Immunotherapy’ fails in Phase III trial
Compound had promised to shorten therapy
An agent that had seemed to hold out the promise of shortening the course of tuberculosis therapy to just two months crashed in a Phase III trial in South Africa. With it died investors’ dreams, as well as clinicians’ hopes for shorter TB therapy times.
Trial results for SRL172, a heat-killed preparation made from a strain of Mycobacterium vaccae, were announced in late September in London, just as the International Union Against Tuberculosis and Lung Disease (IUATLD) was conducting its annual conference in Paris. Results were announced at a late-breaking conference session, scuttling manufacturers’ plans for what they had hoped would be a jubilant press conference before conference members.
Executives at Stanford Rook, the small London-based biotechnology firm that put up half the funding for the South African trial, is fighting hard to keep a stiff upper lip in the face of the trial results.
"We couldn’t show improvement over the best available therapy," says David Kennard, PhD, chief operating officer of Stanford Rook. "But in the real world, under suboptimal conditions, we still believe that by taking our product you’d get a better result."
Throughout its brief but charismatic appearance as a supposed immune-booster for TB patients, SRL172 has drawn more than its share of attention. Jerrold Ellner, MD, director of the TB Research Unit at Case Western Reserve University in Cleveland, has been sufficiently tantalized to put the agent to the test in a Phase II trial starting up now in Uganda.
On the front lines, some clinicians were wondering whether they would soon be adding the agent to their repertoire.
Larry Geiter, MPH, PhD, North American liason for the IUATLD, tells of a physician from Pakistan who confessed to the Paris audience that he had conducted his own trial of SRL172. But when his patients failed to show additional improvement, instead of wondering whether there was something amiss with the drug, he concluded that his own study design must have somehow been at fault.
SRL172’s Phase III trial was conducted in Durban by a team of investigators from the South African Medical Research Council in conjunction with Stanford Rook. Double-blinded and placebo-controlled, it pitted patients receiving the best available treatment against a second group of patients getting the same drugs, plus SRL172.
A higher standard
Stanford Rook’s hope had been that patients in the experimental arm would convert their sputum cultures to negative more rapidly than the controls; but an analysis of the results showed that endpoint failed to materialize, says Geiter, who was a member of the trial’s Data Advisory Committee.
The problem, Kennard says, is that the design of the trials means that SRL172 is being held to a higher standard than other drugs. "With all the TB therapies that have come out in the past 30 years, the only thing the trials have shown is that they’re as good as existing therapies," he says.
What’s more, he says, when these existing therapies are administered according to directly observed therapy, as in the Durban trial, they produce high rates of cure. But by the same token, that very efficacy means it will be difficult for an agent superimposed on top of them, as SRL172 was, to do any better, Kennard says.
It is hard to imagine a trial that would purposefully allow people to lapse into nonadherence, he adds: "We couldn’t very well give people their pills, tell them to come back in a year, and see how many have relapsed."
Geiter disagrees. Designing such a trial "would certainly be very difficult, but it wouldn’t be impossible," he says. As for the design of the trial itself, rifampicin and pyrazinamide were both admitted to the standard regimen of first-line agents precisely because, when measured against available conventional agents, they in fact did outperform them, Geiter says. Thus, the addition of rifampin made it possible to shorten standard therapy to nine months and pyrazinamide to six.
Compensates for other therapies’ failures
In any event, Stanford Rook is banking now that SRL172 will perform more impressively in arenas where existing therapies are not so efficient and for the same reasons, Kennard says, it did badly in the South African trial.
Indeed, in initial testing, the agent shows some promise as an adjunctive therapy for patients with malignant melanoma, Kennard says. It may also prove useful against asthma and hay fever.
Part of what makes the story of SRL172 compelling is the way it pits a small, can-do biotech shop against the Goliaths of the pharmaceutical field.
The saga began decades ago when John Stanford, a microbiologist at University College, London, was in Africa, trying to figure out why the BCG vaccine worked so well in some parts of the world and so poorly in others.
There was a larger question, too. "Ninety percent of patients infected with TB never get the symptoms," says Kennard. "The question is maddening: Why? Obviously, something in the immune system is fighting it off."
Operating on the supposition that some element in the environment might be responsible for the difference, Stanford began hunting around in the African soil. In time, he isolated a benign strain of M. vaccae, returned to London, and told his colleague Graham Rook about his discovery.
Rook, a noted immunologist, had been among the first to delineate the immunological differences between TH1 and TH2, the two populations of T-helper cells (also known as CD4 T-cells) in the immune system. Even before Rook’s discoveries, it had been clear that two distinct series of events were taking place in the body’s immune response to TB.
TH1 cells were associated with a protective response (dubbed "cell-mediated immunity" by earlier researchers), which resulted in pathogens being engulfed and destroyed by macrophages.
TH2 cells, on the other hand, were associated with a mixed bag of effects. They appeared to help the body cope with parasitic infections, but they were also implicated in allergic reactions. In the case of tuberculosis, they seemed to trigger the familiar delayed-type hypersensitivity reaction seen in tuberculin skin testing; but they also were associated with the formation of tubercles and cavities, high fever, and weight loss.
Stanford and Rook concluded that the different ways in which people react to TB sometimes keeping the mycobacterium at bay despite being infected, sometimes succumbing to fulminant disease must mean that people who did well were able to mount a predominantly TH1-centered immune response; while those who did badly had started out with (or perhaps switched over to) a predominantly TH2-centered response.
"In other words, if you’ve got TB, by definition if you like, your TH1 system isn’t working," says Kennard.
Going a step further, then, Stanford and Rook proposed the following hypothesis: The strain of M. vaccae, which Stanford had isolated, held a key to keeping the immune system on the TH1 track. Perhaps, they said, it could be used to intentionally flip the switch.
The two began looking around for a way to develop their new agent. Turned down by conventional funding sources, they wound up forming their own corporation, and began searching out private investors. Eventually, Stanford convinced a stockbroker friend who lived in the same village as he did to come on board; soon, a store of venture capital had been raised.
Early trials in Romania, though not as tightly controlled as the Durban trials, seemed promising. Although all of the Romanian patients achieved a cure, the ones in the SRL172 arm put on weight much more rapidly and reached other secondary endpoints much more quickly than the controls.
Suddenly, anecdotal evidence began piling up, attesting to similar results.
Two other trials of the agent are still under way, one in Uganda and the other in Zambia. But Kennard concedes the question of whether SRL172 could ever live up to its promise as an adjunct to not-so-great TB therapy will probably remain unanswered.
Geiter draws a lesson about the importance of keeping perspective in the face of high hopes.
"Stanford and Rook started out with a plausible hypothesis," he says. "But people took these concepts and began talking about them as if they were true . . . and suddenly, it was as if they were true."
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