Pfizer is currently leading cancer drug development related to the insulin-like growth factor (IGF) pathway, but faces competition from Roche, Amgen, ImClone, and others, investigators said. The IGF receptor target was identified roughly 20 years ago, and increasing evidence is now showing that the IGF pathway may be involved in human cancer progression.
The company will be closely monitoring whether use of diabetic drug metformin enhances the effect of its anti-IGF-I receptor antibody currently in development for non-small cell lung cancer (NSCLC), investigators added.
Dr Anna Barker, deputy director at the National Cancer Institute, said the link between diabetes and cancer is currently one area of intense investigation. She estimated that the obesity and diabetes pandemic will cause an additional 30-40% increase in incidence of total solid tumour cancers over the next 10 years – notably in breast, prostate, and colorectal cancer.
About 20 years ago, IGF-1 receptors were first found on tumour cells, but at that time, the concept that they could be drug targets was ahead of its time, said Dr Michael Pollak, an IGF-1 pioneer who has published over 250 research papers, and holds the Alexander-Goldfarb Research Chair in Medical Oncology at McGill University in Montreal.
In the mid-1990s, Pollak’s group at McGill, in collaboration with investigators at Harvard University, found a relationship between high levels of IGF in the patient’s blood and the risk for some cancers. This led to more intensive studies of the relationship between insulin-like growth factors and neoplasia. “Now we have indirect evidence that IGF biology has something to do with cancer treatment,” Pollak said.
Pollak, an oncologist who studies cancer biology and IGF-1 at McGill, said there is an unusually high level of competition in drug development related to targeting the IGF-I receptor. More than a dozen companies are currently in the race to market, including Merck, Amgen, Roche, and ImClone.
Pfizer’s fully human IgG2 antibody CP-751,871 has currently advanced to Phase III trials for the treatment of advanced NSCLC. “Scientists want to see the results of clinical trials that test the hypothesis that targeting the IGF-I receptor will benefit cancer patients. Nobody is pushing it as fast as Pfizer,” said Pollak.
The Pfizer Phase III trial was preapproved by the FDA, and the endpoints were discussed. Pfizer wanted to make sure the design met all FDA requirements. “That’s my understanding, they reached an agreement,” stressed Pollak. “Of course, the IGF targeting agents could disappoint and have no activity in Phase III, but early results certainly justify accelerated research. These Phase III studies are absolutely critical,” said Pollak.
Dr Antonio Gualberto, head of Pfizer’s global R&D clinical program for CP-751,871, said extensive work was done internally to select this compound. Dose limiting toxicities have not been identified yet clinically. Roche, Amgen, and ImClone also have IGF-1R compounds, but are in early Phase II trials.
One side-effect of IGF inhibitors is hyperglycemia, or high blood sugar, which is related to the drug’s mechanism of action. Pfizer’s drug does not block insulin action, by design – but might cause modest hyperglycemia, noted Pollak. Still, the hyperglycaemia issue is modest, and co-administration of metformin, an agent often used in diabetes treatment, usually controls it.
From what we know now, it is unlikely the Pfizer’s compound will fail due to reasons of safety. There are over 500 patients treated, said Pollak. “We never had to stop a drug because of uncontrollable hyperglycaemia,” added Pollak, who noted the rationale for clinical trials of IGF-I receptor targeting was as strong as the rationale for research programs that eventually led to the development of Avastin and Herceptin, cancer drugs that target other cell signalling systems.
Dr CK Wang, an oncologist with the Cancer Institute of Dallas, agreed that IGF is definitely a viable target, but there is a lot of competition. Pfizer’s compound will inevitably be compared to both Tarceva and Avastin, current biologic treatments used in lung cancer. The hyperglycemia is controllable, and although Pfizer’s drug will offer another option, Wang believed it is unlikely to replace the current standard of care.
In 2002, Pfizer made two important decisions regarding IGF drug development, said Gualberto. One was the move from targeting small molecules, to monoclonal antibodies that have a higher specificity for IGF. The second decision was to target a different type of immunoglobulin, called IgG2, which has a lower affinity regarding fixation to complement, which will hopefully lower the risk for cytotoxicities, Gualberto added.
