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Isis Pharmaceuticals, Inc. Message Board

  • wanna_million wanna_million Dec 16, 2012 9:53 AM Flag

    Metabolic Drugs - Watch in 2013

    From the Transcript 12/7 :
    There are four main points that we hope to take away from this call. First, each of these drugs has a unique and potentially exciting profile. Each drug will be used in combination with other drugs to fill the specific niche in the treatment of relatively advanced Type 2 diabetes and then potentially other diseases.

    Second, while it is still early, we believe the data from the normal volunteer studies suggest that we have drugs that will deliver the desired profiles. Obviously, we will touch these hypotheses in Phase 2 trials.

    Third, the performance of these drugs demonstrates, again, the value of enhanced screening methods that we have implemented. All three are more potent and better tolerated than the second generation as these drugs we created just a few years ago.

    Fourth, for each of these drugs, we have a focused development and partnering plan that we believe will maximize their potential value while limiting the risk to Isis. As an introduction, then let me put these drugs in a strategic context for you.

    The results that we are reporting today enhance our confidence that these metabolic drugs are likely to be attractive licensing candidates within the next 12 to 24 months.

    There are several reasons for us to focus on metabolic drugs. First, there is an undeniably very large medical need. Type 2 diabetes is perhaps the most pressing therapeutic challenge of our time. It's an epidemic affecting more than 300 million people worldwide and is continuing to increase at an alarming rate, especially due to the tremendous increase in obesity.

    Our metabolic drugs are uniquely positioned not only to fill the critical voids in diabetes therapy but also to provide more therapeutic effects including improvements in hypolipidemia and obesity in diabetic patients.

    We have exploited the target and tissue specific action of our drugs to generate drugs that are highly efficacious with a low potential for side effects. Three of these drugs have shown encouraging safety and efficacy data in Phase 1 studies and are positioned to act via distinct mechanisms of action to improve insulin sensitivity or reduce excessive glucose production in the liver thereby causing robust glucose lowering effects.

    Our therapeutic strategy for our metabolic program is to create a portfolio of unique first in class medicines to treat diabetes in different ways through different mechanisms such that they compliment one another as well as complimenting drugs currently available to patients. Our drugs can offer excellent therapeutic single agents but our primary goal is to develop them as adjuncts to existing diabetes therapies during the step therapy approach to the treatment of diabetes.

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    • I highlight this to make note that by the end of 2013, we can see information on licensing agreements related to the metablic drugs, similar to Biogen (neurological) and Astra Zeneca (cancer) licensing drugs after positive Phase 2 trials:

      Here is Stan's remarks from Dec. 7 conference:
      Obviously the value of each of these drugs will be defined by their performance in Phase 2 trials. The results that we are reporting today enhance our confidence that these metabolic drugs are likely to be attractive licensing candidates within the next 12 to 24 months.

    • Additional on label indications that these metabolic drugs can be used for besides diabetes -RA is a market of significance:

      While the program is focused on developing ISIS GCCRRx for the management of diabetes, there are several other very attractive therapeutic opportunities for the drug that are currently being explored. These include diseases in which there is glucocorticoid excess, such as Cushing's disease or conditions whether there is skewered and induced hyperglycemia such as patients with rheumatoid arthritis or Crohn's disease, for example, or high doses of synthetic steroids. An other attractive indication is weight management including weight gain caused by some antipsychotic drugs.

    • Summary of #3 Metabolic Drug NOTE THAT THIS ONE CAN REDUCE OBESITY:

      I will now discuss the third drug in our pipeline, the glucocorticoid receptor inhibitor. Glucocorticoids are critical hormones in the body that also come to regulate the glucoregulatory action of insulin leading to insulin resistance, increase in blood glucose as well as an increase in blood lipids and weight gain. Antagonism of glucocorticoid action could be an extremely attractive therapeutic approach for the treatment of diabetes.

      However, many small molecule inhibitor programs focused on reducing glucocorticoid action have failed, primarily because these small molecules also reduce glucocorticoid action in tissues outside the liver and fat, particularly the brain which leads to an increased secretion of steroids and negative steroid related side effects.

