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Update: How the pharmaceutical/biotechnology industry might develop better insulin sensitizers

 

PPARγ

This article is an update of a three-part series on insulin sensitizers for treatment of type 2 diabetes that was published on this blog in August and September of 2010.

Summary of our August/September 2010 blog articles on insulin sensitizers

In part 1 of the series (posted August 23, 2010), we focused on safety issues with the two marketed thiazolidinedione (TZD) peroxisome proliferator-activated receptor gamma (PPARγ) agonists–rosiglitazone (GlaxoSmithKline’s Avandia) and pioglitazone (Takeda’s Actos). Both of these insulin sensitizing, antidiabetic agents induce weight gain, and carry an increased risk of edema and heart failure. In addition, rosiglitazone carries an increased risk of myocardial infarction. On September 23, 2010, the FDA restricted access to Avandia, and the European Medicines Agency (EMA) recommended that the drug be pulled from the market.

In part 2 of the series (posted on August 29, 2010), we discussed a breakthrough discovery by Bruce Spiegelman (Dana-Farber Cancer Institute and Harvard Medical School, Boston MA) and his colleagues, published in the 22 July 2010 issue of Nature. It was the Spiegelman group that originally identified PPARγ as the master regulator of adipocyte biology and differentiation, which eventual led to the development of the TZD drugs.

In that research, the Spiegelman group found evidence that the insulin sensitizing and antidiabetic effects of PPARγ agonists may not be due to the agonistic effects of these compounds on PPARγ, but to their ability to inhibit phosphorylation (at Ser 273) of PPARγ by the enzyme cyclin-dependent kinase 5 (CDK5). A weak PPARγ agonist, the benzoyl 2-methyl indole (non-TZD) MRL24, inhibits CDK5 phosphorylation of PPARγ as well as rosiglitazone, and also has very good antidiabetic activity.

CDK5 phosphorylation of PPARγ does not change the ability of PPARγ to upregulate transcription of genes involved in adipocyte differentiation. However, it inhibits the ability of PPARγ to upregulate transcription of a set of genes, including the gene for the adipokine adiponectin, that induce insulin sensitivity and resistance to obesity. Although both rosiglitazone and MRL24 inhibit CDK5 phosphorylation of PPARγ, treatment with the strong agonist rosiglitazone results in upregulation of both the adipogenic and the pro-insulin resistance sets of genes, while treatment with MRL24 results only in upregulation of the pro-insulin resistance set.

Researchers hypothesize that it is the upregulation of the adipogenic gene set that is responsible for the adverse effects of strong agonists of PPARγ–weight gain, edema, and the risk of heart failure. In contrast, the upregulation of adiponectin and the other members of the pro-insulin resistance gene set is thought to be responsible for the desirable, antidiabetic effect of PPARγ agonists.

In part 3 of the series (published on September 16, 2010), we discussed two essays, also published in the 22 July 2010 issue of Nature, that discuss using the new breakthrough results of the Spiegelman group to discover and develop improved insulin sensitizers. These essays recommended that researchers screen for compounds that inhibit CDK5 phosporylation of PPARγ rather than those that are strong PPARγ agonists. We also discussed the prospects for early-stage non-TZD partial or selective agonists of PPARγ, which might constitute second-generation insulin sensitizers.

New research from the Spiegelman group based on their 2010 breakthrough result

On September 4, 2011, Nature published, as an “advance online publication”, a new paper [subsequently published in Nature’s 22 September 2011 print edition] by Bruce Spiegelman, Patrick R. Griffin and Theodore Kamenecka (Scripps Research Institute, Jupiter, Florida) and their colleagues on discovery of novel compounds that bind to PPARγ and block its phosphorylation by CDK5, and which completely lack PPARγ agonist activity. (These compounds are thus neither full nor partial/selective agonists of PPARγ.)

One of these compounds, SR1664, exhibited potent antidiabetic and insulin sensitizing activity in two mouse models of obesity-associated type 2 diabetes. However, unlike full agonists such as rosiglitazone, it did not cause fluid retention and weight gain in these animal models. Fluid retention and weight gain are major adverse effects of TZDs in their own right, and are also thought to be related to the even more serious cardiovascular adverse effects of TZDs. Moreover, SR1664 did not interfere with bone mineralization in cultured osteoblasts; this assay is a model for the loss of bone mineral density and increase risk of fracture seen with TZDs.

