Koronis Pharma era stata qualche anno fa una bella scommessa: un meccanismo completamente eterodosso di affrontare l’HIV, attraverso la cosiddetta Viral Decay Acceleration (“VDA”), il cui razionale era (“per chi si fosse perse le puntate precedenti”) quello di provocare un numero così elevato di mutazioni nel virus residente nella persona da indurre, alla fine, delle mutagenesi letali per il virus stesso, inducendo quindi il crollo della viremia. Purtroppo, la teoria, affascinante, non ha retto alla prova dei test di fase II: il candidato farmaco KP-1461 non è stato in grado di provocare il crollo atteso della viremia, né ha mostrato di superare i reservoir. Certo, il KP-1461 s’è dimostrato sicuro e le mutazioni ci sono state, ma ciò non è bastato. Koronis stessa indica tre ostacoli: 1. Penetrare rapidamente i reservoir, perché solo così si può sperare di svuotarli e/o ucciderli attraverso la mutagenesi letale 2. Accrescere l’efficacia mutagena del farmaco, perché se il principio è stato dimostrato, non ha ancora raggiunto l’efficacia attesa 3. Trovare dei soldi per continuare, forse la cosa più difficile. Così Koronis ha tratto le conclusioni e deciso di “diventare una compagnia virtuale”. In buona sostanza chiudere la baracca per continuare le ricerche quando e dove i soldi ci saranno, utilizzando strutture di terzi, il know-how fin qui sviluppato e indirizzando i fondi che si riusciranno a raccogliere direttamente ai laboratori che saranno coinvolti nelle ricerche. Trattandosi di americani, la loro comunicazione si chiude con il solito ottimismo ma, per ora, un bel po’ di magone mi resta…

1. In the past we’ve told you about the Viral Decay Acceleration (“VDA”) drug mechanism[1], so you’re
probably aware of the challenges associated with the HIV pandemic. We want to update you on our new
approach to develop a curative VDA-based molecule against HIV.
After glancing at headlines that announced the recent UNAIDS report, the casual reader sees,
“...enormous progress” and might conclude that HIV has officially become yesterday’s problem. We’re
pleased that the world-wide rate-of-growth for new HIV infections is declining, but it’s hard to imagine
satisfaction among the 2.3 million people that became infected in 2012 and pushed the world’s total
HIV-infected over 35 million. HIV remains a public health challenge without a cure on the horizon.
Twelve-million people are fortunate to be on anti-retroviral therapeutic (“ART”) drug regimens. If they
comply with the lifelong drug regime, they can consider HIV to be a chronic disease. But for the others,
HIV remains an AIDS death sentence.
ART could be a practical long-term answer to HIV, if not for three inherent issues:
1. ART therapy has long-term adverse side effects. Patients may no longer die from AIDS and
may have near-normal life spans, but their quality-of-life suffers.
2. The high per-patient direct cost[2] to provide ART is declining but this statistic grossly
underestimates the all-in cost of HIV because the treatment expense for collateral
complications is excluded. Making matters worse, all-in costs are likely to grow exponentially
as the number of treated-patients expands and ages.
3. Providing ART on a chronic lifetime basis is a daunting logistical challenge that overwhelms
many health-care delivery systems in the world.
The answer is a “curative HIV therapy” as called for last summer by HIV opinion-leaders at the 7th IAS
Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia. Unfortunately,
there is a dearth of practical and economical curative programs under development.
The development program of Koronis’ new VDA agent will test its potential to advance a cure for HIV.
Even though Phase 2a clinical results (the “201” trial) using the initial VDA molecule [KP-1461] did not
show an actual collapse of a patient’s viral load, nor, importantly, that the reservoir can be penetrated and
eliminated, those results showed a favorable safety profile and confirmed that supplemental viral
mutations accumulated in treated patients.
The development of Koronis’ new compounds faces three hurdles...
1. The need to be effective against viral reservoirs—those HIV-infected cells that rejuvenate
the infection. For a durable clinical outcome, a limited-duration regimen must nullify these
cells.
2. Increase the mutagenic power[3] of the drug. The fundamental VDA principle[4] has been
demonstrated. Now it’s time for a more robust molecule to prove VDA’s clinical usefulness.
