LONDON - A dream was revived at Stanford Rook Holding plc when a U.S. National Institutes of Health (NIH) study in Uganda demonstrated the benefits of using the company's SRL 172 compound as an adjunct to standard chemotherapy in tuberculosis.
Stanford dropped development in this indication last October after it failed in a Phase III trial in Durban, South Africa.
Thomas Lang, Stanford's director of business development, told BioWorld International, “We can't just dismiss a negative Phase III trial. What we can say as a result of this trial in Uganda is that the results of the Durban study are no longer cut and dried.“
The NIH-funded study of 120 patients in a randomized, placebo controlled Phase I/II trial began before Stanford, based in London, received results of the South Africa study. Lang said the company will now await the results of a further trial, funded by the U.K. Department for International Development, which has just finished recruitment of 1,200 patients in Zambia.
“There was considerable build-up to the South African trial announcement, and we were very optimistic,“ Lang said. “Therefore there was a general disappointment, both internally and externally, that it failed. This required us to take stock, and we said we would not invest in further clinical trials [in TB] at that stage.“
NIH Trial Rallies Stanford Shares
Shares in Stanford fell by £3.90 to £1.50 at the beginning of October 1997, when it announced that SRL 172 failed in the South African Phase III trial of 347 patients. It was a devastating setback for the company, which was founded in 1992 to commercialize SRL 172 in TB and had predicated its commercial strategy on getting the vaccine on the market in South Africa in 1998.
When the NIH results were announced last week, shares in the company, which is listed on London's Alternative Investment Market, initially rose £0.16 to £0.995. But they then fell to end the week unchanged at £0.835.
SRL 172 is a heat-killed preparation of mycobacterium vaccae. The company's founding researchers - John Stanford, a microbiologist, and Gordon Rook, an immunologist, both formerly of University College London - said it acts as an immune switch, shifting the body's immune response to infection from production of the subgroup of Th2 lymphocytes to production of the Th1 subgroup.
In TB, a Th1 response destroys baccilli-containing cells, while a Th2 response triggers antibody formation and causes massive and inappropriate tissue destruction. This is responsible for the formation of lung cavities in which the tubercle baccilli replicate and gain access to cough spray, thereby passing on the infection.
Although TB is curable, medication must be taken daily over six months. Many patients fail to complete the course of antibiotics; the disease flares again and they remain infectious.
In addition some strains are resistant to available antibiotics. Stanford's aim was not to replace existing treatment, but to cut the duration of standard chemotherapy from six to three months by administering the SRL 172 vaccine when treatment commenced.
In the NIH trial in Uganda, 34 percent of 61 patients who received SRL 172 in addition to standard chemotherapy showed sputum culture conversion after one month compared with 15 percent of 59 patients who received chemotherapy alone.
Patients who received SRL 172 also showed significantly reduced lung damage at six and 12 months in the trial.
Zambia Study Eagerly Awaited
The NIH may decide to fund further studies, in which case Lang said Stanford “would be happy to cooperate.“ But, he added, “We don't want to put in more money at this stage.“
He said that if the study in Zambia, which is due to report in 1999, is positive “the regulatory authorities would view the data favorably.“
While the average cure rate for TB is 50 percent, in the Phase III trial in South Africa 95 percent of all patients were cured. Everyone in the trial was treated in a hospital.
Lang observed that although the study did not achieve its endpoint of demonstrating SRL 172 improved cure rates over standard therapy, “what we appear to have done is prove the World Health Organization's claim that if everyone was treated in hospital, most would be cured.“
He said the conditions under which the NIH Uganda trial was conducted were “closer to real life,“ with a much lower level of supervision.
Since the failure of the South African trial, Stanford has been concentrating on use of SRL 172 as an antigen vector in cancer immunotherapy, as an allergy treatment and as a vaccine adjuvant.
Lang said the company would consider proposals to do further trials in TB, but “we intend to keep the focus on cancer and allergy, because we think that's important too.“
A Phase III trial in malignant melanoma is under way, and the company is preparing to start a Phase III trial in lung cancer later this year. It also will report results of a two-year follow up of hay fever sufferers at the end of the year. *