Hampar and Vicken Karageozian

The father-son team behind Allegro Ophthalmics

By Jerry Helzner, Senior Contributing Editor | Retinal Physician, May 2014

In the highly competitive arena of ophthalmic drug development, probably the keenest competition exists in the area of new therapies for retinal disease. Though anti-VEGF therapies have emerged in the past decade as standard-of-care treatments for a range of retinal diseases, experienced innovators Hampar and Vicken Karageozian, of Allegro Ophthalmics, believe they have developed a drug that will provide a much different way to combat retinal disease.

The track record in drug development of the Allegro team, which also includes Allegro cofounders John Park, Marc Kirshbaum, and Lisa Karageozian, indicates that they should be taken seriously. Allegro CEO and cofounder Hampar Karageozian, MSc, MBA, has experience in ophthalmic drug innovation going back more than 40 years. He was head of R&D at Allergan when that company was in its infancy. He also was cofounder of ISTA Pharmaceuticals, where he and Vicken developed the spreading agent Vitrase and several other products.

Vicken Karageozian, MD, a practicing ophthalmologist, was a cofounder of ISTA with his father and is currently the chief technical officer at Allegro. He has broad experience in creating ophthalmic drug start-up companies and in conducting clinical trials for investigational drugs.

WHAT’S DIFFERENT ABOUT ALG-1001

The drug that has this team so enthusiastic is called ALG-1001, an integrin peptide inhibitor developed in cooperation with scientists at California Institute of Technology. Small early-stage human trials of ALG-1001 in wet AMD and DME have demonstrated a durable response at 3 to 6 months after a set of loading doses. In these trials, ALG-1001 actually became more effective 30 to 60 days after injection, compared with anti-VEGF agents whose efficacy begins to wane after several weeks. What makes ALG-1001 unique is that, as Vicken Karageozian explains, it attacks the “machinery” that creates neovascularization directly, as well as the signaling of VEGF itself.

“By disrupting the machinery that creates these unwanted blood vessels, ALG-1001 makes it more difficult for that machinery to regenerate itself and restart,” says Vicken.

The initial human study of ALG-1001 for wet AMD was as monotherapy. A 3.2 mg dose produced the best results, including interim data showing a mean gain of 8 letters 60 days after administration of the last dose. Before the first wet AMD study, Allegro conducted a study in end-stage DME subjects in which eight of 15 individuals experienced a 3- to 5-line improvement in BCVA at 90 days off treatment.

More recently, the company initiated a phase 1b/2a study using a combination of ALG-1001 and bevacizumab (Avastin, Genentech) to treat DME. This cohort will be compared with a group receiving bevacizumab monotherapy. Last fall, Allegro announced the FDA allowed the company to proceed with a phase 2 study of ALG-1001 for wet AMD that may include both monotherapy and combination arms.

“A high percentage of patients with wet AMD do not respond to anti-VEGF therapies to a point where they return to functional vision, or they are only limited responders,” says Vicken. “We believe the different mechanism of action of ALG-1001 may be effective for patients who do not do well on anti-VEGF therapies, not to mention the potential longer duration of effect.”

Integrin peptide therapy could also have a role in treating vitreomacular traction (VMT), where early tests with ALG-1001 in patients with severe diabetes have shown a 55% success rate in achieving total posterior vitreous detachment after one to three injections. Allegro recently began a phase 2 study with ALG-1001 for VMT.

ALG-1001: A NUMBER OF OPTIONS

The Karageozians believe they have a number of options as they further develop ALG-1001. “We know we have a drug that works, that produces a durable response, and that isn’t anti-VEGF,” says Vicken. “So far, we have self-funded Allegro along with a series A round, a generous grant from the Helmsley Charitable Trust, and a licensing agreement with Senju Pharmaceutical. We are funding the phase 2/3 trials with the money we have and are evaluating our options for additional funding that will allow us to achieve even more clinical milestones and eventual commercialization. These options range from additional regional licensing, global licensing, venture capital, and even possibly an initial public offering.”

ALG-1001 may have the greatest potential as one element of a combination therapy. Some observers outside the company have suggested a combination therapy may be the best role for ALG-1001 because it has taken weeks after injection for the drug to reach full effectiveness in the early trials.

Vicken dismisses that suggestion. “We haven’t even established an optimum dosing schedule for ALG-1001,” he says. “We still have a lot of work to do. I am not ready to say that we need another drug to go with ALG-1001 to produce earlier gains in vision.”

UNLOCKING THE SCIENCE

For years, Hampar Karageozian and Dr. Park, vice president of product development, were interested in the therapeutic potential of integrin peptide inhibitors in the form of a specific amino acid. However, they were unable to obtain a license from the German company that owned the molecule.

“Instead, we went to Dr. Julia Kornfield at Caltech for molecule discovery and Dr. Hugo Quiroz-Mercado at the University of Colorado for early safety studies to work on an innovative, new peptide molecule that we could use instead of the amino acid sequence,” says Hampar. “We were able to do it, and we got a clear biological signal that the synthetic molecule worked and was safe in animals. Next, we proved that the integrin peptide inhibitor was safe in humans.”

The team has a policy of “torture testing” its drug innovations as soon as possible so they know whether the drug has possibilities or should be discarded.

“We spend a great portion of our lives doing this research,” says Vicken. “Why waste time? We like to know what we have and go from there.”

THE INNOVATION PROCESS

The Allegro team believes that the innovative process works best with a core group of committed researchers and individuals with business backgrounds with a clear vision of what they want to accomplish. They surround this core with a circle of consultants who can be called upon to furnish specific individual expertise.

Allegro’s executive management team:  From left to right, Vicken Karageozian, MD, CTO; John Park, PhD, vice president of product development; Hampar Karageozian, MSc, MBA, CEO; Lisa Karageozian, director of clinical research; and Marc Kirshbaum, JD, COO.

Calling on his decades of experience in ophthalmic innovation, Hampar describes the ideal makeup of an innovation team.

“Your core group should have a broad range of experience and be highly motivated,” he says. “They should have realistic attitudes and show perseverance and tenacity because they will encounter many obstacles. Innovation is not an easy process. You don’t usually succeed on the first try.”

“The team should have good chemistry together,” adds Vicken. “You experience many ups and downs. You have to trust each other. You have to respect each other. And the team members should have complementary skills. We are very fortunate to have this chemistry in the team we have in place here at Allegro.”

Hampar prefers working in a small start-up company rather than as part of a larger company. “In a larger company, you may get funding for one year, and then the next year, the funding goes somewhere else regardless of the promise of your pursuit,” he says. “You are constantly concerned about getting enough resources to continue your research.”

“Sometimes, getting substantial external funding for a project at an early stage can be more of a curse than a blessing,” says Vicken. “Too much money can be distracting,” he adds. “It is easy to get caught up in expanding head counts and office space when you have a big budget. We prefer to stay lean at this stage and put all of our energy into optimizing and bringing to market a drug with the potential to significantly advance ophthalmic patient care.” ■