Tuesday, May 11, 2010

AMD Update 11: Potential Breakthrough Drug Delivery System for AMD

Earlier last week, I was reading a report on Dr. Robert Langer’s keynote address from the recent ARVO meeting held in Ft. Lauderdale, FL, “The Future of Regenerative Medicine in Ophthalmology”, and thought that his idea of a prototype microchip or polymer implant, that contained pockets or drug reservoirs that could be selectively controlled or opened by a patient’s physician, in this case the individual pocket or drug reservoir opened by the application of a focused laser beam, could really be useful in treating AMD. Instead of monthly injections of anti-VEGF agents, a single implant containing multiple doses could be implanted and each dose activated by a simple ophthalmic laser beam upon need.

Then, lo and behold, last Friday morning I received a news release from a company called On Demand Therapeutics, Inc., which, it turns out, holds the rights from Dr. Langer’s laboratory at MIT and spin-off companies, to develop just such a device. John Santini is the president of the new company. He is the co-founder and former president of MicroCHIPs, a company founded by Santini and Dr. Langer in 1999, to develop proprietary reservoir arrays that are used to store and protect chemical sensors or potent drugs within the body for long periods of time, based on the research and inventions derived from Dr. Langer’s MIT laboratories.

A Little History

In 1976, Dr. Langer and Judah Folkman, MD, a pioneer in anti-angiogenic research, devised a polymer material that released an angiogenic inhibitor. The agent thwarted neovascularization and stunted the growth of tumors in rabbit corneas. The research bore fruit when the U.S. Food and Drug Administration approved the anti-VEGF agents Macugen (pegaptanib sodium solution, Eyetech/Pfizer) in 2004 and Lucentis (ranibizumab, Genentech) in 2006.

Santini, a former graduate assistant of Robert Langer, founded MicroCHIPS along with Langer and MIT colleague Michael Cima in 1999. He led the firm for 11 years, through several funding rounds, including a recent round resulting in nearly $16.5 million raised that took the total to $70 million.

Santini has now moved on to head up On Demand Therapeutics Inc., a San Francisco-based MicroCHIPS spinout.

The Problem and a Possible Solution

In his ARVO address, Dr. Langer said the researchers' main dilemma in developing a drug release reservoir was designing polymers that could elute large bioactive molecules. Porous polymers enable timed and controlled elution of almost any bioactive molecule, regardless of its size. "These pores are large enough so that molecules, even of millions of molecular weight, can get through," according to Dr. Langer.

Newer technologies show promise. For example, a prototype microchip device comprises tiny pockets or drug reservoirs. The application of an electrode dissolves a gold coating on the chip, allowing the drug agent to elute in a timed and controlled way. Such devices are being developed by MicroCHIPS for the treatment of severe osteoporosis through the delivery of an anabolic bone-building hormone, and also for continuous glucose monitoring for people with diabetes.

Dr. Langer said that the chip (or drug reservoirs) may also have applications in retinal drug delivery.

A physician-controlled retinal drug delivery technology would involve an implant with sealed drug reservoirs. The targeted application of an ophthalmic laser to open one or more of the wells to allow the release of the respective drug into the eye, could constitute a breakthrough, said Dr. Langer.

On Demand Therapeutics, Inc. (ODTx)

ODTx was formed in May 2009 as a unique joint venture between MicroCHIPS, a developer of intelligent implant systems, and InterWest Partners, a leading diversified venture capital firm. ODTx leverages the intellectual property and technical expertise of MicroCHIPS combined with the ophthalmic domain expertise and financial resources of InterWest. The company has an exclusive, worldwide license to 60 issued patents and numerous pending applications related to ophthalmic on-demand drug delivery and related technologies.

The ODTx device is a biocompatible, non-resorbable injectable rod, comprised of multiple discrete reservoirs designed to release, on demand, specific drugs in clinically optimized doses. (See Figure 1.) Each reservoir can safely store small or large molecule drugs in the eye until release is initiated using a standard ophthalmic laser during a simple, routine, office-based procedure. (See Figure 2.)

Figure 1. The Drug Reservoir Implant

Figure 2. Initiation of Drug Release

Typical retinal drug delivery procedures, such as for treating CNV (choirodal neovascularizaion, or “wet” AMD) require monthly intravitreal needle injections. Current implantable devices are largely focused on steroids and/or deliver sustained release formulations which have no mechanism for control of dosing, leading to significant side effects such as glaucoma or cataracts. In contrast, once the ODTx device is implanted during an in-office procedure, the ophthalmologist can control drug delivery by focusing a laser beam on one of the multiple sealed reservoirs.

Administering a laser pulse creates a micro-opening in the device that releases the drug into the eye. Unactivated reservoirs remain intact until those doses are indicated. There is no need for monthly injections and the patient is easily maintained through regular follow-up visits and subsequent non-invasive laser activation procedures.

Current Status of the Development

Multi-reservoir devices have been fabricated and used in three in vivo feasibility studies. These studies demonstrated the implantation procedure, that the devices were well tolerated, and that both small and large molecule drugs could be released on demand when their reservoirs were opened by an ophthalmic laser. The company is now considering various opportunities, including venture investment and corporate deals with pharmaceutical and medical device companies, to quickly move products utilizing this innovative drug delivery platform into the clinic.

Some Questions......

In thinking about this innovative approach to providing on-demand drugs to the retina, I came up with a series of questions that will have to be answered before this invention can be comercialized and brought to market.

Here are my questions – and I’m sure there are others – I look forward to your comments.

1. What size will the drug reservoir have to be to contain the equivalent of five or so 0.5 mg doses of, say, Avastin?

2. As “floaters” (small strands of clumped vitreous) can become annoying, what effect on vision would the reservoir have? Would it be implanted in the retina, or free floating? Would it be “visible” just sitting in the back of the eye?

3. Would a small puncture of an individual cell allow all of the drug contained within that cell to release, to become available to the retina?

4. How will the company distinguish between full and empty cells – perhaps by coloring the solutions?

5. Finally, how long will it take to answer all of the questions and obtain FDA marketing clearance?

My guess is a minimum of three to five years.


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