September 2012, Vol 1, No 4
Novel Approaches to Delivering Personalized Medicine:
Interview with the Innovators
An Interview with Thomas C. Reynolds, MD, PhD
Seattle Genetics is a biotechnology company focused on the development and commercialization of empowered monoclonal antibody–based therapies for the treatment of cancer. Their product, brentuximab vedotin (Adcetris), was granted FDA accelerated approval in August 2011 for 2 indications: the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least 2 prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and the treatment of patients with systemic anaplastic large cell lymphoma (ALCL) after failure of at least 1 prior multiagent chemotherapy regimen. Seattle Genetics is developing Adcetris in collaboration with Millennium: The Takeda Oncology Company.
Currently, Seattle Genetics has 3 other clinical-stage antibody-drug conjugate (ADC) programs: SGN-75, ASG-5ME, and ASG-22ME. In addition, the company has stated that over the next 12 months, 3 additional INDs will be submitted to move preclinical ADC product candidates into the clinic, and multiple other ADC candidates are in development by collaborators using Seattle Genetics’ ADC technology. Personalized Medicine in Oncology had the pleasure of speaking with the Chief Medical Officer of Seattle Genetics to discuss ADC technology, finding unique antigens that are common among several cancer types, and Seattle Genetics’ approach to personalized medicine. To view the interview in its entirety, please visit www.PersonalizedMedOnc.com/videolibrary.
PMO How do you define personalized medicine in oncology, particularly as it relates to the treatment of patients with lymphoma?
Dr Reynolds Personalized medicine in oncology is matching a patient and their tumor and the stage of their disease with the best available therapy. That may be using molecular markers, pathways, or other considerations, but really trying to give them the best available therapy to maximize their chance for a cure, for long-term survival, and for a great quality of life.
PMO ADC technology is a novel approach to personalized medicine in oncology and translational medicine in that monoclonal antibodies are developed to unique antigens on the surface of cancer cells and linked to toxic drugs. Can you describe how they work?
Dr Reynolds An antibody-drug conjugate is just what the name implies, it’s an antibody hooked to drugs through a stable linker. The beauty of this is that it allows us to deliver a very potent cytotoxic molecule and minimize side effects for the patient.
We do this by using an antibody that has exquisite sensitivity and specificity for binding to a target on the surface of a cancer cell, in this case CD30 for Adcetris. After binding to its target, the cytotoxic molecules enter and can kill a cancer cell. The drug is inactive as it moves through the bloodstream, looking for its target. It’s designed to minimize toxicity, but once it’s inside the cancer cell, the cell’s machinery clips the link between the antibody and the drug. This is a critical aspect of Seattle Genetics’ technology – utilizing a linker that can hold the drug securely while it’s in the blood but then release it appropriately once it’s in the cancer cell.
Once inside the cancer cell, these “smart bombs” basically detonate and kill the cancer cell through apoptosis. What we have here is high specificity for delivering these potent molecules just to the tumor cell and sparing healthy cells. Therefore, we think this is a way to achieve good efficacy and minimize side effects and achieve a good safety profile.
PMO In your opinion, is the promise of personalizing cancer treatments occurring for lymphoma patients being managed by community oncologists?
Dr Reynolds The promise of personalizing cancer treatments is becoming a reality for community oncologists and has been for some time. There are a number of targeted therapies that are now being used in the community setting and really helping patients every day.
I think one of the best examples is Rituxan. It’s a monoclonal antibody that’s been around for a number of years. Oncologists who take care of patients with blood cancers use it every single day. It’s targeted to CD20, and so the community oncologist is aware of what you need to do to determine if CD20 is present.
We are developing Adcetris following the same model. Testing for CD30, the target of Adcetris, is available, and community oncologists have access to it and are using it every day to make the diagnosis of Hodgkin lymphoma and other lymphoma types. If CD30 is present on these tumor types, then the patient is potentially a candidate for Adcetris therapy whether through our approved indications or a clinical trial.
