INNOVATION IN RETINA

Drs. Michael Trese and George Williams

Ocriplasmin: two decades of commitment to a concept.

Jerry Helzner, Senior Editor
Edited By Emmettt. Cunningham JR, MD. PhD, MPH, And Pravin U. Dugel, MD

Many ophthalmic innovators place a timeframe of five to seven years on the acceptable development period for the commercialization of a new therapy. However, Michael T. Trese, MD, and George A. Williams, MD, of Associated Retinal Consultants in Royal Oak, MI, have spent more than 22 years creating, testing, and then helping to shepherd the first pharmacologic therapy for treating symptomatic vitreomacular adhesion (VMA) from initial concept toward FDA approval.

Now, they and their corporate partner are nearing the final hurdle that would confirm a medical breakthrough of the highest magnitude.

“In the words of the Grateful Dead, ‘What a long, strange trip it's been,’ but we've just kept truckin',” says Dr. Williams.

To bring readers up to date on the progress of ocriplasmin, in late July, the therapy was recommended for approval by the FDA advisory committee that reviews ophthalmic drugs by a unanimous vote of 10-0. The FDA will make its ruling in mid-October, and most observers believe approval is likely. The stakes are high, as injectable ocriplasmin has the potential to replace vitrectomy as the first-line treatment for VMA, related traction and macular hole. More importantly, it will provide a new treatment option to many patients who do not qualify for vitrectomy due to the risks associated with it.

The United States commercial rights to ocriplasmin are owned by ThromboGenics, which is based in Belgium, with a US affiliate located in Iselin, NJ. ThromboGenics recently entered into a strategic deal with Alcon (Novartis) to maximize ocriplasmin's commercial potential outside the US. The deal is potentially worth hundreds of millions of dollars in upfront, milestone, and royalty payments.

THE SAGA BEGINS

The ocriplasmin story began in 1989, when Dr. Trese was seeking a way to separate the retina from the vitreous in infants.

“The vitreous is much more adherent to the retina in children,” he notes, “so I was looking for an enzyme that could help achieve separation. George suggested plasmin.”

This idea was evaluated in the laboratory through animal studies, and the first paper demonstrating proof of concept was published in 1992.

During these early studies, Dr. Williams and Dr. Trese came up with the idea of using the patient's own blood to produce autologous plasmin. This plasmin could then be processed and reinjected into the eye.

The two doctors then received institutional review board (IRB) approval to conduct human studies of autologous plasmin that eventually encompassed approximately 500 patients.

“We first used autologous plasmin in babies with difficult retina detachments,” says Dr. Trese. “We initially saw it as a surgical adjunct, but as time evolved, we began to see it as an alternative to surgery.”

Highly encouraging results convinced Drs. Trese and Williams to use their own money to start a company called NuVue Technologies, which was dedicated to the commercial development of plasmin.

ENTER THROMBOGENICS

Though NuVue had a highly knowledgeable investor “angel,” who helped fund the company, and a manager named Chuck Mosher, who provided invaluable business advice, it had a relatively short history because fate intervened in the form of ThromboGenics.

“Around 2004, ThromboGenics was a cardiovascular company working on a recombinant truncated form of plasmin enzyme that was much more convenient than our autologous plasmin,” says Dr. Trese. “The recombinant form had the potential to be produced on a large commercial scale with long-term stability and sterility.”

“Though ThromboGenics was at that time primarily interested in cardiovascular indications, they became aware of our data for using plasmin in the eye,” continues Dr. Williams. “Our data were no secret, as we had been talking about it for over a decade.”

At that point, NuVue and ThromboGenics realized that each had achieved important breakthroughs that could be much more powerful if leveraged in a partnership.

In 2004, NuVue and ThromboGenics signed a collaborative agreement that gave ThromboGenics the freedom to continue the development process for ocriplasmin, which had been referred to as microplasmin until then.

