EMERGING ISSUES
Matrix Metalloproteinase Inhibitors for Cancer Therapy Are Reports of Their Death Exaggerated? Executive Summary atrix metalloproteinases (MMPs) are enzymes that occur naturally in the body and perform a variety of roles, including rearranging tissues during growth. In addition, there is a strong body of evidence to suggest that cancer cells hijack MMPs to enable their spread around the body. For this reason, there has been great interest in developing MMP inhibitors (MMPIs) for cancer therapy. Preclinical and early clinical trials of MMPIs were promising and pivotal clinical trials began in the mid to late 1990s. However, most of the drugs failed these trials leading to general disillusionment with the concept of MMPIs for cancer therapy. Despite this, MMPI technology for cancer therapy is not yet dead. The failed pivotal trials were conducted in patients with advanced cancers. However, recent advances in knowledge of the science behind MMPIs suggest that they would be more effective for treatment of early-stage cancer. This would explain the success of the preclinical studies, which were conducted in animal models of early-stage cancers. Currently, 4 MMPIs remain in pivotal clinical trials: marimastat, BMS275291, neovastat and prinomastat. Apart from these, few novel MMPIs are coming through the R&D pipeline for cancer therapy. This lack of new development probably reflects the unwillingness of pharma companies to pour more money into an area most notable for its failures. Despite this, there is still some activity; a search of the R&D Insight™ pipeline database found 4 new drug candidates in active development: COL-3 (Metastat) from CollaGenex Pharmaceuticals, S-3304 from Shionogi, ABT-518 from Abbott and MPI-176716 from Myriad Pharmaceuticals. In addition, other companies have research programs underway to discover new MMPIs for cancer therapy, including 3-Dimensional Pharmaceuticals and Pharmacia Corporation. British Biotech and Schering-Plough are also collaborating in such a research program. It may be that pharma is adopting a `wait and see’ attitude until the pivotal trials on marimastat, BMS-275291 and neovastat are complete. If one or more of these drugs does show significant clinical effectiveness and subsequently makes it to market, this would surely re-ignite serious pharma investment into the MMPI field for cancer therapy. After all, cancer drugs comprise a multi-billion dollar global market that is forecast for strong growth. Thus it seems that the fate of MMPIs for cancer therapy rests with large pharma. There is no doubt that this drug class does have clinical potential. What is not so clear is whether companies will be willing to pour millions of dollars more into further development of MMPIs when many have failed so spectacularly in pivotal clinical trials. Under the harsh gaze of the international investment community, there are more than just scientific considerations to be taken into account.
M
Matrix metalloproteinases (MMP) are enzymes that are naturally found in the body and perform a variety of roles essential for normal tissue growth. In addition, there is a strong body of evidence to suggest that cancer cells hijack MMPs to enable their spread (metastasis) around the body. For this reason, there has been great interest in using MMP inhibitors (MMPIs) as a therapy for cancer. Based on preclinical and early clinical trials, MMPIs were initially hailed as a very exciting and promising therapy for cancer. However, they failed to live up to expectations in pivotal clinical trials, with no significant effectiveness demonstrated. Development of MMPIs for Cancer Therapy MMPI technology is mostly small-molecule-based. First-generation compounds had poor bioavailability and were rapidly superseded by second-generation, orally available drugs. Early MMPIs were broadspectrum inhibitors, i.e. inhibiting most or all MMP enzymes; however, more recent drugs have greater selectivity, inhibiting only a small number of MMPs.
Early trials promising… Animal studies with these drugs showed that they blocked spread of cancer in experimental mouse models, thus validating MMPs as valid drug targets. Subsequently, early clinical trials also yielded favourable results and, taken together, these findings provided the impetus for pivotal clinical trials. …but the drugs failed pivotal trials However, nearly all of the MMPIs failed these pivotal clinical trials, with results indicating that the therapeutic effects of MMPIs were no better than placebo and, in one notorious case, actually seemed to worsen the cancer (see “The Tanomastat Story” text box). The company most affected was British Biotech, which had several MMPIs in development for various cancers. A string of failures of the British Biotech drugs in pivotal clinical trials led to a plunge
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Matrix Metalloproteinase Inhibitors for Cancer Therapy – Are Reports of Their Death Exaggerated?
in the company’s share price and a subsequent realignment of corporate strategy. Although the company is continuing trials in cancer for one of its MMPI drugs (marimastat, see below), it has now switched focus to develop MMPIs to treat infectious diseases rather than cancer.
