Adamas Pharmaceuticals' Triple Combination Antiviral Drug (TCAD) Therapy is Well Tolerated in a Pilot Study of Immunocompromised Patients With Influenza A -- Additional Data Demonstrate TCAD Has Broad Spectrum Activity In Vivo and Can Impede the Development of Drug Resistant Influenza --

EMERYVILLE, Calif., April 28 /PRNewswire/ -- Adamas Pharmaceuticals, Inc., a privately held company, announced today the results from the first clinical study evaluating triple combination antiviral drug (TCAD) therapy for the treatment of influenza A in immunocompromised patients.  Data from this Phase 1b study were presented by clinical investigator Dr. Janet Englund in a clinical symposium at the 23rd International Conference on Antiviral Research (ICAR) in San Francisco.

"This pilot study was an important first step in validating that the combination of three antivirals can provide a virologic and clinical benefit to patients at risk for complications of influenza," said Janet Englund, M.D., Professor of Pediatrics, Seattle Children's Hospital and Clinical Associate, Fred Hutchinson Cancer Research Center, Seattle, Washington.  "These findings warrant continued investigation of TCAD as a potentially broad spectrum treatment to address drug resistant influenza."

During treatment of patients with severe influenza or at risk for complications, mounting evidence suggests that the use of antivirals as monotherapy results in the emergence of strains resistant to both classes of approved drugs, creating a pressing need for new combination influenza therapies.  

The study conducted by investigators at the Fred Hutchinson Cancer Research Center in Seattle, Washington, and Seattle Children's Hospital, was a randomized, open-label study of TCAD therapy (amantadine and ribavirin administered with oseltamivir) versus oseltamivir monotherapy in immunocompromised patients with Influenza A.  The objective of the study was to assess the safety, tolerability, and virologic benefit of oral TCAD therapy.  A total of seven patients with confirmed influenza A were enrolled.  Data from the study demonstrated that up to 10 days of TCAD therapy was observed to be well tolerated, with five of six TCAD-treated subjects who completed the study achieving a clinical response by day 10.  In contrast, the single patient in the oseltamivir monotherapy treatment arm did not respond to 20 days of treatment.  Importantly, this patient developed an oseltamivir resistant strain by day seven that persisted to the end of treatment, resulting in the shedding of a multidrug resistant (MDR) strain of influenza.

"These results represent the first report of triple combination therapy in human clinical studies of influenza," said Gregory T. Went, Ph.D., Chairman and Chief Executive Officer of Adamas.  "We are committed to developing a broad spectrum therapy to fill a significant gap in healthcare, specifically, an influenza drug treatment that remains active during a full course of therapy, and reduces the risk of multidrug resistance."

Additional Presentations of Preclinical Data

Also at ICAR, researchers from Adamas and its academic collaborators presented the results from in vivo animal studies and in vitro tests which demonstrate that TCAD therapy is superior to double combinations and monotherapy against pandemic H1N1 influenza viruses.

Today, Adamas scientist Matthew Gross will present data in a podium presentation which demonstrate that the triple combination of amantadine, ribavirin, and oseltamivir is highly active against amantadine resistant pandemic 2009 H1N1 influenza virus in mouse treatment models in which physiologic concentrations of oseltamivir provided modest protection. Importantly, amantadine made a statistically significant contribution to the activity when present in the TCAD combination.  

In a poster session Monday, April 26th, Adamas scientist Jack Nguyen, Ph.D., presented data which show that TCAD suppresses the generation of resistant influenza A viruses in vitro, whereas double combinations did not.   Also on Monday, Adamas collaborator Justin Hoopes, Ph.D., from Utah State University reported data that each drug in the TCAD regimen contributes to suppression of virus breakthrough and preventing the emergence of resistance.

These data build upon recently published in vitro studies (PLoS One, AAC), and address fundamental questions about the viral kinetics of susceptible and resistant strains of the influenza A virus in response to drug pressure (i.e., single, double and triple).

Dr. Went added, "This body of data generated over several years in collaboration with leading academic centers, government scientists at the US Naval Health Research Center in San Diego, and infectious disease experts, provides exciting evidence that use of a triple drug combination against serious influenza should be further explored, especially given the concern posed by continued use of antivirals as monotherapy, which can lead to multidrug resistant influenza."

The Need for Broad Spectrum Antiviral Therapy

The recent H1N1 pandemic has highlighted the impact of influenza to public health and the healthcare system.  Serious influenza remains an untreatable disease that cannot be adequately prevented by vaccination alone, thereby threatening public health, military preparedness and groups of people in confined spaces.  The greatest impact of influenza infection and drug resistance is felt in at-risk groups especially vulnerable to infections such as patients with cardiovascular disease, diabetes, asthma and those who are immunocompromised.  Immunocompromised patients, who do not typically respond to vaccination, are most at risk for treatment resistance, treatment failure, severe morbidity and mortality.  According to the World Health Organization, more than 17,000 deaths occurred in the U.S. alone during the last flu season.  In addition, the WHO has reported over 285 cases of multidrug resistant influenza, with over 30 percent attributable to treatment with monotherapy, underscoring the need for an effective broad spectrum therapy that is able to impede the emergence of resistant strains and treat resistant and susceptible strains.

About TCAD Therapy

Adamas is pioneering triple combination antiviral drug (TCAD) therapy for influenza, which is designed to inhibit viral replication at multiple points in the virus proliferation pathway.  TCAD therapy includes Adamas' investigational proprietary fixed-dose combination of amantadine and ribavirin, to be administered adjunctively with a neuraminidase inhibitor such as Tamiflu® (oseltamivir phosphate, Roche), Peramivir (neuraminidase inhibitor, Biocryst) or Relenza® (Zanamivir, GlaxoSmithkline).

Preclinical data indicate that the in vitro combination of these drugs, each with independent mechanisms of action, act synergistically to provide increased antiviral activity over single or double drug combination therapies.  In preclinical studies to date, TCAD therapy also has been found to provide greater antiviral activity across more than 13 strains of seasonal, pandemic, and avian influenza A (H1N1, H3N2 and H5N1) virus, including six amantadine resistant strains and two oseltamivir-resistant strains.  Phase 1 and 1b clinical studies have been completed and additional studies are being planned.

About Adamas

Adamas is an emerging pharmaceutical company focused on developing small molecule Advantaged Therapeutics to treat neurological and infectious diseases, including influenza A, the cause of the current flu pandemic.  Adamas' approach to product development is to identify unmet needs where existing drugs can be developed as optimized combination drug therapies to increase safety, efficacy and compliance, thus improving upon the standard of care. Adamas is headquartered in Emeryville, California, with operations in Bangalore, India.  For more information about Adamas, please visit www.adamaspharma.com.  

SOURCE Adamas Pharmaceuticals, Inc.



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