      In fact, Korlym, also known as RU-486 or the abortion pill, an inhibitor of the glucocorticoid receptor was shown to increase ACTH in patients with Cushing's disease, indicating an effect on the central nervous system. Due to the antagonism of glucocorticoid action systemically, Korlym also produced adrenal insufficiency and an electrolyte imbalance, two serious side effects.

      In contrast, our drug inhibits the glucocorticoid receptor specifically in the liver and fat tissues without crossing the drug bearing barrier, which should provide a significant advantage over small molecule approaches. Although this study in healthy volunteers was principally focused on safety, we also wanted to confirm our preclinical findings and show that there were no effects on glucocorticoid action in tissues outside of liver and fat and no changes in blood pressure.

      Because of the robust lowering of multiple lipid parameters that we observed in preclinical studies, we were also hoping to see this effect in the current Phase 1 study. In the Phase 1 study ISIS-GCGRRx was well tolerated and did not cause any changes in vital signs or mapped parameters, no hypoglycemia. Importantly, in contrast to data reported for small molecules we did not observe any change in plasma ACTH levels which indicates a lack of an effect on the brain.

      We also did not observe any changes on other markers of systemic glucocorticoid action such as plasma renin, aldosterone and angiotensin II level. Even more encouraging were data showing lack of an effect on blood pressure and no orthostatic hypotension, two key side effects associated with antagonizing glucocorticoid action throughout the body. Interestingly, even though the healthy volunteers had normal lipid levels, we observed a decrease in multiple lipid parameters, including field triglycerides, LDL-cholesterol and total cholesterol. This is consistent with our expectations and the profile we have observed in our preclinical studies.

      Furthermore, in this study, we also gave the subjects dexamethasone, a synthetic steroid for a period of two days which resulted in insulin resistance in the liver, as indicated by an increase in blood insulin levels. ISIS GCCRRx attenuated this dexamethasone induced insulin resistance, resulting in a reduction in plasma insulin levels in these patients. The promising therapeutic profile from this drug means that there are many distinct patient populations who could benefit from a glucocorticoid receptor inhibitor.

      We plan to develop ISIS GCCR RX as an add-on therapy in combination with oral antidiabetic drugs or GLP-1 agonists in uncontrolled diabetic patients. Because the drug has been shown to reduce triglycerides and cholesterol, it could also be of significant benefit to patients with Type 2 diabetes who were also dyslipidemic. Of course there are patients with diabetes that have associated excessive glucocorticoid activity as these patients will also benefit tremendously from a selective glucocorticoid receptor inhibitor.

      In our Phase 2 program, we hope to demonstrate a reduction in glucose and lipids, as well as body weight loss in Type 2 diabetic patients with a safety profile that is consistent with our preclinical studies and Phase 1 study. We will also evaluate the drug's affects on multiple short-term measures of glucose control.

      • 2 Replies to wanna_million
      • I am highlighting Additional comments on drug #3 which may demonstrate WEIGHT LOSS in Type 2 diabetic patients. Apparently the drug is doing it in animales and healthy volunteers, so let's see how it does for the diabetic population in Phase II........

        Stanley Crooke - Chairman of the Board, President, Chief Executive Officer
        Just one final point. The thing you have to avoid with glucocorticoid antagonists and this has been known for many, many, many years is the rebound increase in ACTH, which then basically counteracts any benefit that you get out of the drug and in many cases can make things worse. So in Cushing's and psychotropic induced lipodystrophies and obesity and in diabetes the effects of glucocorticoids are systemic. They are occurring in every tissue. What you need to do is to fix the tissues that are driving the metabolic consequences and not drive a compensatory change in ACTH that then leads to actually blunting or perhaps even making the situation worse.

        And that’s what this drug is doing. It's doing it in mice. It's doing it in rats. It's doing it in monkeys. Now it's doing it in normal volunteers.

      • What a line of the same 20 year promises. None have worked but it sounds good for a another pay raise for the insiders. Shame on them ! Face it !

