Bruce Dorsey, Joseph Vacca

Crixvian, HIV treatment method

Non-European countries
Technical field
Merck Inc.
In this 1993 patent, American scientist Joseph Vacca and his team at Merck Inc. created the compound which would become Crixivan, a revolutionary treatment for patients with HIV. The release of the drug into the market in 1996 brought almost instantaneous results, changing the disease from a death sentence to a manageable condition.

European Inventor of the Year 2007 in the category "Non-European countries"

HIV/AIDS is one of the greatest challenges facing humanity at the present time. The numbers are daunting: In its 2006 paper on the global pandemic, the Centers for Disease Control and Prevention reported that in 2005 approximately 38.6 million people around the world were living with the HIV virus - and ultimately facing death.

It's this particular group that Joseph Vacca's invention has been helping for the past ten years. While Vacca's team - consisting of Katharine Holloway, Bruce Dorsey, Randall Hungate and James Guare - may not have been the first to create an HIV treatment, their compound broke new ground by helping to significantly extend the lives of those suffering from the condition.

The drug created from the patent was called Indinavir, but was marketed as Crixivan. On its release, it was unlike any other treatment on the market: Crixivan was original because it was able to attack a different viral target - the HIV protease.

From difficult times to breakthroughs

Even the company responsible for the patent, Merck Inc., admits that the road to the drug's ultimate success was filled with setbacks - not least the death of original project leader Irving Sigal, who passed away in 1988.

But despite this tragedy and numerous other difficulties along the way, it took just four years from first synthesis to the approved drug reaching the market, something of a miracle in this often slow-moving industry.

Vacca, an American, was one of the two group leaders on the HIV protease project trying out different design ideas. One of the compound series credited to Vacca was the combination of a piece from the clinical compound created at Hoffman LaRoche (LaRoche's drug eventually became Saquinavir) with part of a compound that his own group had developed three years earlier.

The first example of this combination series was created by James Guare, and showed some weak activity. Vacca then made the key compound in the series. It was this compound that - after so many disappointments - gave the team hope that they could find an optimal solution.

Another team member, Bruce Dorsey, took over this series from Vacca and eventually arrived at the compound that later became Crixivan and went on to generate substantial market success for Merck Inc., including $294 million revenue in 2002 alone.

A team effort that made history

As bumpy as the road to success may have been at times, the history-making team effort that helped create Crixivan still evokes fond memories among its members.

Looking back over his 25 years with the company, Vacca - who is still with Merck and currently serves as the company's executive director of medicinal chemistry - says the Crixivan era was the most thrilling and rewarding.

"We were working on an important disease that at the time had no treatment options," said Vacca, adding that it was very exciting to see the clinical data come out from the trials that showed how powerful protease inhibitors were compared to nucleoside analogues.

Meanwhile, patent co-author Katharine Holloway calls herself a "virtual chemist." Her role in the process was to model proposed HIV protease inhibitors in order to help prioritise those which were most interesting for synthesis. Holloway modelled a novel inhibitor template based on an idea developed by Vacca, and demonstrated its potential for further work.

The team knew that HIV could rapidly develop resistance to any single therapy, and so from the very beginning HIV protease inhibitors were taken in a "cocktail" with other antiretroviral drugs as part of HAART (Highly Active AntiRetroviral Therapy).

And the cocktail worked. In 1997, the number of AIDS-related deaths in the United States dropped by 47 percent according to the FDA, a significant decrease that came quickly after protease inhibitors were introduced to the market.

To this day, drugs such as Crixivan have made the lives of those facing the deadly disease HIV/AIDS much more liveable - and longer.

How it works

HIV is the etiological (causal) agent of a disease that includes the progressive destruction of the immune system (AIDS) and the degeneration of the nervous system.

The team led by Joseph Vacca found that a genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. In other words, they discovered that inhibiting the HIV protease was a viable method for HIV treatment.

As a protease inhibitor, Crixivan actually stops viral replication by inhibiting the activity of protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new virons.

The drug lowers the viral loads in patients with HIV and prevents the virus from developing into AIDS. It is taken as a "cocktail" with two other drugs (called reverse transcriptase inhibitors) and can help reduce the chances of patients getting illnesses associated with HIV.


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