We think models like this will move quickly into the community practice setting and really allow a good match between available therapeutics and the patient’s disease.
PMO What are the advantages of the ADC approach compared with the more conventional approach of developing drugs that target specific molecular pathways involved in the growth and development of a subpopulation of cancer cells?
Dr Reynolds ADCs have some unique advantages in the delivery of personalized oncology medicine to patients in need. One of the beauties of ADCs is their unique and exquisite specificity for targeting antigens that are found predominantly on cancer cells. We select targets that are found on the tumor and either not found on or found at extremely low levels on normal cells. This has a 2-fold advantage. One, it delivers very high concentrations of an active cytotoxic drug to the tumor in greater amounts than we could if we were just delivering this as an intravenous chemotherapeutic. And second, the healthy tissues in the body are exposed to much lower quantities of the cytotoxic because they lack the marker, they lack the target. Therefore, patients experience is enhanced efficacy and minimized toxicity.
We’ve had patients being able to receive Adcetris for over 3 years with a very acceptable quality of life. One patient who has come and talked with us said nobody asks if he has cancer anymore. He’s in a complete remission. He’s taking the drug long-term. I think that’s a testament to the activity of the drug that it is able to keep that cancer from coming back, but also that the side effects are tolerable, and he can go to work, have a family life, and really have a high quality of life.
PMO Are there advantages to the ADC approach with respect to drug development costs?
Dr Reynolds Antibody-drug conjugates are not inexpensive drugs to develop. We have worked for over a decade to develop Adcetris. We think we have a really good idea of how to do this efficiently, but there were a number of challenges in bringing together a biologic, an antibody, and a potent cytotoxic agent, orastatin.
This is really a hybrid molecule. It is complicated to manufacture and has required us to come up with new regulatory paradigms to work with the FDA and with the European Medicines Agency (EMA) to show them that we can make a uniform, reproducible, quality product that’s safe and efficacious to give to patients.
PMO What implications do ADCs have on the treatment of cancer, and what does this mean for patients and physicians?
Dr Reynolds ADCs are going to have a profound implication on the treatment of cancer. I think ADCs are part of a renaissance that’s occurring in oncology using targeted therapy in a personalized approach to really maximize patient care for people living with cancer.
ADCs are extremely potent, yet they have a very good safety profile. Adcetris has validated this approach and really established a regulatory precedent. There are now over 25 ADCs in clinical development for other oncology applications. Over half of those use our technology. So we’re really pleased that we’ve been able to work with others to enable the development of new molecules that hopefully will help people live longer and better even though they have cancer.
PMO Adcetris is the first approved ADC directed to CD30-expressing cells and the first therapeutic advance in Hodgkin lymphoma in 30 years, but it’s also currently being evaluated in clinical trials for other CD30-positive tumors. Is this the model for ADC technology – that is, find a unique antigen that is common among several cancer types that can be targeted by a monoclonal antibody?
Dr Reynolds The model for ADC development is to find an antigen that’s unique on a cancer cell but typically not found or found at low levels in normal tissues, and then figure out whether that molecule can be effective and safe when delivered to multiple different tumor types.
I think a good example of this model includes Adcetris receiving approval in 2 indications – relapsed Hodgkin lymphoma and systemic ALCL – and then exploring it further through clinical trials in a number of other tumor types that express CD30, including other lymphomas as well as solid tumors.
Another example is a program that we’re investigating in the clinic that targets an antigen known as nectin-4. Nectin-4 is found on many different solid tumor types, so the clinical study that we’re running allows anyone who has nectin-4 on the surface of their tumor to enroll.
As more and more ADCs move forward and there’s proof of concept in 1 indication, there’s then a desire to look for that antigen or target in many other types of cancers. We believe that this is akin to treating cancer based on the target and not the cell of origin. I think this is a fundamental paradigm shift that can easily be brought out into the community by the use of simple testing to look for these markers on the surface of the cell.
