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Isis Pharmaceuticals, Inc. (NASDAQ:ISIS)

Discuss Cancer Franchise

June 03, 2013 02:00 PM ET

Executives

Stan Crooke - Chairman and CEO

Lynne Parshall - COO

Brett Monia - SVP of Antisense Drug Discovery

Wade Walke - Executive Director of Corporate Communications and Investor Relations

Analyst

Operator

Welcome to ISIS Pharmaceutical’s Conference Call to discuss its cancer franchise. Leading the call today from ISIS is Dr. Stan Crooke, Isis Chairman and CEO. Dr. Crooke, please begin.

Stan Crooke

Good morning everyone, thanks for joining us on today’s call. What we will be doing is discuss a number of recent highlights from our cancer program and our new and already successful oncology collaboration with AstraZeneca. We’ve invented a second drug candidate from that collaboration to our cancer franchise and that’s ISIS-ARRx. And today we presented encouraging clinical data, at ASCO from the study on ISIS-STAT3Rx, the most advanced drug in the AstraZeneca collaboration.

Joining me on today’s call are Lynne Parshall, COO; Brett Monia, Senior Vice President of Antisense Drug Discovery and Wade Walke, Executive Director of Corporate Communications and Investor Relations. And now Wade, will you read our forward-looking language statement, please?

Wade Walke

Thanks Stan. A reminder to everyone that this webcast includes forward-looking statements regarding Isis’ business including Isis’ alliance with AstraZeneca, Isis’ research and development opportunities in cancer and the discovery development activity, therapeutic and commercial potential and safety of ISIS-STAT3Rx and ISIS-ARRx. Any statements describing Isis’ goals, expectations, financial or other projections, intentions or beliefs including the commercial potential of KYNAMRO is a forward-looking statement and should be considered in net-risk statement.

Such statements are subject to certain risks and uncertainties particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs.

Isis’ forward-looking statements also involve assumptions that if they never materialize or prove correct could cause its results to differ materially from those expressed or implied by such forward-looking statements.

Although Isis’ forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis’ programs are described in additional detail in Isis’ annual report on Form 10-K for the year ended December 31, 2012 and its most recent quarterly report on Form 10Q which are on file with the SEC. Copies of these and other documents are available from the company.

Now, I'll turn the call back over to Stan.

Stan Crooke

Thanks Wade. Today we have announced that we have received the first milestone payment of $10 million from AstraZeneca. This milestone is associated with the development of ISIS-ARRx, an antisense drug targeting the androgen receptor to treat patients with prostate cancer. This is the second anti-cancer drug in development that’s a part of our collaboration with AZ. This collaboration we think is indeed after a great start and we are looking forward to maintaining the momentum, and that it’s already achieved.

On the call today Brett will discuss the unique role of an antisense drug targeting the androgen receptor in the treatment of prostate cancer and why we and AstraZeneca believe that this approach could offer unique therapeutic potential compared to other approaches to this target. Brett will then review our clinical experience with ISIS-STAT3Rx. ISIS-STAT3Rx, you remember as the first generation 2.5 antisense drug in clinical development, and the drug that we are developing in collaboration with AstraZeneca.

Today we reported the full data from our Phase 1 study on ISIS-STAT3Rx in patients with cancer. Results from the Phase 1 study showed that treatment with ISIS-STAT3Rx resulted in encouraging responses in patients with advanced lymphoma who were refractory to multiple prior chemotherapeutic treatments. Based on these results, we and AstraZeneca have initiated a Phase 2 study evaluating ISIS-STAT3Rx in patients with these refractory lymphomas. AstraZeneca is also in the process for evaluating additional Phase 2 opportunities for STAT3Rx and has begun dosing in the second Phase 2 study and patients with liver cancer.

Then finally, Lynne will briefly review the terms of our collaboration with AZ and the benefit we gain from AstraZeneca’s internal and external resources. I’ll close the call with the review of upcoming milestones for our cancer franchise and of course after our prepared remarks we’ll open the call for questions.

