What’s next in sustained-release drug delivery?

Glaucoma and anti-VEGF are the major opportunities.

By Jerry Helzner, Senior Editor

“Developing new drugs to achieve transformational change, which is Big Pharma’s traditional path, is very time consuming, risky and expensive. On average it takes over 13 years to develop a new drug, fewer than one in 20,000 new drug candidates ever make it to approval, and the average cost is well over $1 billion. Fewer than 25% of approved drugs even cover their own development costs. New drug discovery is a daunting undertaking, but when successful the rewards for drugs that provide transformational change can be huge. However, there is another way to do this, through what I call Strategic Drug Delivery.”

These are the words of Paul Ashton, PhD, CEO of pSivida, a worldwide leader in the field of sustained-release delivery of ophthalmic drugs. Dr. Ashton’s words are not to be taken lightly. Since 1996, four sustained-release drugs that use the principle of Strategic Drug Delivery have been approved, either in the United States or internationally. pSivida has been involved in the development of three of them:

• Vitrasert (ganciclovir) for the treatment of cytomegalovirus in AIDS patients.

• Retisert (fluocinolone acetonide implant) for the treatment of chronic non-infectious posterior uveitis.

• Iluvien (fluocinolone acetonide) for the treatment of diabetic macular edema.

Both Vitrasert and Retisert are marketed under license by Bausch + Lomb. Iluvien was developed in cooperation with Alimera Sciences and has been approved in six European countries. The fourth approved sustained-release drug is Ozurdex (dexamethasone intravitreal implant 0.7 mg, Allergan) for the treatment of macular edema associated with retinal vein occlusion and for non-infectious posterior uveitis.

WHAT IS STRATEGIC DRUG DELIVERY?

Dr. Ashton believes that with Strategic Drug Delivery, companies can make more patient-friendly products that provide transformative change and are also profitable. He says they can also do it at fractions of the time, risk and cost of developing a new drug molecule.

“Strategic Drug Delivery looks for the therapeutic gaps in clinical practice and applies currently available drugs plus new delivery technology to fill those gaps and to create transformational change,” he says. “When you change the delivery route and duration of the drug, you essentially change the whole drug for the better.”

A single Retisert implant has been proven to effectively deliver its drug for up to 30 months, although side effects such as glaucoma or cataract have occurred in these patients.

Iluvien is smaller, lasts longer (three years) and has fewer side effects, but even so the FDA has raised questions that have delayed approval in the United States. The developers recently refiled a revised FDA application. They contend the therapeutic effects of the implant offset the treatable side effects.

THE NEXT BIG OPPORTUNITY

Interestingly, all four of the sustained-release drugs approved thus far have been for back-of-the-eye diseases, yet equally promising opportunities for these longer-duration formats exist in the more prevalent front-of-the eye diseases and conditions, such as glaucoma, dry eye and bacterial conjunctivitis.

“That’s an interesting issue,” says Dr. Ashton. “I’m a back-of-the-eye man myself. For delivery into the back of the eye, we can place the implant directly into the vitreous and that works very well. For the front of the eye, you may have to go under the eyelid, the anterior chamber or somewhere else. The challenges are bigger in the front of the eye. The implant can cause the patient discomfort or it might even fall out.”

Targeting glaucoma therapy

Although these challenges may have deterred drug-delivery researchers before, they are now confident they can overcome them, especially when developing a sustained-release format for treating glaucoma. Currently, three major efforts are under way:

• pSivida and Pfizer partnering for a longer-duration sustained-release delivery of latanoprost (Xalatan).

• Allergan conducting clinical trials with a sustained-release format for three-month delivery of bimatoprost (Lumigan).

• Icon Bioscience entering clinical trials with a longer-duration method (several months) of delivering latanoprost.

In addition, Ocular Therapeutix and Mati Therapeutics have been developing proprietary punctal-plug technologies to deliver glaucoma medications for up to two months. Mati recently purchased the punctal plug drug-deliver technology that by QLT Inc. had initiated (“Punctal plugs for drug delivery,” page 43).

Problem with glaucoma drops

Two major drivers of efforts to develop a sustained-release format for delivering glaucoma medications are the issues of noncompliance and inadequate dosing of eyedrops.

“Noncompliance is a huge issue,” says Dr. Ashton. “You have patients who don’t take their drops until a week before they have an appointment with their ophthalmologist.”

The tiny size of the Retisert implant is illustrated as it sits on a fingertip.

William (Sandy) White, CEO of Icon Bioscience, says he is aware of studies that indicate, on average, fewer than 50% of self-administered glaucoma medications are used as directed by the physician. “It’s an archaic way to delivery these drugs,” he says. “I think we have recognized in recent years that we must have an alternative to drops for chronic ophthalmic diseases such as glaucoma.”

NEW APPROACHES NEEDED

Andrew Rabinowitz, MD, glaucoma specialist for the Barnet, Dulaney, Perkins practice in Phoenix, would welcome a long-duration implant (perhaps six months) that replaces eyedrops.

“If the patient is a type A personality who obsesses about learning the proper technique to instill the drops, we can get amazing IOP improvement with drops,” he notes. “But most patients aren’t like that. Eyedrops are perhaps the most difficult type of medication to deliver to the body. Unlike when a patient has to take a pill, when patients use eyedrops they have far more challenges that impact the success of getting the medication into the eye.”

