Allegro – the musical term indicating a fast or bright tempo – seems equally appropriate to describe a biotech that moved its lead compound from discovery to the clinic in just two years. That was two years ago, and the compound, ALG-1001, is now in a Phase II study in vitreomacular traction.

Such is the cadence for Allegro Ophthalmics LLC, of San Juan Capistrano, Calif., established in 2009 by a team of executives with more than 100 years of combined experience in ophthalmic drug discovery, development and manufacturing. The goal was to focus on treatments for eye diseases that represent the leading causes of blindness, working quickly and methodically to advance a small molecule with a new mechanism of action.

“The idea has been to find out quickly – especially when we’re spending our own money, as we did in the beginning – whether we have a drug that is safe and effective,” explained Marc Kirshbaum, Allegro’s chief operating officer. “If not, let’s move on, because there are better ways to spend our time than curing blindness in mice and rabbits.”

While existing treatments for vascular eye diseases such as wet age-related macular degeneration (AMD) and diabetic macular edema (DME) simply sequester a patient’s pre-existing VEGF supply, Allegro’s integrin peptide therapy uses an extremely small molecule to turn off VEGF production at an earlier stage of the angiogenic cascade.

“When you’re targeting VEGF, you’re targeting the signaling process for angiogenesis,” explained Vicken Karageozian, Allegro co-founder and chief technical officer. “When you’re targeting integrins, as we are, you’re targeting the construction phase. VEGF is a switch to turn on the factory. We’re actually dismantling the machinery in the factory.”

The distinction is critical, he added, since AMD and DME, combined, affect more than 5 million people in the U.S., alone, but only an estimated 45 percent respond well to existing drugs.

“It’s like trying to treat every infection with penicillin and nothing else,” Karageozian said. “That’s kind of where we’re at right now in this space.”

‘NO FLUFF IN THE SYSTEM’

The molecule was discovered by Allegro co-founder and CEO Hampar Karageozian, who founded and served as chief technology officer of Ista Pharmaceuticals Inc., and co-founder and vice president of product development, John Park, who was an Ista researcher and later principal research scientist at Allergan Inc. Researchers at the California Institute of Technology were collaborators.

Preclinical studies showed that Allegro’s compound inhibits cell adhesion in vitro and arrests aberrant blood vessel growth in vivo, both systemically and in the eye. In vitro testing showed that ALG-1001 inhibits cell adhesion meditated by the alpha-5-beta-1, alpha-v-beta-3 and alpha-v-beta-5 integrins, which are implicated in the angiogenic process and known to be expressed in neovascular ocular tissue from patients with wet AMD and diabetic retinopathy.

Preclinical safety studies of the compound in rabbits and mice with both a single injection and repeated multiple injections showed positive initial safety and efficacy. ALG-1001 produced rapid, complete liquefaction of rabbit vitreous and induced posterior vitreous detachment in one to two days, with no apparent toxicity or immunologic side effects.

In 2011, Allegro completed a Phase I safety study, enrolling 15 end-stage DME patients who received three monthly intravitreal injections of ALG-1001 and were followed for an additional three months off-treatment. No serious or significant adverse events occurred, and eight of the patients improved three to five lines on the eye chart – four of them improving from legally blind to functional sighted in the 20/40 to 20/60 range. Eight patients experienced 30 percent to 80 percent reduction in the thickness of their macula. Several patients in the group had failed to respond to Avastin (bevacizumab, Roche AG), and some have proliferative diabetic retinopathy.

Following presentation of the results at the American Academy of Ophthalmology Conference in October 2011 and the Association for Research in Vision and Ophthalmology Conference in May 2012, Allegro’s investigational new drug application was approved by the FDA for Phase II studies of ALG-1001 in wet AMD and symptomatic vitreomacular traction.

Allegro completed enrollment in its Phase Ib/IIa wet AMD study. The dose-ranging, monotherapy study has a primary endpoint of safety and a secondary endpoint of improvement in both best corrected visual acuity and OCT central macular thickness. Subjects received three monthly injections and are being followed off-treatment for an additional four months.

In November, Allegro initiated its second DME study. This blinded trial is evaluating the clinical benefit of therapy with ALG-1001 in combination with Avastin vs. Avastin alone. The study will enroll 30 subjects, divided into three groups, with two receiving four monthly intravitreal injections of Avastin in combination with two study doses of ALG-1001 and the third receiving four monthly injections of Avastin and a sham injection. Following treatment, the subjects will be observed for 30 days off-treatment. Results are expected in mid-2014.

The company has been dancing across the piano keys, so far with flawless execution.

“We’ve been very fortunate that we have a combination of a good molecule and an excellent team, and everybody’s on the same page,” Karageozian told BioWorld Today. “That’s a formula for being extremely focused and answering all the tough questions as fast as possible with no fluff in the system.”

In May, based on Phase I data in multiple indications, the company forged a strategic partnership with Osaka, Japan-based Senju Pharmaceutical Co. Ltd. to co-develop and market ALG-1001. The agreement – the first significant infusion following seed capital from the founders, grant funding and a Series A from “a short list” of individual investors – covers use of the product in Japan for vascular eye diseases such as wet AMD and DME. Senju paid Allegro an eight-digit up-front license fee and agreed to additional development and sales milestone fees, plus a percentage royalty on net sales.

“That partnership is enabling us to continue to move forward on our clinical plan, including taking us through our first Phase III study,” Kirshbaum said.

While the company remains focused on execution, “there has been great interest in both our mechanism of action and approach as well as the results we’ve seen to date,” both from potential investors and strategic partners, he added.

The company’s intellectual property covers the entire drug discovery platform, creating the possibility that Allegro will continue to make beautiful music.

“Because of the team’s expertise and relationships, we chose to pursue ophthalmology first,” Kirshbaum said. “But it certainly has applications for lots of systemic conditions, as well, including – like Avastin – oncology.”