“It was basically a licensing agreement for intellectual property,” says Dr. Williams. “We had intellectual property that ThromboGenics needed to move forward, and we also had the understanding of how the product could work in the eye. We had also been in discussion with the FDA, and could help ThromboGenics in designing clinical trials and setting study endpoints that were relevant to managing vitreoretinal diseases.”

In other words, the partnership between NuVue and ThromboGenics was a good match, combining highly complementary knowledge bases with strong potential for the development of a commercial product.

“All in all, working together has gone well,” says Dr. Williams.

THE MIVI TRIALS

Once the NuVue/ThromboGenics combination was established, ThromboGenics began a series of trials that were conducted under the umbrella title of MIVI. The phase 1/2 trials began in late 2004 and the phase 3 clinical program was initiated both in the United States and Europe starting in late 2008. The data from the pivotal studies (MIVI-Trust) were recently published in the August 16 issue of the New England Journal of Medicine.

“It's not often that an ophthalmic program gets published in the prestigious NEJM,” says Dr. Trese. “The results are impressive and the data suggest that ocriplasmin is superior to placebo in resolving VMA, associated traction and macular holes. “

“This is just the tip of the iceberg and based on 22 years of our own research with enzymatic vitreolysis, ocriplasmin could also be beneficial across many vitreoretinal pathologies,” adds Dr. Williams.

With years of clinical trial results confirming the safety and efficacy of ocriplasmin, ThromboGenics was ready to bring the therapy before the FDA this year. ThromboGenics is also seeking European Union approval for ocriplasmin.

Then, on July 26, the FDA advisory committee voted 10-0 in favor of ocriplasmin and that its benefits outweigh the risks of treatment for symptomatic VMA. The vote came two days after the FDA briefing package was published on the FDA Web site highlighting some specific ocular adverse events that occurred at a higher rate in ocriplasmin-treated patients as compared to placebo.

At left, macular hole prior to ocriplasmin injection, with VA of 20/63. Ar right, six months following treatment VA has improved to 20/25.

Dr. Williams was not overly concerned with the comments in the FDA briefing package as all the concerns raised were addressable with the available clinical data.

“Actually, the higher incidence of transient floaters experienced by patients receiving ocriplasmin were proof of the intended pharmacologic effect of the drug,” adds Dr. Trese. “These same kinds of floaters are typically noticed by patients whose VMA resolved without therapeutic intervention. So you could look at the floaters as essentially an indication of therapeutic effect.”

Drs. Trese and Williams would not predict how the FDA might rule on ocriplasmin approval, but they project confidence and eagerly await the November decision.

THE INNOVATION EXPERIENCE

Drs. Trese and Williams have learned much by going through the process of innovation, including funding, finding the right partner, along with licensing and regulatory issues.

“Going through this process is like getting a PhD,” says Dr. Trese. “Physician-innovators may have the medical knowledge, but they also have to learn the business side to succeed. This is something that really should be given some attention in our training programs.”

Dr. Williams says that the keys to successful innovation are believing in your idea, knowing more about it than anyone else in the world, and being your own biggest critic.

“Mike and I would often go back and forth trying to identify what was wrong with our ideas,” says Dr. Williams. “We had to convince each other before we would put our own money behind the concept.”

Dr. Williams says his “aha moment” as a believer in the future of plasmin came when his fellows would tell him how impressed they were with the efficacy of the drug in their patients.

For his part, Dr. Trese thought early on that the plasmin concept was going to succeed. “I was convinced by the original animal studies and by our initial successes with children,” he says.

INSIGHTS FROM 20 YEARS OF INNOVATION

Dr. Trese says the bar for successful drug innovation is set far higher than the standard for the development of handheld surgical instruments, which many ophthalmologists can do by working with established instrument companies. “It's just a much more complex process that you have to go through,” he asserts. “We were fortunate in that we had the angel investor and our NuVue manager Chuck Mosher to advise us along the way. Most physicians are not prepared to deal with all of the nonmedical issues involved with innovation. These are rare skill sets that have to be acquired. If we help more young ophthalmologists gain these skills, they can make significant and lasting contributions to our profession.” RP