Before I turn the call over to Brett, let me just revisit why we believe antisense drugs will offer an effective and safe approach to treating patients with cancer. Although, significant advances have increased our knowledge of cancer biology, cancer remains extraordinarily complex. As such much of work remains to fully understand the process that lead to the development and progression of cancer and we believe that antisense technology supports better target selection, rapid and lower cost target validation and the ability to work on a boarder repertoire of potential targets.

Antisense is also a valuable tool with which to understand cancer. And because of these attributes that we believe using antisense can turn test as particularly challenging for many others into a significant competitive advantage for us.

For example, there is a wealth of information created essentially every day that leads to the identification of new targets for cancer. Any of these targets are on drug with small molecules of protein therapeutics. Of course because antisense drugs target RNA and cells, we can specifically inhibit targets that cannot be selectively reduced or reduced at all using traditional approaches.

While they show a number of target opportunities is donning for other technologies, for us it is straight forward to rapidly identify selective antisense inhibitors to each new target and do evaluate all targets of the interest in appropriate model systems. As process allows us early in the drug discovery process to read our target that are too non-specific or toxic or that do not lead to the projected effects on various pathways which itself is a major advantage for antisense technology in many therapeutic areas and is particularly useful in something as complex as cancer.

Another major advantage of our antisense technology is the ability to develop antisense drugs that are specific to a particular target thereby avoiding non-specific affects commonly observed with other approach such as small molecules. We can (design) antisense drugs that selectively target a particular gene mutation which could then be linked to a worse disease outcomes, disease progressions or treatment resistance. We can also discriminate between genes with disease associated mutations and normal genes that may perform important cellular functions.

Another advantage is that antisense technology allows us to decrease the time and cost to advance from molecular target identification to clinical proof of concept compared to traditional approaches. This efficiency is achievable because our drugs all use the same basic chemistry. And we have a good understanding of our drugs will behave in preclinical and clinical studies. Our drugs are all manufactured, formulated, analyzed by the same processes this of course is different from small molecules which require that each of these processes, the independently established for each new molecule.

Redesigning all of these processes for every new molecule is costly and time consuming and may result in failure during development or a more traditional approaches. Using antisense technology we have created a broad growing cancer franchise consisting of promising antisense drugs designed to influence growth, metastasis and the effects of the cancer on the (hooks).

With the efficiency of antisense technology, we can rapidly evaluate both traditional targets for cancer as well as novel targets to determine which are better targets to reduce the growth and the lethality of cancer cells and we can do this with a relatively small highly efficient group of coyotes supported by the efficiency of our antisense technology platform.

So we think there is a very substantial role in understanding cancer and developing anti-cancer drugs for antisense and these two drugs represent a small part of the work that we think is exciting and going on in cancer with antisense technology.

So I’ll turn it over to Brett now to discuss the androgen receptor program and ISIS-STAT3Rx data that was presented today at ASCO.

Brett Monia

Thanks Stan and good afternoon everyone and thanks for joining us. Advances of treatment of cancer have been encouraging in a number of new medicines are in development especially to treat patients with prostate cancer. In our pipeline, we now have four drugs in development to treat men with prostate cancer each of which approaches the disease in a unique way. Prostate cancer is the second most common type of cancer in men approximately one out of six men will be diagnosed with prostate cancer during his lifetime. Initial treatments for prostate cancer involves surgery or radiation and are generally very affective at halting the disease particularly if the disease is diagnosed early. However, as we know many men still die of prostate cancer. Prostate cancer growth, proliferation and progression are all androgen dependent processes and androgen receptor function is involved in disease progression at all stages of prostate cancer. For this reason, the androgen receptor has been a target of interest in the industry for some time this has had a significant impact on current treatment paradigms for metastatic prostate cancer.

Today, the initial treatment for patients with metastatic prostate cancer typically involves anti-androgen therapies these anti-androgen therapies are used to oppose the action of androgens either by blocking the androgen receptor or by reducing circulating androgen hormones. Although initially affective as lung disease progression eventually anti-androgen therapies fail and chemotherapeutic intervention such as docetaxel is required. Of course in many cases chemotherapy also eventually failed to halt progression of the prostate cancer.

