[Pharm-policy] Development of Stavudine (d4T)

[James Love]

Since there is a dispute in Thailand regarding Stavudine (d4T), I
thought it would be useful to review some of the background in the
drug.  Thanks for Thiru for gathering this information.

        Discovery of d4T

Stavudine (d4t) was originally synthesized by Dr. Jerome Horowitz of the
Michigan Cancer Foundation in 1966 on a grant from the National Cancer
Institute.  (Incidentally, some researchers apparently use this date to
estimate the length on time it takes a company to develop an HIV/AIDS
drug, even though this research was publicly funded, and not done by a
drug company).


        Discovery that d4T would treat HIV/AIDs

Dr. William Prusoff of Yale University first discovered d4T's capability
to treat HIV/AIDS. Yale University holds the key use patent.  The patent
number in the USA is 4,978,655, which lists the inventors as Tai-Shun
Lin and William H. Prusoff.  The patent is assigned to Yale University. 
On the patent, it isays:

   This invention was made with United States government 
   support under Grant CA-28852 from the NIH. The United 
   States Government has certain rights in this 
   invention. 

Yale filed for patent rights in the USA, Australia, Canada, Denmark,
Egypt, Ireland, Israel, Korea, Mexico, New Zealand, Philippines,
Portugal, Singapore, South Africa, Taiwan, Romania, Austria, Belgium,
France, Germany, Great Britain, Greece, Netherlands, Italy, Luxembourg,
Spain, Sweden, and Switzerland.  

It is possible that other firms may be sought to obtain patents on d4T
in other countries, particularly in countries that have a "first to
file" system.  Other persons may also hold other patents on d4T, such as
formulation, dose or treatment regime patents.  We have not looked at
this yet.  But the US "orange" book only lists the Yale patent.  

        License to BMS

The Yale patent was filed in the US on December 17, 1986, and approved
on December 18, 1990.  But Yale licensed its marketing and distribution
rights to Bristol-Myers Squibb on January 12, 1988.

        NIAID and BMS Phase I/II trials

On March 23, 1989, one year and two months after the Yale license to
BMS, NIAID and BMS began a Phase I/II trial for d4T.  The projected
accrual was 40 patients, 5 per treatment arm (10 week induction up to
104 weeks maintenance). 
        

        BMS trial used in NDA

The trial used by BMS for Marketing approval was AI455-019, which looked
at d4T in monotherapy.  It was conducted between May 19, 1992 and August
12, 1994.  This was a BMS sponsored Phase II/III trial with 822
patients.  The median analysis time was 6 months.   The trial began one
year and five months after the Yale patent was approved.  


        NDA approval

The NDA was filed on December 28, 1993, and approved in less than six
months, on June 24, 1994.  This was 2 years, one month and five days
after the beginning of the Ai455-019 trial.  


   There was subsequent testing of d4T, and expanded marketing approvals
for use in combination therapy.  



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James Love, Director           | http://www.cptech.org
Consumer Project on Technology | mailto:love@cptech.org 
P.O. Box 19367                 | voice: 1.202.387.8030
Washington, DC 20036           | fax:   1.202.234.5176
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