In 1996 at the height of the AIDS epidemic, the HIV team at the Swiss Pharmaceutical Company Ciba-Geigy discovered atazanavir, the world’s first once-daily protease inhibitor. As the 25^th Conference on Retroviruses and Opportunistic Infections (CROI) continues this week in Boston, Dr. Janis Lazdins-Held, former group leader of the Ciba-Geigy team, writes about the challenges of discovering the breakthrough treatment.

The MPP licensed atazanavir from Bristol-Myers Squibb in 2013 to ensure its availability in developing countries.

By Janis K. Lazdins-Helds, M.D., Ph.D. 

The mid-1980s was a difficult time for biomedical research globally. The United States government had slashed research funds by 23%, the United Kingdom had implemented a “level funding” policy and the situation across Europe fared no better.  Against this backdrop, many scientists had to reassess their careers and look for new horizons. After years of working at the Venezuelan Institute for Scientific, U.S. National Institutes of Health in Bethesda and academic tenures at Harvard University and Universita degli studi di Roma “La Sapienza”, Italy , I landed at the Swiss pharmaceutical company Ciba-Geigy in Basel. Ciba-Geigy was an “incubator” for scientists recently arrived from the United Kingdom, Germany, France, Italy, Argentina, Venezuela, etc.

I started working at the company in 1986, a watershed moment in global public health. Three years after Francoise Barre-Sinoussi isolated a retrovirus that killed T-cells from the lymph system at the Pasteur Institute in Paris, the scientific community adopted the name human immunodeficiency virus for the cause of AIDS. In the New York Times that same year, NIAID Director Anthony Fauci predicted that one million Americans had already been infected with the virus and that this number would jump to two to three million within five to 10 years. We saw not only many of our cultural icons perish day after day, but also many of us were personally touched by the disease. In the company, the perception of AIDS was evolving, a change sparked by an emerging leader Professor Alex Matter, best known for his contribution to the discovery of Glivec/Gleevec, one of the world’s first tyrosine kinase inhibitor drugs against chronic myeloid leukemia (CML). As the head of drug discovery oncology / virology at Ciba-Geigy, he argued the company should tap its new talent to find more effective ways to fight the AIDS epidemic.

The campaign was not easy. Ciba-Geigy was a relative latecomer in HIV/AIDS treatment and senior management questioned the business case for investing further in the field. It was the persistence of Alex that succeeded to tilt the balance and in 1988 the company established the AIDS/HIV Ciba-Geigy Discovery Multi-Disciplinary Team. Ciba-Geigy dedicated 10 scientists, with expertise in molecular biology, virology, cell biology, immunology, enzymology, pharmacology and chemistry, supported by 22 technical staff. I had the privilege of being the group leader.

Our entry strategy was simple, but innovative. Rather than taking a linear, step-by-step approach to HIV treatment development, we sought to tackle as many viral targets as possible, and by 1990 it was clear that our best option for success was in the area of HIV protease inhibitors (PIs).  At the time, many pharmaceutical companies had already introduced PIs, and therefore our aim was not to duplicate efforts, but rather to overcome current early protease inhibitors’ clinical limitations. We established a Target Product Profile-Driven discovery programme to identify new compounds that would have an antiviral activity superior to the drugs available at that time; that were active against HIV strains resistant to other inhibitors and that would reduce the need for multiple daily treatments. But perhaps most importantly, the visionary team’s ideal candidate would be simpler to produce (less steps and less expensive starting materials) to greatly improve patient access. Although the marketed PIs were efficacious, we believed that an even more potent molecule could be developed to improve health outcomes for people living with HIV/AIDS.

With these parameters in mind we engaged in our “utopic “quest. The team structured our discovery programme streaming thousands of molecules that the chemists[1] designed based on enzymology information, to be rapidly progressed through diverse in-vitro and in vivo assays.[2] We assessed potency and specifically resistance capabilities, then quickly moved on to testing in infected cell lines as well as in primary human lymphocytes and macrophages. Simultaneous to all this in-vitro work, we determined plasma levels in mice after oral administration, and quickly fed data back to the chemists for further optimization of the compounds.