Summarizing, once you find proof of concept in terms of efficacy and safety with a given marker in a given tumor type, the race is then on to see whether this also works in all the other tumor types that express that marker.
PMO If brentuximab vedotin is approved for cancers other than Hodgkin lymphoma, will this affect pricing of the drug?
Dr Reynolds Brentuximab vedotin is priced for its current indications in relapsed Hodgkin lymphoma and ALCL. We are investigating through clinical trials whether it can be safe and efficacious in other tumor types, but it’s premature to speculate on what that might do to the price at that point in the future.
PMO Seattle Genetics is testing ADCs directed at other unique antigens, including CD70, AGS-5, nectin-4, and CD19, but several of these antigens can be expressed on normal tissues as well. How do the adverse events associated with ADCs compare with those encountered with other forms of personalized medicine in oncology in which drugs are developed against molecular biomarkers found on subpopulations of cancer cells?
Dr Reynolds All molecules that we develop for the treatment of cancer have side effects, and we really strive to understand them early in development using preclinical models and models that we’ve run in the lab to try to predict what might happen to people who are exposed to these agents, especially new treatments like ADCs where we just don’t have a long history. We also focus on selecting target antigens with restricted expression profiles and limited expression on normal tissue.
We were very fortunate as we developed Adcetris in that we were able to fully characterize its preclinical safety profile, and when we translated that into people, it worked very well and had fewer side effects than we saw in the preclinical models. So we were grateful
Many patients can take Adcetris for very long periods of time and have a very acceptable safety profile. There are some patients, as with any drug, who don’t respond well to the drug or may have a side effect that causes them to stop using the drug.
I think if you summarize this you’d say that ADCs are like most drugs. They have efficacy – we think more efficacy than many drugs. And they have side effects – we think maybe a little fewer than other types of therapy.
PMO Incorporating molecular biomarker profiling into the management plan for all cancer patients is an expensive undertaking. ADC technology appears to circumvent this process because the unique antigens to which the monoclonal antibodies are targeted are present on cancer cells of a specific type. As a result, will ADC technology result in personalized medicine at a reduced cost to the patient and healthcare system because it doesn’t require molecular biomarker testing for each individual patient?
Dr Reynolds ADC technology will be widely deployed into the community at a reasonably cost-effective rate, and the reason is that looking for targets on the surface of the cell is fairly inexpensive. Immunohistochemistry has been a technology that’s widely deployed by pathologists in the community as well as through central labs. It’s been available for over 50 years. It’s simple, it’s reproducible, and it’s relatively inexpensive.
So patients, especially in the blood cancer space, often have large panels of markers that are tested for to best characterize their disease and to match it with the available therapy. It’s already being done.
I also believe that molecular testing is going to be important, but we need to refine our test methods so that they become more robust and less expensive, so we can get higher throughput and really do our best job matching available therapies as they evolve to patients and their tumor types.
PMO One of the challenges oncologists face is the patient who wants a specific therapy despite the fact that he/she tests negative for the biomarker driving that therapy. Does ADC avoid this issue?
Dr Reynolds ADCs are very much like other targeted therapies that require pathways or markers. If you don’t have the marker or the pathway, it’s not likely that you’ll maximally benefit from the drug.
We think ADCs should be given to people that have the marker on their cell surface. Now, over time we may find that even patients with low levels of marker may benefit from the drug, or that other agents in combination may potentiate the drug and offer new hope to patients who currently don’t have other options.
I think we’re going to keep prosecuting the science to find out how best to use these agents, to find out how much of the target you need on the cell surface, and to continue to develop new molecules to new targets so that we can keep helping people who are living every day with cancer.
PMO Are there any special regulatory challenges Seattle Genetics faces regarding ADC technology?
Dr Reynolds ADC technology has some unique regulatory challenges. We have the first of a new generation of ADCs to go through the FDA and gain approval, not only for 1 indication but for 2 at the same time.