`Patent issues, competition and impatience contributed to the decision to proceed at an unprecedented pace in an inappropriate setting.’
Why didn’t they work? It appears that the stage of the cancer was the fundamental difference between the animal models of cancer, in which MMPIs had promising therapeutic effects, and the pivotal clinical trials, in which the drugs failed to demonstrate significant effectiveness. In the animal studies, the MMPIs were administered at early stages of disease, whereas in the clinical trials they were given to patients with advanced cancers. However, in the time since the pivotal trials began, the knowledge of MMP enzymes and their role in normal tissue growth and cancer growth has advanced substantially. Experts now believe that MMPIs may be effective in treating primary tumors, by inhibiting angiogenesis, and for keeping small metastases in a dormant state. In addition, at the time of design of several of the pivotal trials, there was also a lack of understanding of
which MMPs were expressed in which cancers and at what stages of the disease, resulting in some MMPIs being used in an inappropriate disease setting. For example, tanomastat, which mainly inhibits MMP-2 and has very little activity against MMP-11, was tested in clinical trials of patients with small-cell lung cancer, a tumor type that mainly expresses MMP-11 and MMP-14.
A recent review in Nature noted, with regard to a failed pivotal trial of a particular MMPI, that `patent issues, competition and impatience contributed to the decision to proceed [to pivotal trials] at an unprecedented pace in an inappropriate setting, and these factors will undoubtedly continue to influence drug development decisions in the future.’ It seems that a lot more basic science needs to be done to clarify the role of MMPs in cancer, particularly to determine the specific enzymes produced in each type and stage of cancer.
All is not lost; some pivotal clinical trials continue… Despite these serious setbacks, MMPI technology for cancer therapy is not yet dead. Pivotal clinical trials are continuing with four MMPIs: marimastat, BMS-275291, AE-941 (Neovastat) and prinomastat (table 1).
MMPIs: the evidence for their role in promoting cancer The extracellular matrix is a complex structural mixture of proteins and carbohydrates that surrounds cells in multicellular organisms. It has many functions, one of which is to physically bind together cells in a particular tissue. Primary tumors spread in a process involving many steps, one of which is the degradation of extracellular matrix and basement membrane barriers. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes that degrade extracellular components during matrix remodeling, a process critical for tumor cell invasion and spread (metastasis), as well as for the growth and development of normal tissue. In physiologic conditions there is a balance between the activity of MMPs and the expression of their natural inhibitors (TIMPs). However, in pathologic conditions such as cancer growth, this equilibrium is lost. Currently, 24 MMP enzymes have been identified in various vertebrates and, of these, MMP-2 and MMP-9 are most strongly implicated in tumor progression. The early model for the role of MMPs in cancer growth was that cells in a primary tumor produce various MMPs that destroy the extracellular matrix surrounding the tumor and allow its cells to enter surrounding tissues, the bloodstream and eventually distant organs. In other words, MMPs directly assist the spread of cancer. Supporting evidence for this came from three general observations: MMPs are upregulated in nearly all human tumor types; overexpression of natural inhibitors of MMPs reduces metastasis in experimental models of cancer; depletion of the natural inhibitors promotes cancer. However, it is now thought that MMPIs play a much more diverse role in cancer growth, including cell death, cell growth, cell differentiation, tumorassociated growth of blood vessels (angiogenesis) and conversion of benign tumors to malignant cancers.
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August 2002
EMERGING ISSUES
Table 1. Ongoing pivotal clinical trials of MMPIs MMPI
Indication
Phase Company
Marimastat
Pancreatic cancer III
British Biotech
Marimastat
Gastric (stomach) cancer
III
British Biotech
BMS 275291
Non-small cell lung cancer
III
Bristol-Myers Squibb
Neovastat
Non-small cell lung cancer
III
AEterna Laboratories
Neovastat
Renal (kidney) cancer
III
AEterna Laboratories
Prinomastat
Non-small cell lung cancer
II
Agouron Pharmaceuticals
Prinomastat
Brain cancer
II
Agouron Pharmaceuticals
Source: R&D Insight (Adis International)
British Biotech was conducting pivotal clinical trials of marimastat for several types of cancer. The drug showed some promising anticancer activity in some cancers during the initial stages of the trials; notably in breast, small cell and non-small cell lung cancers, ovarian cancer and glioma. However, final analyses revealed that marimastat was no more effective than placebo in glioblastoma and no more effective than gemcitabine in pancreatic cancer. As a result, British Biotech discontinued most trials. The only pivotal trials of marimastat still running are those for gastric cancer patients, where a secondary endpoint follow-up analysis revealed that the drug may improve survival rates, and in pancreatic cancer where lack of clinical efficacy did not meet stopping criteria. Bristol-Myers Squibb began a phase II study of BMS275291 in patients with non-small cell lung cancer. This trial has since been extended into a large phase II/III study that is evaluating the drug in combination with paclitaxel and carboplatin.
