By Kaspar Mossman
QB3 researchers at the UCSF Sandler Center for Basic Research in Parasitic Diseases are preparing to apply for FDA approval to test an Investigational New Drug (IND) for Chagas disease, in what could become the first drug to emerge from UCSF without an industry partner.
Electron micrograph of the parasite Trypanosoma cruzi. Photo by Stephanie Hopkins and Juan Engel.
If approved, this would pave the way for UCSF to conduct a Phase I clinical trial for the compound, the first targeted therapy for the deadly disease. It would also offer an alternative to current therapies, which are not specific to the Chagas parasite and inflict severe side effects on patients, according to James McKerrow, MD, PhD, UCSF professor and a member of California Institute for Quantitative Biosciences (QB3).
“The current therapy is for 60 to 120 days,” said McKerrow, a parasitologist who first identified the compound in 1989 during research on the biology of the Chagas parasite. “It’s almost impossible to expect someone to take that drug for that long. We were looking for something that you would take for 15 to 30 days, more like what you'd expect with an antibiotic.”
The compound, known as K777, inhibits a vital enzyme called cruzain in the protozoan Trypanosoma cruzi, the parasite that causes Chagas disease. Because cruzain has no direct counterpart in humans, McKerrow said K777 may have minimal side effects. If clinical trials bear out its promise, it could cure millions suffering from what is considered the most serious parasitic disease to affect people in the Americas.
Chagas disease is endemic throughout Mexico, Central and South America, and affects an estimated 8 million to 11 million people, according to the US Centers for Disease Control and Prevention. Initial symptoms are mild, but years later, T. cruzi moves on to colonize the heart and intestines, eventually killing upwards of 20,000 people per year. The disease is spread via the triatomine bug, an insect known by several names, including the "assassin bug" and the “kissing beetle,” since it often bites people near the mouth as they sleep.
“T. cruzi is a very effective and historically old parasite,” said McKerrow. “It started out as an infection of animals in the wild and has evolved into a parasite of humans as well. From an evolutionary standpoint it’s very interesting in terms of the way it switched its hosts, how it evades the immune response, and how it lives within host cells. The flip side is that it’s a huge health problem.”
Despite the extent and severity of the disease, McKerrow said, therapies for Chagas have generally not been pursued by large pharmaceutical companies due to the minimal profits such research might generate. As a result, the challenges are left to research centers and universities such as UCSF, but in a public-university setting, that process of discovery-to-IND takes decades to carry out.
That has certainly been true with K777, which McKerrow, Sandler scientists Juan Engel and Patricia Doyle-Engel, and colleagues discovered two decades ago in their research on the cruzain protease.
“We were trying to understand what the protease does for the parasite,” he said. “In the course of doing that, we produced enough cruzain that we could begin to look for inhibitors. Initially we were interested in using them as research tools.”
Effective Against Many Strains
A friend of his, Jim Palmer, working at Khepri Pharmaceuticals, a Bay Area biotech company, donated some compounds for McKerrow to try.
“One of them was the parent of K777,” McKerrow said. “It was the best thing we saw.”
This image shows a T. cruzi-infected heart muscle (A) and skeletal muscle (B) as compared to non-infected tissues (C and D, respectively). Image courtesy of Patricia Doyle-Engel.
Khepri modified the compound to behave as a better drug. The new compound was K777, which is soluble but "greasy enough" to get through a cell membrane to reach its target on the surface of T. cruzi. T. cruzi then ingests the toxin. “We’re probably tricking the parasite into thinking this is something it wants to eat,” McKerrow said.
There are many strains of T. cruzi, which raises the concern that an effective drug for one strain might not work for others. But McKerrow and his Sandler colleagues have shown that K777 is effective in the laboratory against nine different strains, including some that are resistant to the current therapies, nifurtimox and benznidazole. A colleague in Brazil verified that K777 worked in several local strains.
"K777 continued to be really excellent," McKerrow said. "We thought there'd be a lot of reasons it would fail early on, but it never did."
But before a drug can enter Phase 1 clinical trials in humans, the FDA must approve an Investigational New Drug (IND) application. That step is rarely performed by universities and is a new challenge for academic institutions like UCSF, according to Tracy Saxton, PhD, Director of Alliance Management at QB3, who was recruited in 2008 from the biotechnology industry to facilitate the translation of research like McKerrow’s for clinical use. Saxton has been working closely with Stephanie Robertson, PhD, the Project Director at the Sandler Center, on the regulatory hurdles involved with developing the K777 IND package.
Need for Financial Support
“Universities are ideal places to conduct basic research and to generate lead compounds with potential, but normally they don’t have the funding or the full breadth of expertise required to translate that research into the clinical arena,” Saxton said. “Where a private company might have a large, fully dedicated team working on a 100 percent funded project to meet the FDA deliverable on a tight deadline, we have one small team squeezing it in with other work that we do for the University, trying to raise the funds through various government grants and private donations in order to keep the program moving forward.”
In September, Saxton joined McKerrow and Robertson in a meeting with FDA officials to agree on the content of the data package required for an IND application for K777. Two major studies remain to be completed: rounding out the toxicology data with a formal preclinical study, and developing the "good manufacturing practices" required to ensure that K777 is produced at the quality required for human clinical investigation.
The cost of these steps will be $2.5 million, Robertson and Saxton said. They need $750,000 for the toxicology study and $1.75 million for optimizing manufacturing and the dosage for patients. Saxton and Robertson are applying for philanthropic and governmental funding to take K777 over this hurdle.
"If we were a big company, we would have told the FDA we'd file in a month, because we'd already have the money," McKerrow said. "But since we're not a big company, we have to get the money somehow."
Difficulty in finding money is nothing new for this project, though, McKerrow said. "We scraped together support at every stage."
The K777/Chagas team includes Juan Engel, Patricia Doyle-Engel, Stephanie Hopkins, Jim McKerrow, Stephanie Robertson, and Tracy Saxton.
Kaspar Mossman, PhD, is communications director for the California Institute for Quantitative Biosciences (QB3)