One of the major challenges is the marrying of 2 very different types of molecules that have very different regulatory paradigms: a biologic, the antibody component, and the drug linker, which is a small molecule. They’re regulated by different divisions of the FDA. And one thing that was extremely exciting about bringing the ADC forward was to watch those 2 regulatory divisions come together, provide outstanding reviews of the manufacturing, preclinical and clinical data, and come to a common consensus that Adcetris was efficacious and had a tolerable safety profile and should be approved, and approved ahead of its scheduled FDA action date.
We think we’ve blazed some new ground here. That regulatory pathway has been validated, and we look forward to new molecules being brought forward to the FDA and across the pond to the EMA for approval to help patients with cancer soon.
PMO Education of providers, pharmacists, payers, and patients is vital in achieving personalized medicine. What effort is Seattle Genetics making in educating these stakeholders?
Dr Reynolds Seattle Genetics recognizes it is critical to educate our stakeholders in the power and the promise of ADC technology and in how Adcetris might benefit their patients.
We have a multipronged approach. One is our commercial team. We have, we think, one of the top-notch sales forces in oncology. They know how to explain the product to physicians and the staff in the office and help them understand which patients may be available on the labeled indication, and then how best to use the drug and to manage those patients. So they are a fountain of information.
Second, we have a medical affairs group that is able to answer questions physicians have about other places this drug might be used and how we could do further studies, investigator-sponsored studies, to better understand other uses of Adcetris. Then third, we work with payers through our managed markets group to ensure they understand the benefits of Adcetris and the data that support reimbursement decisions.
Those 3 groups work very well together to ensure that every patient who could benefit from Adcetris has access.
PMO In the advent of the personalized medicine era, we are seeing collaborations between companies in an effort to bring better, targeted therapy to patients. How important are intercompany collaborations to Seattle Genetics’ mission?
Dr Reynolds Intercompany collaborations are mission critical to really fully developing ADC technology to help patients with cancer. I think a good example is the work that we’ve done in licensing our technology to companies that own targets or markers on cells and have strong intellectual property but really need to punch up the antibody to fully benefit patients.
An example is our licensing deals with, among others, Genentech, Astellas, and GlaxoSmithKline. Genentech has prosecuted our technology very widely for a number of targets. They have 8 molecules now in the clinic that are using our ADC technology. In fact, at a recent investor event hosted by Genentech’s parent company Roche, patient data from 5 ADC product candidates that all use our technology were highlighted, showing objective responses in both hematologic and solid tumors. We expect to see a lot more data coming from our collaborators, and we think it will be another step to affirm the validation that Adcetris has brought to the ADC landscape.
PMO Will it still make sense for Seattle Genetics to develop agents that impact only 5% to 10% of a given patient population?
Dr Reynolds The community is very important in bringing forward new technologies like ADC to maximally benefit patients with cancer. One of the biggest challenges we face today is that only 2% to 3% of patients with cancer participate in a clinical trial. We have got to do better than that, and a lot of this is going to come from the community.
As we develop personal oncology approaches, smaller and smaller patient populations are going to be available for any given, very targeted therapy. So our only way to do this quickly is for the community to educate patients and to make these trials accessible and easy for patients to enroll in, so we can get the data to develop new drugs and to best match these really cutting-edge therapies with the patients whose lives can be extended and improved upon.
Molecularly targeted therapies change the vascular milieu and can cause hypertension, fluid retention, and thromboembolic phenomena. However, the absolute risk of cardiotoxicity is much lower with targeted therapies compared with anthracyclines, stated Michael S. Ewer, MD, from the MD Anderson Cancer Center in Houston, Texas, at the recent meeting of [ Read More ]
Although weightlifting reduced the need for lymphedema treatment by 50% compared with standard treatment in breast cancer survivors who participated in the Physical Activity Lymphedema (PAL) trial, weightlifting is not without its own risks. A retrospective analysis of the PAL trial found that the rate of injury was higher in [ Read More ]