As chemistry efforts intensified we focused on a peptidomimetic inhibitor and, by 1993, we progressed CGP-53437 [3] to full development. Unfortunately, due to prohibitive toxicology, we were unable to further develop this compound. But as science is often “one step forward, two steps back”, a new molecule emerged, CGP 61755, a compound with high potency, including against protease resistant enzymes and viruses, and boasting high absorption in animals as well as strong bioavailability.[4] This compound also informed our progress on a new series of potential candidates (CGP75355, CGP-73547, CGP-73547A, CGP-75136 and CGP-75176) with similar or better attributes to anything seen so far. [5]

In June 1996, the team prioritized CGP 61755, CGP-73547 and the methane sulfonate CGP-73547A for early clinical evaluation based on:

• Favorable, simplified synthesis when compared to current PI saquinavir (23 steps), indinavir and ritonavir (>20 steps)
• In-vitro antiviral activity superior to any of the known inhibitors
• Minimal effect of α1-Acid Glycoprotein on reducing antiviral activity
• Activity against HIV strains resistant to other HIV protease inhibitors
• Feasibility of user-friendly formulation
• Chemical nature that would suggest reduced harmful drug-drug or drug-food interactions
• Indication for low frequency of dosing and thus less toxicity, potentially leading to better adherence.

Once we had accumulated all the information on these promising compounds, we were convinced that the “utopic” ambitions of the team to improve standard of care for people living with HIV/AIDS were achievable. As the only physician with a background in HIV/AIDS in the company, I was to lead the clinical development of these candidates with the support of our in-house team and a strong network of European clinical specialists and HIV activists.  However, that same year Ciba-Geigy merged with Sandoz to form Novartis. The new company took a strategic decision to terminate all its HIV projects. By December 1996, the Biological Safety Level 3 laboratories (where we had conducted our research) were closed and team responsibilities were reallocated to other projects. Some of us stayed coordinating the out-licensing activities of the HIV compounds and by early 1997 they had a new home at Bristol-Myers Squibb (BMS).[6] [7]

After conducting the necessary preclinical and clinical studies, Bristol-Myers Squibb discontinued CGP-61755. CGP-73547A was renamed BMS-232632, generic name atazanavir sulfate with REYATAZ as its brand name. Atazanavir progressed through full development obtaining US Food and Drug Administration approval in June 2003. The treatment is now on the World Health Organization’s Essential Medicines List and is WHO-recommended as part of the preferred second-line treatment for adults and children.

In July 2017, the Medicines Patent Pool signed an extension of its licence agreement with Bristol-Myers Squibb allowing generic manufacture of atazanavir for sale in at least 122 countries that together are home to 89% of people living with HIV in low and middle-income countries. The dream that started in a laboratory in Basel nearly three decades ago has now become a reality.  With widespread access, atazanavir has the potential of improving the lives of millions of people living with the virus.

[1] Marc Lang, Guido Bold, Alex Fässler, Hans Capraro, Peter Schneider and others

[2] Johannes Rösel, Thomas Klimkait, Enrica Altei, Bernard Poncioni, Maja Walker, Kathie Woods-Cook, Juergen Mestan; Robert Cozens

[3] CGP 53437 a peptidomimetic inhibitor containing a hydroxyethylene isoster, an orally bioavailable inhibitor of human immunodeficiency virus type 1 protease with potent antiviral activity. E Alteri, G Bold, R Cozens, A Faessler, T Klimkait, M Lang, J Lazdins, B Poncioni, J L Roesel, P Schneider. Antimicrob Agents Chemother. 1993 Oct;37(10): 2087–2092.).

[4]Synthesis of potent and orally active HIV-protease inhibitors. Capraro HG, Bold G, Fässler A, Cozens R, Klimkait T, Lazdins J, Mestan J, Poncioni B, Rösel JL, Stover D, Lang M. Arch Pharm (Weinheim). 1996 Jun;329(6):273-8.

[5] New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease Inhibitors: candidates for clinical development, Bold G1, Fässler A, Capraro HG, Cozens R, Klimkait T, Lazdins J, Mestan J, Poncioni B, Rösel J, Stover D, Tintelnot-Blomley M, Acemoglu F, Beck W, Boss E, Eschbach M, Hürlimann T, Masso E, Roussel S, Ucci-Stoll K, Wyss D, Lang M. J Med Chem. 1998 Aug 27;41(18):3387-401.

[6] Patent Landscape Report on Atazanavir, a patent landscape report prepared for the World Intellectual Property Organization (WIPO) by Thomson Reuters, IP Solutions, IP Consulting Group, in cooperation with the Medicines Patent Pool, November 2011 http://www.wipo.int/edocs/pubdocs/en/patents/946/wipo_pub_946_2.pdf

[7] Thereafter I went to manage the development of the antimalarial fixed dose combination Coartem, but that is another story. By 1998 I left Novartis to join the World Health Organization, UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) in Geneva, Switzerland where I stayed until my retirement in 2009.