    • A summary of the 1 of 3 metabolic drugs:
      The first drug in our pipeline, an antisense inhibitor of protein tyrosine phosphatase-1B represents a new generation of very attractive and safe insulin sensitizers. The need for an effective and safe insulin sensitizer is both urgent and unmet. This is a growing market. 50% of diabetic patients will eventually need insulin therapy but unfortunately insulin becomes ineffective in a large proportion of these patients.
      In addition, a reduction in LDL-cholesterol is a significant benefit in this population of diabetic patients who are at high cardiovascular risk. Furthermore ISIS-PTP1BRx did not cause hypoglycemia, a key side effect of many therapies including insulin. Finally we do not expect to have any problem with cardiotoxicity, drugs or interactions or any contraindications such as suggestive heart failure that have plagued PPARs.

      Our previous PTP1B drug allowed us to validate PTP1B as an important therapeutic target in humans for the very first time. Although this earlier PTP1B Inhibitor demonstrated significant therapeutic potential with a favorable safety profile, we felt that a more potent inhibitor would significantly enhance the program. Improvements in our technology and screening procedures have allowed us to identify more potent inhibitors to a number of targets.

      So we applied this technology to PTP1B and identified ISIS PTP1BRx, a drug that is significantly more potent with up to a five fold rate of potency than our previous PTP 1B inhibitor and one that would also offer a significantly longer patent life. This is a drug that we have moved forward into development.

      • 2 Replies to wanna_million
      • Thank you for that summary. It really put things in perspective for me. I added a few more shares of ISIS today.


        Sentiment: Strong Buy

      • Summary of #2 Metabolic drug:

        The second drug in our pipeline is our glucagon receptor inhibitor. Glucagon is a hormone that opposes the action of insulin. In patients with advanced diabetes, uncontrolled glucagon action leads to excessive glucose production by the liver and significant increases in blood glucose levels. Historically, small molecule efforts to target the glucagon receptor were largely unsuccessful. In recent years, a few small molecule inhibitors have been identified and shown to be effective in lowering blood glucose levels in diabetic patients, further validating the target for Type 2 diabetes.

        However these small molecules have been associated with significant side effects, including about a 16% increase in LDL-cholesterol as well as an increase in blood pressure. The precise reasons underlying these side effects are unknown but have resulted in termination of development efforts in some instances.

        To evaluate ISIS-GCGRRx we conducted a phase 1 study in healthy volunteers. Although this was a safety study, we were hoping to confirm our preclinical results and to observe increases in total and active GLP-1 levels with no increases in blood lipids or blood pressure in this study. In this study, ISIS-GCGRRx was well tolerated and not associated with any changes in vital signs, hematology or serum biochemistry.

        We observed no hypoglycemia and no clinically significant increases in triglycerides, total cholesterol, LDL-cholesterol or blood pressure. The favorable safety profile observed in this study suggest that this drug should not have the limitations of the small molecule GCGR inhibitors.

        Here we show the changes in GLP-1 levels from our Phase 1 study. We saw an increase in both total and active GLP-1 levels, a finding that is consistent with the known mechanism of action of our drug. This confirms our observations in preclinical studies and because small molecules do not increase active GLP-1 levels at therapeutic doses, we believe that our drug will have better efficacy.

        Now let's look at where an effective and safe glucagon receptor drug would fit into the treatment paradigm for Type 2 diabetes. The dual mode of action with the increase in active GLP-1 levels which could lead to protection of the pancreas and potentially disease modification, suggests that our drug would be very effective at lowering glucose levels in severely diabetic patients who are failing or have failed all existing therapies including insulin, and would benefit from robust glucose lowering without any significant side effects. We will evaluate this possibility by conducting a study in Type 2 diabetic patients who are uncontrolled on metformin.

        If the Phase 1 data are replicated and extended in the Phase 2 study, we will have a very potent compound with an excellent therapeutic index that is superior to the glucagon receptor small molecules. With these data in hand, we believe that we will have very compelling data package for this drug that would be of noted interest to our partners.

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