With eyedrops, patients not only need to remember to purchase and use their drops, they need to have impeccable technique to instill the medication without missing the eye or spilling it onto the cheek.

“Eyedrops are at best moderately effective in the majority of patients,” Dr. Rabinowitz says. “The development of sustained-release delivery systems would greatly improve the prognosis for patients with glaucoma. These benefits would be most profound in the more severe cases who are dependent on three to four different types of medications, several of which are currently dosed three times a day.”

The Ozurdex sustained-release implant is inserted in the office using a specially designed applicator.

Where efforts now stand

The effort to develop a sustained-release format for delivering glaucoma medications over several months via an implant has essentially turned into a horse race. The pSivida-Pfizer initiative using latanoprost is in a phase 1/2 trial. The Allergan initiative with bimatorpost (Lumigan) is in a phase 2 trial, and Icon Bioscience is about to begin its first human trial of a latanoprost-filled implant.

All three of these initiatives have their own specific advantages. For pSivida and Pfizer, the edge comes from pSivida’s long experience in successfully developing sustained-release formats combined with Pfizer’s status as a deep-pocketed major drug company with the market-leading Xalatan.

For Allergan, a major advantage is that the company already has a successful sustained-release platform in Ozurdex and can apply its experience with that sophisticated technology to other sustained-release initiatives. Allergan is doing just that in conducting a sustained-release phase 2 clinical trial of brimonodine as a treatment for dry AMD, according to Scott M. Whitcup, MD, chief scientific officer and executive vice president for R&D at Allergan.

The shorter-acting Ozurdex implant may also be highly suitable for delivering anti-VEGF medications if Allergan chooses to take up that initiative, according to Shree K. Kurup, MD. director of research at the Wake Forest University Eye Center, Winston Salem, N.C. “You need different types of delivery systems for glaucoma and wet AMD,” Dr. Kurup says. “The Ozurdex platform could be very effective, as it could overwhelm the VEGF more quickly than a longer-duration format.”

BANKING ON VERISOME TECHNOLOGY

Icon Bioscience is singularly focused on sustained-release development, with seven different formulations for various ophthalmic indications either in clinical trials or well along in their preclinical testing. All these drugs employ Icon’s proprietary Verisome technology, a versatile delivery system that can deliver drugs as solids, gels, semi-liquids and liquids, and with controlled dose and duration tailored to the individual physical characteristics of each drug and the area of the eye the implant will be placed.

Much of the Verisome technology stems from the work of Icon Biosecience chairman and founder Vernon G. Wong, MD, who almost single-handedly developed the Ozurdex implant at Oculex before Allergan acquired that company.

“With the Verisome technology, we work backwards from the desired clinical end result,” Mr. White says. “We have now formulated probably more than two dozen products using various classes of agents. That is the unique power of this technology. We target creating a product that delivers a drug for the desired period of time from a single biodegradable sphere that disappears concurrently with the drug release.”

Sustained-release for wet AMD

Talk to Dr. Ashton of pSivida, and you get the impression that, with his experience in back-of-the-eye sustained-release formats, he is eager to develop a sustained-release implant for an anti-VEGF drug. He envisions a long-duration, biodegradable implant that could be placed in the patient’s eye via a minimally invasive office-based procedure. Such a breakthrough would be a game-changer, freeing retina specialists and patients alike from the time-consuming regimen of repeated intravitreal injections, with their accompanying complications and costs.

“We now have developed a system at pSivida to deliver proteins, peptides and monoclonal antibodies that are the basis of anti-VEGF drugs in a sustained-release format,” Dr. Ashton says. “In fact, we just recently entered into a technology evaluation agreement with a global company that has an approved anti-VEGF drug.” pSivida is not divulging the name of the company.

ForSight Vision4, part of the ForSight Labs ophthalmic incubator in Menlo Park, Calif., is a start-up company developing a sustained-release delivery system for anti-VEGF drugs. ForSight Vision4 has already received a milestone payment from Genentech for its progress in developing a delivery system for ranibizumab (Lucentis).

The concept that ForSight is using can be compared to a “refillable gas tank such as would be used in a car,” Dr. Kurup notes.

In addition, Neurotech, based in Cumberland, R.I., has developed a proprietary sustained-release implant using encapsulated cell technology (ECT), which can deliver genetically engineered recombinant biotherapeutics directly into the vitreous continuously for up to two years. The company’s NT-503 anti-VEGF formulation for the treatment of wet AMD is now in clinical trials. The company has also developed a sustained-release drug called Renexus for the treatment of the dry form of AMD (geographic atrophy) and for blinding diseases such as retinitis pigmentosa. This implant has gone through several phase 2 trials with promising results in both geographic atrophy and RP.

HOW FAR AWAY?

No one is saying that a sustained-release glaucoma or anti-VEGF implant is just around the corner. Dr. Ashton estimates FDA approvals for both indications are five to six years away, even using an already approved wet AMD or glaucoma drug.

Mr. White of Icon Bioscience estimates approval could be about four years away for a sustained-release implant delivering a glaucoma medication for up to six months, but he believes any side effects would be no greater than those from eyedrops. Fewer side effects would be positive in terms of advancing the approval process.

“I suspect that the FDA would require a 1,000-patient trial with significant follow-up to approve a breakthrough of this magnitude for a glaucoma medication, Dr. Ashton says. But he does think such a breakthrough is coming in the near future “because the truth is that patients do a horrible job of taking their drops.” OM