The researchers developed SR1664 by starting with a partial agonist of PPARγ developed by GlaxoSmithKline, known as compound 7b. Using compound 7b as a scaffold for chemical modification, the researchers optimized for (1) high binding affinity for PPARγ, (2) blocking of CDK5-mediated PPARγ phosphorylation and (3) lacking classical agonism. The structure of two resulting compounds, SR1664 and SR1824, are given in the new Spiegelman/Griffin paper.

Although the new study suggests that SR1664 may be as efficacious an insulin sensitizer as TZDs without inducing their major adverse effects, the safety of these compounds in humans (as opposed to the mouse models) remains unproven. Moreover, SR1664 has unfavorable pharmacokinetic properties and is thus not a good candidate for development as a drug. According to a press release, Dr. Griffin’s molecular therapeutics group and Dr. Kamenecka’s medicinal chemistry group at Scripps have been using S1664 as a molecular scaffold for the discovery of derivatives with improved pharmacokinetic properties. They are advancing such newer compounds into additional studies.

Why develop new insulin sensitizers rather than depending on current antidiabetic drugs?

In Heidi Ledford’s commentary published in the 22 July 2010 issue of Nature, the author points out that some observers believe that pharmaceutical companies will be reluctant to attempt to develop new insulin sensitizers that target PPARγ, given the checkered history of that class of drugs. And other medical authorities believe that the older, inexpensive, and well proven type 2 diabetes drugs–insulin, metformin, and sulfonylureas–are adequate for the treatment of type 2 diabetes.

However, there remain important unmet needs in the treatment of type 2 diabetes. These especially include dealing with the relentlessly progressive nature of type 2 diabetes–for example, even patients who initially succeed in reaching glycemic goals with only diet/exercise and metformin will eventually need multidrug treatment, including insulin. Progression of type 2 diabetes is mainly due to the loss of pancreatic beta-cell function, which results in increased impairment of a patient’s ability to produce insulin in response to increased blood glucose.

Despite the major safety issues with TZDs, there is both animal model and human evidence that these agents may work to preserve and/or enhance beta-cell function. It will be important to determine if nonagonist second-generation insulin sensitizer candidates, such as those being developed by the Spiegelman and Griffin groups, also have the beta-cell preserving or enhancing effects of TZDs.

The Harvard/Scripps efforts to discover safer insulin sensitizers illustrate the potential role of academia (based on breakthrough science) in areas of drug discovery and development that industry is reluctant to undertake. However, although these academic groups might potentially take the nonagonist insulin sensitizers through lead optimization and preclinical studies, eventually industry (whether a biotech company or a pharmaceutical company) will need to take the compounds through clinical trials in order for any drugs to reach the market.
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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Crizotinib (Pfizer’s Xalkori), a multitargeted kinase inhibitor, approved by the FDA for treatment of ALK-driven lung cancer

 

Crizotinib

On Aug. 26, 2011, the FDA approved the kinase inhibitor crizotinib (Pfizer’s Xalkori, originally known as  PF-02341066) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), in which tumor cells exhibit rearrangements in the anaplastic lymphoma kinase (ALK) gene. These rearrangements of the ALK gene constitute driver mutations that are critical for the malignant phenotype of lung adenocarcinomas that have the mutations.

Most ALK rearrangements in lung adenocarcinoma result from a deletion and inversion in chromosome 2, which produces EML4-ALK fusion genes. (EML4 refers to the echinoderm microtubule-associated protein-like 4 gene.) EML4-ALK rearrangements are found in about 4% to 5% of patients with NSCLC. This small percentage of lung cancer patients constitutes about 8,000 to 10,000 patients each year in the United States, and a worldwide patient population of around 40,000.

Crizotinib was approved together with a companion diagnostic, Abbott’s Vysis ALK Break Apart FISH Probe Kit, which is designed to help determine if a patient’s tumors have the abnormal ALK gene. The kit is designed to Identify all ALK gene rearrangements with fusion partners, including but not restricted to: EML4, TFG (TRK-fused gene), and KIF5B (kinesin family member 5B).