The structural diversity in the hinge region of IgG subclasses entails differences in their ability to activate complement. Out of the four IgG classes, only IgG3 has an approximate half-life of 7, in comparison to 21 days for the other classes. Pfizer’s IGF compound has a half-life of approximately 20 days, said Gualberto. The hematological toxicities and shorter half-life of IgG1 antibodies may be important factors when combined with chemotherapy, as the majority of the chemotherapy regimens are given once every three weeks and already have some degree of hematological toxicity, he said.
ImClone’s IMC-A12 is a fully human, anti-insulin-like growth factor-1 IgG1 receptor monoclonal antibody. OSI Pharmaceuticals is developing a small molecule IGF-1R compound (OSI-906) currently in Phase I trials.
Kinase inhibitors by Bristol-Myers Squibb and OSI Pharmaceuticals do potentially block insulin as well as IGF-I receptors, said Pollak. They are very interesting compounds and in some ways have the potential to be more potent cancer drugs, but they are potentially more dangerous and may carry more severe risks for hyperglycemia. “That is why their Phase I dose escalations are very small, and are being examined cautiously,” he added. The results of early trials of these agents have not yet been published.
Pfizer wanted to select a molecule that was very safe which could reach high doses, without dose limiting hematologic toxicities, such as neutropenia or thrombocytopenia, said Gualberto.
Related current research is evaluating the association between diabetes and cancer. There is increasing prevalence of obesity and hyperinsulinemia globally, together with a secular trend for increasing IGF-I levels. This implies an increasing prevalence of factors that we now recognize increase cancer risk and worsen cancer prognosis, according to Pollak. High levels of insulin may stimulate tumour growth, said Pollak. Older, widely diabetes drugs like metformin are known to reduce both glucose and insulin levels and are under study to see whether they have any role to play in cancer treatment. Metformin acts through AMPK to attenuate insulin and IGF-I stimulated proliferation of cancer in certain preclinical models. “The intersection of diabetes and cancer is a very real thing.”
Dr Philip Cohen, a pioneer and world leader in the field of protein kinases, and director of research in the School of Life Sciences at University of Dundee, said “Current results with metformin and other similar compounds delayed the appearance of the tumour in mice models by several months. “These compounds are strongly protective against the onset of cancer, but they do not address the question of whether they have any effect on treating cancer,” he said. Scientists in Cohen’s research team identified the biochemical pathway by which insulin controls the metabolism of glucose. Dr Dario Alessi, a colleague at the University of Dundee, is working on establishing a potential link between cancer and diabetes, by characterising the functions of various protein kinase-signalling networks, including PDK1 and LKB1.
From Alessi’s research, data from patient records over ten years, have shown that patients on metformin reported a lower incidence of cancer. So far, patients on metformin showed anywhere between a 30-40% protection against all forms of cancer, over this period, said Cohen.
”Pfizer is one of the companies we work with. They will basically be the first to know about this result,” Cohen said. Patients on Pfizer’s current trials are given metformin when they develop hyperglycemia, said Pollak, and there is a lot of interest in the possibility that metformin may also help with anti-cancer activity. “Pfizer is keeping very careful notes,” Pollak added.
Cohen recommended that all companies should include metformin with their normal cancer drugs because they may actually enhance the efficacy of their drugs.
Dr Luis Paz-Ares, an investigator for Pfizer, and chief of the Division of Medical Oncology, Virgen del Rocio University Hospital in Seville, Spain, said Pfizer will be monitoring this issue closely, but metformin’s effect as an anti-cancer agent is still unclear. Although Pfizer’s compound induces hyperglycemia, there is currently no difference in patients who receive metformin in the company’s current NSCLC trials, he added.
The primary objective of the Phase III studies is to test the safety and clinical benefit of the addition of CP-751,871 to standard-of-care chemotherapy.
Dr Philip Rowlands, the development team leader for the CP-751,871 program in Pfizer Oncology, said the company will certainly look at all the data from the patients for other factors that may impact the drug’s risk-benefit profile, including any safety management practices that may be applied during the studies, including metformin treatment to manage hyperglycemia, but that these are not part of the primary endpoints of the study protocol.
Pfizer’s Phase III NSCLC trial is designed to determine if the company’s anti-IGF-I receptor antibody will enhance the benefit of chemotherapy for that disease, but it may also provide clues concerning any further effect of metformin, Pollak said.
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