Despite the advancement of new therapies, metastatic prostate cancer remains very difficult to treat. This is primarily because of the de-emergence of resistance to anti-androgen therapy. This resistance occurs through a variety of mechanisms including amplification of the androgen receptor gene over expression of the androgen receptor gene alternative slicing of androgen receptor RNA or emergence of mutations in the androgen receptor gene all of which enabled the androgen receptor to escape the effects of current treatment modalities, even in the absence of androgens. Therefore in order for a drug to be effective, we have to maintain efficacy in metastatic prostate cancer. It must inhabit or block all forms of the androgen receptor including alternatively (sliced) forms and (mutant) forms. Unfortunately, this is proven to be a very challenging; it's not an impossible task for small molecules.

ISIS-ARRx represents a novel approach for androgen receptor inhibition. Based on its unique mechanism, it may be effective in early metastatic prostate cancer, either alone, or in combination with other anti-androgen therapies. And in later strategies it is used prior to or in combination with chemotherapy.

Because ISIS-ARRx targets a (sight), that is conserved in the androgen receptor messenger RNA, they can block the production of all known forms of the androgen receptor, including both normal and altered forms, thereby blocking androgen receptor function in tumor cells regardless of the common genetic changes that occur in the androgen receptor gene that causes resistance to current treatments.

In fact, we have shown that our androgen, our antisense approach is highly effective in models of androgen resistant prostate cancer and which other anti-androgen therapies are in effective. In addition, ISIS-ARRx should be easy to use in combination the current anti androgen therapies and with chemotherapies because it is conveniently administered and would be expected to have no dilatory strop of interactions. It is for these reasons that we in AstraZeneca are excited about the potential benefit that ISIS-ARRx might bring to prostate cancer patients.

We believe that ISIS-ARRx will be used initially in combination with current anti-androgen drugs and/or with chemotherapy to delay the emergence of resistance. Our next step, if you complete the necessary pre-clinical studies to support clinical development and then advance ISIS-ARRx into clinical trials in (in) prostate cancer. And just as we are doing with our Stat3 program, we in AstraZeneca appointed to conduct the broad Phase2 Program for ISIS-ARRx that evaluates the drug in a variety of clinical settings including patients who developed resistance to current anti-androgen therapies in combination with these therapies and in combination with chemotherapy.

Now I will switch gears and talk about the other generation 2.5 anti-cancer drug we are developing with AstraZeneca, ISIS-STAT3Rx which targets the transcription factor Stat3. We are encouraged by the early results of ISIS-STAT3Rx. This drug is the first drug in our pipeline that incorporates our generation 2.5 chemistry which was developed to increase the potency of our antisense drugs.

Stat3 of course is an important cancer target because Stat3 activity has been strongly linked to the growth, invasiveness and (metaphases) of many types of cancer. However, Stat3 has proven to be a difficult target to inhibit safely with small molecule drugs because it is a transcription factor, proteins difficultly considered to be undruggable, making Stat3 an important and highly novel drug, making ISIS-STAT3Rx an important highly novel to treat cancer.

Our initial clinical evaluation of ISIS-STAT3Rx was a Phase1 study in cancer patients. The solid tumors and in forma who were relapsed or refractory to multiple chemotherapy regiments. This study was an open label, dose escalations study designed to determine the safety and preliminary efficacy of ISIS-STAT3Rx in cancer patients. The data which were presented today, and ASCO in Chicago, demonstrates that ISIS-STAT3Rx treatment produced tumor responses in patients with advanced diffuse large B-cell lymphoma. We also observed encouraging data in patients with Hodgkin's lymphoma.

The Phase 1 study was completed in 15 patients with advanced cancers. Three of the 15 patients had diffused large B-cell lymphoma and two of these three patients experienced durable, partial responses as a consequence of ISIS-STAT3 treatment. One of these patients is a 63 year old female who had a difficult to treat diffuse large B-cell lymphoma that relapsed or was refractory to 10 previous chemotherapy regimens.

