Inverseon Inc.
This article was originally published in Start Up
Executive Summary
Beta inverse agonists, also known as beta blockers, have always been considered excellent therapy for hypertension, but not so excellent for asthma. They have a reputation for impressive short-term efficacy, but at great expense: namely, an unfortunate tendency to worsen asthmatic conditions over time. Inverseon Inc., however, doesn't see that as an inevitability. In fact, the company claims its lead product, a beta-adrenergic inverse agonist called INV102, has beneficial effects on asthma with long-term use.
An unorthodox approach to respiratory disease therapy
1701 Jackson Street, Suite 102
San Francisco, CA 94109
Phone: (415) 440-7400
Fax: (415) 440-7402
Contact: William J. Garner, MD, CEO
Web Site: www.inverseon.com
Industry Segment: Pharmaceuticals
Business: Drug development
Founded: February 2004
Founders: William Garner; Richard A. Bond; Michael Flashner, PhD; Amie E. Franklin, PhD; Thomas E. Jurgensen
Employees: 3
Financing to Date: $460,000 Seed financing and grants
Investors: EGB Advisors, LLC; Kansas Technology Enterprise Corp.
Board of Directors: William Garner (EGB Advisors); Michael T. Sember (BioPharma); Michael Flashner (EGB Advisors)
Scientific Advisor: Richard Bond, PhD (University of Houston)
Beta inverse agonists, also known as beta blockers, have always been considered excellent therapy for hypertension, but not so excellent for asthma. They have a reputation for impressive short-term efficacy, but at great expense: namely, an unfortunate tendency to worsen asthmatic conditions over time. Inverseon Inc. , however, doesn't see that as an inevitability. In fact, the company claims its lead product, a beta-adrenergic inverse agonist called INV102, has beneficial effects on asthma with long-term use.
Beta agonists activate beta-adrenergic receptors, while beta-inverse agonists, a subclass of beta blockers, inactivate these same receptors. They block beta-adrenergic receptors on the membranes of cells, which bind to hormones such as adrenaline and cause the vessels to contract. In the lungs, beta agonists activate these receptors. The use of beta agonists opens the airways in the short term, but long-term use has been linked to an increase in respiratory failure and even death, possibly because the inflammation caused by the asthma wasn't being addressed. That situation is somewhat ameliorated by the concurrent use of anti-inflammatory steroids, as in the case of combination products such as salmeterol plus fluticasone (Advair) from GlaxoSmithKline PLC and formoterol plus budesonide from AstraZeneca PLC (Symbicort). In 2003, Advair racked up $3.7 billion in sales and was the ninth-best selling drug worldwide, according to IMS Health Inc. Whether there's enough room for one more asthma therapy, even a nonsteroidal one, remains to be seen.
According to Inverseon, the problem with beta agonists for treating asthma lies not so much in the use of them, or whether combining them with steroids improves them, but in how long asthmatics continue to use them. To that end, the company is basing its business not on a new drug, but rather on the findings of a landmark study that they're banking will put an old standby, nadolol, on a whole new footing.
Nadolol was first approved by the FDA in 1979. It has continued to be a popular drug, known commercially as Corgard, in the treatment of angina and hypertension. For asthma, though, it sat firmly on the no-go list of beta blockers. That is, it did until 2003, when animal studies at the University of Houston showed that chronic dosing with nadolol exerted a compensatory response in which beta-adrenergic receptors were upregulated nearly 700%, resulting in dramatically improved bronchoprotection during asthma attacks. Inverseon's proprietary formulation of nadolol, INV102, is an orally available small molecule that the company claims increases the number of active receptors in the lungs and prevents bronchoconstriction during an asthma attack.
Beta blockers, which had been contraindicated for congestive heart failure patients until the 1990s, are now part of first-line therapy for CHF. Inverseon believes its spin on nadolol will be vindicated for asthma the same way beta blockers were for CHF, and that INV102 can do for humans what it did for mice. According to Inverseon, some 17-20 million Americans suffer from asthma. That's a lot of vindication, dollars-wise.
