A First-in-Class HIV Therapeutic

Koronis’ lead product candidate, KP-1461, represents a new approach to the treatment of HIV unlike any of the existing classes of drugs on the market or in development. It is the first anti-viral therapeutic developed through a novel therapeutic mechanism Viral Decay Acceleration™™ (VDA). Utilizing VDA, KP-1212 (the active moiety of the prodrug KP-1461) is directly incorporated into the viral genome. Following incorporation and multiple rounds of replication, KP-1212 increases the high mutation rate of HIV beyond its threshold of viability, leading to viral collapse.

Potential to Avoid HIV Drug Resistance

Unlike approved HIV therapeutics, KP-1461 does not inhibit or exert selective pressure on the virus by targeting a specific viral or cellular protein/enzyme. Instead, it randomly inserts mutations across the entire 10,000 nucleotide HIV genome and, as such, may potentially avoid the development of drug resistance.

Clinical Milestones

Phase 2a Trial Designed to Provide Validation of Viral Decay Acceleration™™ Approach

A Phase 2a trial of KP-1461, currently underway, is designed to provide validation of a Viral Decay Acceleration™™ (VDA) therapeutic. The Phase 2 study (KP-1461-201) is an open label trial that will evaluate the safety, efficacy and tolerability of KP-1461, an oral small molecule drug, as a monotherapy in treatment-experienced HIV-infected patients. The study will enroll up to 32 patients with HIV who have not been on antiretroviral treatment for at least 16 weeks, have HIV-1 RNA levels greater than 2,500 copies/mL, and CD4 counts greater than 250 cells per mm3.

Patients will receive 1600 mg of KP-1461 twice daily for 124 days. The primary endpoint of the trial is safety and tolerability, and secondary endpoints are RNA reduction, CD4 count change, viral sequencing and genotype/phenotype change. The study will be conducted at clinical research centers throughout the United States.

Press Release: Koronis Pharmaceuticals Begins Phase 2a Proof of Concept Study of KP-1461, a Novel, Viral Decay Acceleration™ Agent for HIV Infection.

Phase 1b Trial Confirms Safety & Efficacy of KP-1461 in HIV-positive patients

Results from a Phase 1b multi-center, randomized, double-blinded, placebo-controlled safety and pharmacology trial in therapy-experienced HIV-infected patients have demonstrated KP-1461 to be generally safe and well tolerated. The trial involved approximately 40 HIV positive patients.

Press Release: Koronis Pharmaceuticals Begins Phase 1b Clinical Trial of Novel Anti-Viral HIV/AIDS Therapeutic in HIV-Positive Patients.

Phase 1a Trial Demonstrates Safety & Tolerability of KP-1461

KP-1461 has been evaluated in a Phase 1a trial that accrued 42 healthy volunteers and demonstrated the product candidate to be well-tolerated, with no dose-related toxicities. KP-1461 has completed Phase 1a human clinical trials with endpoints of safety and pharmacokinetics. The Phase 1a trial was a single dose, dose escalation, placebo controlled study of KP-1461 in 42 healthy volunteers. It was shown to be well tolerated at each dose through the highest dose level tested. There were no SAE’s.

Mechanism of Action -- VDA

Introducing Random Mutations to Target HIV Virus Destruction

The VDA approach was developed to take advantage of the natural highly error-prone viral reverse transcriptase. Koronis' scientific founders hypothesized that by presenting HIV with an error-inducing nucleoside triphosphate substrate, the viral genome mutation rate could be pushed beyond the allowable range of diversity thus extinguishing the population (Lethal mutagenesis of HIV with mutagenic nucleoside analogs. Proceedings of the National Academy of Sciences. 1999; 96:1492-1497).

The VDA approach has been demonstrated in cell culture using a nucleoside analog that normally base pairs with guanine but also frequently base pairs with adenine. This non-complementary base-pairing increased G to A and A to G mutations and ultimately, over the course of several viral replication cycles, resulted in viral ablation.

Origins

The development of KP-1461 stems from the leading research of Larry Loeb, University of Washington, John Essigmann, Massachusetts Institute of Technology, and Jim Mullins, University of Washington. These researchers reduced to practice -- through the development of Viral Decay Acceleration™™ -- a theory originally conceived by Nobel laureate Manfred Eigen. Eigen described the complex and dynamic nature of viruses as “quasispecies,” and introduced the idea that it may be possible to defeat a virus by exploiting its complex, rapidly mutating form.

KP-1461 Publications

• KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Harris, K.S., Brabant, W., Styrchak, S., Gall, A., Diafuku, R. Antiviral research. 2005; 67: 1-9.
• Mechanism of action of a novel viral mutagenic covert nucleotide: molecular interactions with HIV-1 reverse transcriptase and host DNA polymerases. Murakami, E., Basavapathrumi, A., Bradley, W.D., Anderson, K.S.
  Antiviral Research. 2005; 67:10-17.
• Lethal mutagenesis of HIV. Smith, R.A., Loeb, L.A., Preston, B.D.
  Viral Research. 2005; 107:215-228.
• Viral error catastrophe by mutagenic nucleosides. Anderson, J.P., Daifuku, R., Loeb, L.A.
  Annual Review of Microbiology. 2004; September:58.
• Stealth Nucleosides: mode of action and potential use in the treatment of viral diseases Daifuku, R.
  BioDrugs. 2003; 17(3):169-177.
• Broad spectrum antiviral activity of a novel mutagenic ribonucleoside analog. Li, L., Faske, S.K., Daifuku, R.
  Program and Abstracts of the Forty-First Interscience Conference on Antimicrobials and Chemotherapy. 2001. Abstract F-1675, p.239.
• Lethal mutagenesis of HIV by mutagenic ribonucleoside analogs. Loeb, L.A., Mullins, J.I.
  AIDS Research and Human Retroviruses. 2000; 16:1-3.

Intellectual Property

Koronis has established a strong intellectual property position related to Viral Decay Acceleration™™ (VDA) and KP-1461. This patent portfolio includes five issued U.S. patents related to VDA and an allowed patent related to the use and composition of KP-1461.

Press Release: Koronis Pharmaceuticals Receives Notice of Allowance on Patent for Novel Therapeutic KP-1461 in Development for Treatment of HIV.