says Ashton. "That the DME trials showed a lower side effect profile than Retisert is very encouraging and augurs well for the trials in uveitis."

pSivida has licensed a bioerodible version of Durasert to Pfizer ($PFE) to deliver latanoprost into the white of the eye for the treatment of glaucoma. Delivery will last 6 months, which fits in with regular clinic visits. This is currently in Phase I/II trials.

In evaluation with an undisclosed biopharma company, pSivida's Tethadur is a silicon-based delivery system for the delivery of biological molecules including antibodies and proteins. This is licensed from QinetiQ, formed from the U.K. government's Defense Evaluation and Research Agency (DERA), and is a very pure silicon wafer with minute pores that are 1 molecule in diameter.

"We can control the pore size so that it has a huge surface area, of up to two tennis courts per gram, and includes up to 6 million miles of minute tubes per cubic centimeter. This acts as a nanostructured 'egg box,' keeping proteins apart and stopping them aggregating," says Ashton.

Elsewhere in the field

Other companies developing controlled-release drugs for the eye include Allergan ($AGN) with Ozurdex, a bioerodible implant delivering dexamethasone over 6 months, which is approved for the treatment of uveitis and vein occlusion, and QLT ($QLTI), which has punctal plugs delivering latanoprost in Phase II for the treatment of glaucoma--however, analysts have been somewhat skeptical about this program.

"My concern about the use of punctal plugs is that they can block the drainage of tears, and could even fall out," says Ashton. -- Suzanne Elvidge (email)