AEterna Laboratories is conducting two pivotal phase III trials in Canada and the US of Neovastat for the treatment of non-small cell lung cancer in combination with standard chemotherapy and radiotherapy. AEterna Laboratories is also conducting a pivotal phase III trial of Neovastat for treatment of renal cell cancer in Canada, Europe and the USA. Agouron Pharmaceuticals (now a subsidiary of Pfizer) was developing prinomastat in phase III clinical trials for the treatment of advanced non-small cell lung cancer (in combination with paclitaxel and carboplatin) and advanced hormone-refractory prostate cancer (in combination with mitoxantrone and prednisone) in the USA. However, these trials were discontinued in August 2000 after preliminary analysis did not show any convincing beneficial effects in these patient groups, and the primary study objectives were not met. Pfizer intends to continue investigation of prinomastat in other tumor types and in earlier-stage disease. Patients with earlierstage (IIIB) non-small cell lung cancer recruited into a second ongoing trial will continue in Australia, Europe and North America. Agouron is also conducting a phase II study in patients with newly diagnosed glioblastoma multiforme, the most lethal form of brain cancer.
…and some new candidates are in the pipeline Although the pivotal trials of the 4 older MMPIs are still running, there are few novel MMPIs coming through the R&D pipeline for cancer therapy (although several are being developed for other diseases such as osteoarthritis). The lack of new development probably reflects the unwillingness of pharma companies to pour more money into an area most notable for its failures. However, there is still some activity; a search of the R&D Insight™ pipeline database found 4 newer drug candidates currently in active development (table 2). In addition, other companies have research programs underway to discover new MMPIs for cancer therapy, including 3-Dimensional Pharmaceuticals and Pharmacia Corporation. British Biotech and Schering-Plough are also collaborating in such a research program.
The Tanomastat Story Bayer was developing tanomastat for treatment of pancreatic cancer, non-small cell lung cancer and small cell lung cancer. The drug was undergoing phase III trials in the US for these indications. However, Bayer discontinued all development of tanomastat in September 1999, after an interim review found that the drug was less effective than placebo. In other words, tanomastat actually made the cancer worse.
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Matrix Metalloproteinase Inhibitors for Cancer Therapy – Are Reports of Their Death Exaggerated?
Table 2. New MMPIs coming down the pipeline for cancer therapy MMPI
Phase of development
Company
COL-3 (metastat)
II
CollaGenex Pharmaceuticals
ABT-518
I
Abbott Laboratories
S-3304 MPI-176716
I Preclinical
Shionogi Myriad Pharmaceuticals
Source: R&D Insight (Adis International)
Looking to the Future In the US, CollaGenex began a phase II study of COL-3 (metastat) in HIV patients with Kaposi’s sarcoma in August 2001. Enrolment in a phase I/II trial of COL-3 for the treatment of brain cancer is continuing as well. Abbott has ABT-518 in phase I development for the treatment of solid tumors. Myriad Pharmaceuticals is conducting early preclinical development of MPI-
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176716. Outside the US, Shionogi has completed phase I clinical trials of S-3304 in Europe and the company is preparing to begin phase II trials in the USA. It appears that big pharma is adopting a `wait and see’ attitude until the pivotal trials on marimastat, BMS275291, neovastat and prinomastat are completed. If one or more of these drugs does show true effectiveness and subsequently makes it to the market, this would surely re-ignite serious pharma investment into the MMPI field for cancer therapy. After all, cancer drugs comprise a multi-billion dollar global market that is forecast for strong growth. Thus, it seems that the fate of MMPIs for cancer therapy rests with large pharma. There is no doubt that this drug class does have potential for treatment of cancer. What is not so clear is whether companies will be willing to invest much more money in MMPIs when so many members of the drug class have failed so spectacularly in pivotal clinical trials. Under the harsh gaze of the international investment community, there are more than just scientific considerations to be taken into account. ■
August 2002