This patient entered treatment at a point when she was being referred to hospice by her physician. While on ISIS-STAT3 immunotherapy, she experienced a 50% reduction in tumor burden, which has lasted now for more than a year and she continues to receive weekly Stat3 treatment.

This result is remarkable considering the fact that this patient was all out of therapeutic options but was able to benefit significantly after treatment with ISIS-STAT3Rx. Another patient is a 57 year old male with diffuse large B-cell lymphoma that was refractory to first and second line chemotherapy. When he began treatment, the patient had a lymphoma tumor mass impinging on his esophagus, making it difficult and painful for him to swallow or talk.

After only a few weeks of ISIS-STAT3Rx treatment, his tumor resolved sufficiently to allow him to swallow comfortably. Moreover this patient experienced a 65% reduction in overall tumor burden that lasted more than four months enabling him to become eligible for an autologous stem cell transplant. The result of that transplant has been a complete response and the patient remains free of cancer today.

We are particularly excited by the response of this patient since initially he was not a candidate for transplantation due to his tumor burden, but became eligible due to the tumor response he achieved after treatment with ISIS-STAT3Rx. In addition, in the study there were two patients with mixed responses and Hodgkin's lymphoma. Both patients had very advanced disease and experienced remarkable in tumor mass in some lymph nodes, but unfortunately some new tumor lesions appeared elsewhere.

However, because of the responses that were observed, we and our clinical investigators believe that these types of patients will be excellent candidates for combination therapy involving ISIS-STAT3Rx in future studies. In this study ISIS-STAT3Rx in future studies. In this study ISIS-STAT3Rx displayed an acceptable and manageable safety profile, primary side effect observed was thrombocytopenia, which was manageable and expected and consistent and consistent with the target related effect resulting from STAT3 inhibition.

Thrombocytopenia is also a common side effect with small molecule inhibitors that target JAK2, a protein within the STAT3 signaling pathway. Given the difficulty in finding small molecules to inhibit STAT3, JAK2 inhibitors are being widely developed and evaluated for anti-cancer activity. However JAK2 inhibition also affects signaling pathways unrelated to STAT3 that are critical for a variety of normal cellular functions, leading to significant side effects. For example, in addition to thrombocytopenia, JAK2 inhibitors can cause anemia and gastrointestinal toxicities which we did not observe in our study.

Late last year, AstraZeneca licensed ISIS-STAT3Rx from us and we are pleased to be working with AstraZeneca in the development of this drug. AstraZeneca’s considerable resources, expertise and capabilities to develop anti-cancer drug substantially strengthen our ability to broadly evaluate ISIS-STAT3Rx across the range of cancer types. Given the role of STAT3 in the growth and survival of tumors, we believe that ISIS-STAT3Rx could be beneficial in the treatment of many different types of cancers.

Consequently, together with AZ we have designed the development program to explore the effects of ISIS-STAT3Rx in a number of different cancers. This includes an ongoing Phase 2 study in patients with advanced lymphoma and a recently initiated Phase 2 study evaluating the safety and efficacy of ISIS-STAT3Rx in patients with liver cancer.

The endpoints for these studies include measurements of anti-tumor activity, STAT3 protein levels and tumor biopsies and STAT3 related biomarkers. We believe these studies will provide the information we and AstraZeneca need to establish in the next stage of our development strategy for ISIS-STAT3Rx.

And now, I’d like to turn the call over the Lynne.

Lynne Parshall

Thanks, Brett. AstraZeneca is an ideal partner for us in the area of cancer and we are encouraged by the early success of the collaboration. As Brett mentioned, we already have a Phase 2 clinical program underway for ISIS-STAT3Rx and of course we are pleased to have the next development candidate, ISIS-ARRx advancing towards the (equipment).

This alliance is an example for our partnering strategy in areas like oncology where we partnered earlier to support aggressive development path and to allow us to expand our antisense STAT discovery and development efforts to new targets with the partner that adds tools, knowledge and financing.