Crizotinib is the second targeted kinase inhibitor to be approved together with a companion diagnostic in recent weeks.  The first was vemurafenib (Plexxikon/Roche’s Zelboraf,  PLX4032), which we discussed extensively in this blog, and whose approval we covered in our August 19, 2011 article. Vemurafenib was approved together with Roche’s cobas 4800 BRAF V600 Mutation Test.

The discovery of crizotinib began with research at Sugen (San Francisco, CA), which had been acquired by Pharmacia which was subsequently acquired by Pfizer. The drug resulted from research aimed at discovery of a kinase inhibitor that targeted c-Met. The resulting drug, PF-02341066 (later known as crizotinib), is indeed a c-Met inhibitor, and was entered into Phase 1 clinical trials.  c-Met, or hepatocyte growth factor receptor, is a receptor kinase that has been implicated in cancer cell growth, migration, invasion, and metastasis.

Subsequent studies by Japanese researchers identified the inversion that results in the EML4-ALK fusion gene in a subset of human NSCLCs. They also showed that cultured mouse fibroblasts expressing the EML4-ALK fusion gene generated subcutaneous tumors in nude mice. The researchers hypothesized that the EML4-ALK fusion kinase would be a good therapeutic target, as well as a diagnostic biomarker for a companion diagnostic. Meanwhile,  researchers at Pfizer and the Massachusetts General Hospital found that PF-02341066/crizotinib was a multitargeted kinase inhibitor, which targets ALK in addition to c-Met. Pfizer researchers therefore began preclinical and clinical studies aimed at the commercialization of PF-02341066/crizotinib for treatment of patients with NSCLC carrying activating rearrangements of ALK.

Clinical trials of crizotinib in NSCLC patients with activating rearrangements of ALK

The safety and efficacy of crizotinib in NSCLC patients with activating rearrangements of ALK were established in two multi-center, single-arm studies, including a Phase 2 study (PROFILE 1005) and a Part 2 expansion cohort of a Phase 1 study (Study 1001). The studies enrolled a total of 255 patients with late-stage ALK-positive NSCLC. A sample of each patient’s tumor tissue was tested for ALK gene rearrangements before the patient could be enrolled in the study. The studies were designed to measure objective response rate, i.e., the percentage of patients who experienced complete or partial cancer shrinkage. Most patients in the studies had received prior chemotherapy.

In one study, the objective response rate was 50 percent with a median response duration of 42 weeks. In another, the objective response rate was 61 percent with a median response duration of 48 weeks.

The FDA based its approval of the Vysis ALK Break Apart FISH Probe Kit on data from one of the studies.

As part of the post-marketing requirements, Pfizer continues to evaluate critozinib in two confirmatory, randomized, open-label Phase 3 trials. In these trials, crizotinib is being compared with standard-of-care chemotherapy. One study is being carried out in previously treated patients with advanced ALK-positive NSCLC; the other trial is being carried out in previously untreated patients with advanced ALK-positive non-squamous NSCLC.

Crizotinib as a multitargeted ALK/c-Met kinase inhibitor

The epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib (Genentech/Roche’s Tarceva) and gefitinib (AstraZeneca/Teva’s Iressa) are used for the treatment of patients with NSCLC with activating mutations in the intracellular kinase domain of EGFR. As with  crizotinib and vemurafenib, companion diagnostics are used to determine if a patient is likely to benefit from treatment with erlotinib or gefitinib. Activating mutations in EGFR are found in approximately 10–15% of Caucasian and 30–40% of Asian NSCLC patients.

As with most targeted antitumor drugs, acquired resistance to erlotinib or gefitinib develops in patients treated with these agents. The two most common mechanisms of this acquired resistance are:

  • development of a secondary mutation that blocks binding of the inhibitors to EGFR kinase (responsible for about 50% of acquired drug resistance)
  • amplification and/or activation of the c-Met kinase, or alternatively high-level expression of the natural ligand of c-Met, hepatocyte growth factor (HGF) (responsible for about 20% of acquired drug resistance).