3. Overcoming entrenched attitudes that have closed off traditional sources of financing.
Inexplicably, some consider HIV to be a mature commercial market. Others are wedded only
to vaccines and prevention. Now it’s time to find financing from people and groups that think

2. its time for new ideas.
Koronis has changed. Today, Koronis...
1. Has become a virtual company. A collaborative R&D effort is planned with VDA’s three
scientific founders[5] at their high-profile research labs.
2. Has preserved the entire foundational knowledge accumulated from the 14-year
development of VDA and KP-1461. The three VDA founders continue to work
with CEOJean-Pierre Laurent, Ph.D. This four-person team has over 100 years of combined
experience with HIV, VDA and KP-1461.
3. Plans to seek non-dilutive funding from various organizations. These funds would be
awarded directly to the academic labs for specified development activities.
We believe an experienced core team operating in a collaborative fashion utilizing an existing knowledge
base has a higher chance of demonstrating what KP-1461 failed to show, i.e., error catastrophe in humans
over a reasonable period of administration. We foresee an entirely new VDA molecule with augmented
mutagenic power being validated in an in-vivo HIV animal model.
NOW is the time to find a few more people who want a curative drug for HIV and are ready to change
the HIV status quo by challenging today’s entrenched attitudes.
If this could be you, and you want to learn more, click on this link to respond.
[1] Viral Decay Acceleration—sometimes referred to as viral lethal mutagenesis- has the potential to cause error catastrophe against HIV by
mutational overload. Once the drug’s cumulative effect causes error catastrophe, any virus including the one present in HIV-infected reservoir
cells would lack the fitness required to rejuvenate the infection. Ultimately we believe that treatment with a VDA agent leads to a curative
outcome and no further need for a sustaining drug administration.
[2] ~$19 billion was spent in 2012 to treat ~12 million people; if UNAIDS 2015 treatment goal of 15 million people is achieved, UNAIDS
expects direct treatment costs to be ~$22 billion.
[3] Mutagenic power refers to the ability of a VDA agent to create mutations in the HIV genome. The more mutations created per cycle of viral
replication - the higher the mutagenic power of the VDA agent.
[4] Several VDA molecules clearly triggered error catastrophe of in vitro HIV cultures. The ability of KP-1461, the first generation VDA agent,
to create specific mutations in HIV during treatment was demonstrated over the course of treating 89 patients in three separate clinical trials.
Finally, KP-1461 was found to selectively target the virus; to be safe and well tolerated with no occurrence of serious adverse events; and to
cause supplemental mutations to accumulate in the viral population of 12 HIV-infected patients who completed the Phase 2a trial “201” study
(the “201” study).
[5] John M. Essigmann, Ph.D. is the William R. and Betsy P. Leitch Professor of Chemistry, Toxicology, and Biological Engineering and a
MacVicar Fellow at the Massachusetts Institute of Technology. His laboratory conducts research on the synthesis of programmable therapeutics
and the relationship between these agents and specific biological endpoints of mutation, cancer, and cell death.
Lawrence A. Loeb, M.D., Ph.D. is the Joseph Gottstein Professor of Pathology and Biochemistry at the University of Washington and the
director of the Joseph Gottstein Memorial Cancer Research Laboratory. His laboratory specializes in research relating to DNA mutagenesis as it
relates to cancer, viral infections and other disorders. He has been the keynote speaker at numerous worldwide scientific conferences on
mutagenesis over the past 25 years. In 2014 he will be the keynote speaker at the prestigious Gordon Conference on Mutagenesis.
James Mullins, Ph.D. is a Professor of Microbiology, Medicine and Laboratory Medicine at the University of Washington. He is a long-standing
and prominent thought-leader on the use of molecular, computational, and virus biology techniques to fight the AIDS pandemic. He has more
than 360 scientific publications in the HIV area and has given more than 320 invited presentations on AIDS as seminars and symposium
presentations.
Koronis Pharma is pioneering the development of a new class of anti-viral therapeutics based on a novel mechanism - Viral Decay
Acceleration™.
For more information, please contact us:
Koronis Pharma 800 Fifth Avenue, Suite 4120, Seattle, WA 98104
koronis@koronispharma.com
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