GMHC Treatment Issues - Vol. 9, No. 12 - December 1995
Rick Loftus

Sandoz researchers and their associates reported their findings in a remarkably detailed series of articles published over the last fourteen months.1-4 They found that the cyclosporine family binds to the cellular enzyme cyclophilin A. Cyclophilin probably is involved in folding proteins into their proper shape as well as transporting proteins into cells' nuclei. Cyclophilin binds to one area of HIV gag (core) protein that is little affected by genetic mutation. It is packaged into the core of HIV particles as they bud off from cells.

When NIM 811 or other active members of its family are present, two things happen: 1) the HIV particles budding off of cells are not infectious; and 2) uninfected cells are protected from functional HIV, which never reaches their nuclei. NIM 811 as well as cyclosporine produced these effects in cultures of CD4 lymphocytes and monocytes, the two main cell reservoirs of HIV, and against a wide variety of HIV strains.

NIM 811 seemed preferable to cyclosporine overall on the basis of safety and efficacy. Animal toxicology and oral bioavailability studies all were positive for NIM 811. In mice, rats, dogs and monkeys, concentrations of NIM 811 were safely reached that far exceeded effective levels in the test tube.

And then. . . Sandoz canceled the project just when human trials of NIM 811 were within sight. The company claims it did so because it could not make sufficient quantities of the molecule. Sandoz attempted unsuccessfully to breed the fungi that produce cyclosporine and NIM 811 to increase their output of the latter. The cell cultures died, reportedly because high levels of NIM 811 is poisonous to them.

But there are those who believe that Sandoz gave up too readily. Oswald Weber of Projekt Information in Munich, Germany notes, "[Production difficulties are] an argument we've already heard a number of times whenever pharmaceutical companies start looking for excuses. . . " Indeed, Sandoz has not pursued possible alternative production methods.

There is an underlying reason that could explain the company's lack of motivation: Sandoz's main interest is bone marrow and organ transplants (hence, cyclosporine), which may also involve gene therapy applications. Except for such gene therapy, the company is not interested in infectious disease research. This stance arises from business strategy. It does not represent a particular bias against AIDS: Sandoz recently bought a small, highly regarded American biotech company, one of whose activities is in fact anti-HIV gene therapy research.

This same reasoning was at play in 1991, when Sandoz abandoned its line of monoclonal antibodies. Rights to the antibodies were eventually bought up by Protein Design Labs, another small biotech company, but in the process, development of the products was set back four years. (See Treatment Issues, July/August 1995, pages 7-8.)

Sandoz supposedly is continuing to make available small quantities of the NIM 811 to outside researchers, who could at least prove the principle that a cyclophilin inhibitor like NIM 811 is a practical way to attack HIV. But what company is going to license NIM 811 if it is labeled impossible to mass produce for the market? Right now, the sort of delay encountered by the monoclonal antibodies is the best fate NIM 811 can hope for. --DG

1 Rosenwirth B et al. Antimicrobial Agents & Chemotherapy. Aug 1994; 38(8):1763-72.

2 Thali M et al. Nature. Nov 24 1994; 372(6504):363-5.

3 Steinkasserer A et al. Journal of Virology. Feb 1995; 69(2):814-24.

4 Rosenwirth B et al. Journal of Virology. Apr 1995; 69(4):2451-61.

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