As we discussed in Chapter 5 of our June 2011 book-length report Multitargeted Therapies: Promiscuous Drugs and Combination Therapies, Pfizer researchers and their academic collaborators found in 2010 that one could overcome HGF/c-Met-mediated resistance to erlotinib or gefitinib by combination therapy with an irreversible EGFR kinase inhibitor (such as PF-00299804) and a c-Met inhibitor (such as crizotinib/PF-02341066). The same researchers also developed a rationale for development of a companion diagnostic to identify patients with rare preexisting populations of cells with amplified c-Met genes. Such patients might be treated with the irreversible EGFR kinase inhibitor/c-Met kinase inhibitor combination. This would be expected to bypass the resistance that would develop after standard treatment with erlotinib or gefitinib alone.

Intriguingly, the 2010 Pfizer study thus suggests a second indication for crizotinib–use in combination therapy with an irreversible EGFR kinase inhibitor such as Pfizer’s PF-00299804 to overcome or preemptively circumvent HGF/c-Met-mediated resistance to the approved EGFR kinase inhibitors. However, Pfizer’s PF-00299804 is still in clinical trials, and has not yet been approved by any regulatory agency. Boehringer Ingelheim is also developing an irreversible EGFR kinase inhibitor, and Pfizer has another such agent, neratinib, in clinical trials.

Meanwhile, in addition to crizotinib, there are also other c-Met inhibitors in clinical development, including Daiichi Sankyo/ArQule’s ARQ197 and GSK/Exelixis’ XL880/GSK1363089 (now known as foretinib). ARQ197, which is in Phase 3 trials in NSCLC, is apparently the most advanced compound in development as a c-Met inhibitor.

An important potential use of irreversible EGFR kinase inhibitors is to overcome acquired resistance to first-generation EGFR kinase inhibitors in NSCLC patients due to development of a secondary blocking mutation in EGFR. The development of combination therapies of irreversible EGFR kinase inhibitors with c-Met inhibitors such as crizotinib and ARQ197 would enable their use in overcoming the second major mechanism of acquired resistance to EGFR inhibitors, via HGF/c-Met.

Conclusions

The approval of crizotinib, together with a companion diagnostic, for the treatment of ALK-driven NSCLC represents the newest example of a paradigm shift toward personalized medicine using targeted therapies in the treatment of cancer. Other examples include vemurafenib for the treatment of melanoma, and the original small-molecule targeted kinase inhibitor, imatinib (Novartis’ Gleevec/Glivec) for the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GISTs).

In lung cancer, the use of erlotinib and gefitinib to treat EGFR-driven NSCLC, which represents about 10-15% of cases in the U.S. and Western Europe, is yet another example, even though companion diagnostics for these agents had not yet been developed at the time of their introduction to the market. ALK-driven NSCLC represents yet another 4-5% of cases.

According to researchers at the Lung Cancer Mutation Consortium, nearly 60% of patients with lung adenocarcinoma have 1 of 10 genomic abnormalities for which there is an approved or experimental drug. Paul Bunn, M.D., of the University of Colorado School of Medicine (Aurora, CO) asks, “We have 2 drugs approved now for 2 molecular abnormalities. The question is, will we go 10 for 10?”.  Diagnostic technology for testing for these mutations is also moving forward, and according to Dr. Bunn, it is cheaper to test for all ten abnormalities than it used to be to test for one abnormality.

As we discuss in our June 2011 report, and in several articles on this blog, patients treated with targeted agents usually develop acquired resistance to these drugs. Researchers, with some initial success, have been working on developing drugs to overcome this resistance. This is thus an important aspect of the development of personalized medicine for cancer.

Both EGFR-driven and ALK-driven NSCLCs are usually found in non-smokers or light smokers, while most lung cancer is associated with smoking. Physicians who treat lung cancer, as well as patients, await the development of agents that can effectively treat lung cancer in smokers and former smokers. Smoking rates have been going down in many industrialized countries, including the U.S., but that is not uniformly true in all the world. Moreover, there are still large numbers of smokers and former smokers who are at risk for smoking-induced lung cancer, and lung cancer in never-smokers (which accounts for about 10-15% of lung cancer cases) is by no means a solved problem.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.