AstraZeneca has a long history of successful drug development, has a solid foundation in basic cancer research that enables them to identify novel targets for new therapeutic approaches to cancer. For example, AstraZeneca has existing relationships with numerous world-class academic and industry partners to identify cancer drug mutations and drug targets through the mining of genomic and epigenomic databases. These include partnerships with leading cancer genomic diagnostic companies, the Foundation Medicine and Sage Bionetworks and broad relationships with academic institution such as Cancer Research UK, Massachusetts General Hospital and others.

In addition, AstraZeneca has successfully developed a number of pre-clinical models for cancer and screening systems that will greatly enhance our ability to evaluate potential gene targets quickly. In this way, we can apply our technology to targets that would not have been available to us otherwise and focus our effort on targets with the greatest likelihood of success.

To this end, our teams have made significant progress on identifying the next several targets that will be part of this collaboration. We are optimistic that through our partnership with AstraZeneca, more important new drugs will be made available to benefit cancer patients.

In addition to cancer expertise, novel targets and drug discovery tools that AstraZeneca brings to the table, the economics in this collaboration a very favorable, valued at more than $1 billion. As part of the agreement, we granted AstraZeneca an exclusive license to develop and commercialize ISIS-STAT3Rx and ISIS-ARRx for the treatment of cancer.

The agreement includes $31 million in upfront payments, comprising a $25 million payment we received in December 2012 and a $6 million payment we are eligible to receive this month assuming the research program continues. And of course, today, we announced that we’ve earned the first milestone payment of $10 million associated with the development of ISIS-ARRx. We’re also eligible to receive additional milestone payments, license fees, and double digit royalties on sales that drives resulting from this collaboration.

If AstraZeneca successfully develops drugs from all programs, we could receive milestone payments more than $980 million. In summary, I’ll close by reiterating how pleased we are to be working to AstraZeneca in our cancer franchise and how encouraged we are with the result of the collaboration today. We hope the combining the strength of our antisense drug discovery platform and development expertise with AstraZeneca’s experience in developing personalized medicine or research and development of a number promising new genetically targeted drugs to treat cancer patients.

By working with partners who brings substantial expertise and experience to our partner programs, we’re able to expand our pipeline and advance our drugs more broadly and rapidly then we would be to do our own. We’re already seeing the benefit of working with the knowledgeable committed partner in the oncology space. With that, I’ll turn the call back over to Stan.

Stan Crooke

Thank Lynne, so we’re continuing to deliver on the promise of antisense technology in cancer as well as all the other therapeutic areas in our pipeline. We believe that the value of antisense technology in our pipeline is just beginning to be realized and we’re confident that antisense drugs can be used to treat patients with cancer safely and effectively. We’re encouraged by the early clinical data from ISIS-STAT3Rx, which is our first generation to five drugs to be evaluated in (man). Of course our cancer pipeline is broader than the two drugs that we’ve been discussing today, so over the next year there will be a number of important clinical results. Teva and OncoGenex should complete the first of three Phase 3 studies with OGX-011 in patients with castrate resistant prostate cancer early next year.

OncoGenex plans to complete a phase 2 study of OGX-427 in patients with prostate cancer. This year, we plan to report data from our Phase 2 studies are eIF4E drug this year. And then also this year we planned to complete and report data from the Phase 2 study on ISIS-STAT3Rx in patients with advanced lymphoma.

And so with that, I want to thank you all for joining us today and Denise if you can open this up questions.

Question & Answer Session

Operator

Thank you, Sir. Ladies and gentleman, we’ll now begin the question and answer session. (Operator Instructions). And Dr. Crooke at this time, I’m showing no questions in the queue.

Stan Crooke

Well in that case that means we were absolutely clear and answered all your questions, so we thank you very much and look forward to talking to you again in the near future, thanks very much.

Operator

Ladies and gentleman, the conference has now concluded. We thank you for attending today’s presentation. You may now disconnect your lines.

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