The company's scientific founder, Richard Bond, is a CHF pharmacologist and an associate professor in the pharmacology department at the University of Houston who led the animal study there. He long believed that extended use of beta blockers actually made the lungs less sensitive to asthma attacks, counter to the conventional thinking that blames beta blockers for mortality in asthmatics. After Bond proved his theory in mice, Nick Hanania, MD, director of the Asthma Clinical Research Center at Baylor University 's Baylor College of Medicine in Texas, applied for and received IND approval from the FDA to test nadolol in asthmatics. These trials will be overseen by Hanania and funded by Inverseon, which was created by EGB Advisors to develop INV102 and four other drugs currently in Inverseon's pipeline.
William Garner, MD, Inverseon's CEO, says, "About two years ago we saw confidential data [about Bond's preclinical nadolol] before they were published and thought they were exciting." That led directly to EGB Advisors' providing $260,000 in seed money for continued research and development efforts. Before Inverseon was incorporated, EGB also secured two Small Business Technology Transfer (STTR) grants from the National Institutes of Health totaling $200,000 for Phase I.
A Phase IIa trial of INV102 for mild asthma will commence during Q1 of 2005 with 12 patients at the Baylor College of Medicine. The study is expected to last about nine months. Another asthma treatment, INV103, is currently in preclinical trials. The company also has three more products in its pipeline, all in the discovery stage, for asthma, obesity, and the central nervous system.
Bond and the University of Houston retain ownership of the nadolol-derived technology and have assigned the IP to Inverseon. Inverseon has since filed two worldwide patent applications of its own, one for asthma and a second for programs covering G-protein coupled receptor (GPCR) drugs for indications that include obesity, which are still in the discovery stage.
Garner says that markets for other once-a-day controller drugs like INV102 total more than $1 billion. Most of Inverseon's competition, he says, comes from companies marketing or developing beta agonists for asthma, which he doesn't perceive as direct competition because their products work differently from his. Also, he notes, different asthma products can be and often are taken simultaneously. Among the competing manufacturers are GSK, AZ, and Pfizer Inc. GSK is investigating inverse agonists for CNS applications, and there's ongoing research in them at the academic level. "But in terms of a company that's staked out chronic inverse agonists as its scientific platform," Garner says, "we believe Inverseon is the only one doing that."
To that end, Garner insists, EGB Advisors isn't looking to make a quick sale on its asthma therapy and then move on. "We're looking to grow the company. We think we'll partner out our programs," he says, especially for Phase III trials. Nobody's signed up yet, he says; however, he notes that Inverseon is in discussions with one public company, adding it's too early to disclose any details. "Short- and medium-term, we're looking to develop some other inverse agonists and take them into efficacy studies. Having said that, the management people in the company, Mike Sember in particular, have extensive transactional backgrounds, and we're open if an opportunity presents itself."
Sember, Inverseon's director, has for 30 years negotiated licensing and M&A transactions for Marion Laboratories (now part of Sanofi-Aventis SA), Elan Corp. PLC, Deltagen Inc., and Women First HealthCare Inc. Garner himself is an industry veteran who worked as a venture associate at Paramount Capital and in medical affairs at F. Hoffmann-La Roche before becoming managing director of EGB. Co-founder Tom Jurgensen is an attorney with extensive experience providing IP and regulatory legal counsel to life sciences organizations such as the Salk Institute, Molecular Biosystems Inc., and Ligand Pharmaceuticals Inc. Michael Flashner, PhD, Inverseon's head of drug development, was formerly a VP at Quintiles Transnational Corp. and the project manager for interferon -1b (Betaseron), an FDA-approved treatment for multiple sclerosis now owned by Chiron Corp.
Garner admits that Inverseon's biggest challenges are raising the additional capital for studying INV102 and finding Phase III partners. Clinical development is the company's first priority. "In the old days," he says, "beta blockers were contraindicated in congestive heart failure and asthma. That has changed in CHF. We've taken a beta blocker from contraindication to getting approval to try it in asthma patients."—SS