Drug Development – the Herceptin Story
Transcript of Part 1: Drug Development – the Herceptin Story
00:00:14.19 I am Sue Desmond-Hellman. I am Chancellor at the University of California, San Francisco, 00:00:20.06 and I want to tell you about the drug development story 00:00:23.12 for Herceptin. Let me start by telling you 00:00:27.26 about my background. I am a medical oncologist by training. 00:00:31.12 After medical school I came to the University of California, San Francisco 00:00:35.19 and did my training in internal medicine and then medical oncology. 00:00:40.23 and had the great fortune during the last couple of years 00:00:44.08 as a faculty member in the late 80s of spending time in Kampala, Uganda 00:00:49.28 as the leader of the adult cancer center, 00:00:53.18 caring for patients with Kaposi's sarcoma. 00:00:55.23 And a lot of my early thinking about product development 00:00:59.26 actually came from the time I spent in Uganda caring for patients with Kaposi's sarcoma 00:01:04.29 and a real quest and a passion to make life better for patients. 00:01:08.05 In the mid 90s I came to San Francisco again 00:01:13.09 to join Genentech, the first biotech company, 00:01:17.05 and I had a lot of wonderful experiences in product development at Genentech. 00:01:20.00 And one of those great experiences is the story that I 00:01:23.00 want to tell you about today. 00:01:25.28 So let's talk about some big picture things about 00:01:29.27 great drug development. 00:01:31.06 And when I say drug development, I mean the entire process 00:01:34.19 of bringing an idea or a concept from the labs 00:01:38.16 into the clinic and then through the approval process 00:01:43.04 so that the medicine can be broadly available for patients. 00:01:46.00 First and foremost, and you can't do great drug development without it, 00:01:50.13 you need a very deep understanding of the basic science. 00:01:54.18 What's the hypothesis that you are testing? 00:01:56.23 What's the question you are asking? 00:01:58.22 And does that question make sense 00:02:00.24 given the basic science and the fundamentals behind what you are trying to prove? 00:02:05.03 The characteristics of the drug are important. If the drug doesn't get to the target, 00:02:09.23 or it doesn't stay long enough in the circulation, 00:02:12.26 the half life, then you can't improve the outcome for that patient. 00:02:16.29 Targeting the right patients, or personalizing the therapy 00:02:21.00 is the modern way to do drug development, and in part 00:02:23.27 it's the modern way to do drug development based on experiences 00:02:26.28 like the one we had with Herceptin. 00:02:28.25 Setting a high bar in the clinic isn't something everyone does. 00:02:34.24 The risk of setting a high bar in the clinic 00:02:36.02 is that you can fail. 00:02:38.06 The benefit of setting a high bar in the clinic 00:02:40.24 is that if you succeed, it matters a lot. 00:02:44.02 It makes a big difference. People need to re-write the textbooks. 00:02:48.04 Think again about what is possible for those patients. 00:02:52.04 So setting a high bar in the clinic is the most inspirational way to do great drug development. 00:02:57.29 And what I actually like most about great drug development is 00:03:01.07 you don't do it alone. You have to work 00:03:03.21 effectively with colleagues in a collaborative way. 00:03:06.21 and you particularly have to work effectively with key regulatory decision makers. 00:03:11.15 In America, that's the Food and Drug Administration, 00:03:14.29 but there are similar bodies all over the world, 00:03:17.03 and you have to work effectively with those regulators 00:03:20.01 so you can do the clinical trials, and ultimately, 00:03:23.08 so you can have broad applicability of your new product. 00:03:26.06 So let me start the Herceptin story with telling you about the scientific rationale 00:03:32.08 in breast cancer. And this story really rests on 00:03:37.00 some critical information about the role of oncogenes in driving cancer. 00:03:41.17 And this specific oncogene, Human Epidermal Growth Factor Receptor 2, 00:03:47.18 or HER2, is a gene that was thought to be associated with 00:03:52.13 accelerating the growth of breast cancer. 00:03:55.15 And the first clinical description of that growth acceleration 00:03:59.02 came from Dennis Slamon and his colleagues as published in 00:04:01.24 Science in 1987, and it is shown on this slide. 00:04:05.21 If patients had too much HER2, either amplification or overexpression of HER2, 00:04:11.15 as measured by FISH or immunohistochemistry, 00:04:16.03 that was associated with a shorter survival. 00:04:19.22 So about 25% of women in this trial were 00:04:24.08 HER2 positive, or over-expressing, and their median survival was only 3 years. 00:04:30.22 Whereas the HER2 normal, about 75% of women 00:04:34.00 who had a normal amount of HER2 lived a median of 6 to 7 years. 00:04:39.07 That's a dramatic difference, and that matters in 00:04:42.22 the clinic. That had a big impact, when I was a practicing oncologist 00:04:46.14 on how I thought about the outcomes in those patients. 00:04:49.27 So what that meant for a patient was that she could only expect to work half as long 00:04:54.19 as her fellow breast cancer patients who were HER2 normal. 00:04:58.11 At the time this study was done it was particularly troubling to see this outcome 00:05:02.02 because we had no remedy for this HER2 positive status in the patient. 00:05:06.11 So this description was scientifically compelling, 00:05:10.07 but in terms of drug development it also outlined for us an unmet need. 00:05:14.27 A difficult situation for patients that potentially 00:05:18.01 we could fix. So here is the molecule that allowed 00:05:22.14 us to think about addressing this HER2 positive 00:05:26.21 or HER2 over-expressing breast cancer. 00:05:29.27 And this is the picture or a cartoon showing 00:05:33.19 Trastuzumab. Trastuzumab is the USAN name, or what some people call the 00:05:39.08 generic name for Herceptin. 00:05:41.19 I am going to use Herceptin because it less of a mouthful. 00:05:44.06 But this is the monoclonal antibody. 00:05:47.03 And monoclonal antibodies, at the time that Herceptin was developed 00:05:50.24 were thought to be kind of a pie in the sky dream for a smart bullet, 00:05:55.19 a guided missile targeted to certain things like HER2 00:06:00.26 that were expressed on cancer cells. 00:06:02.24 And the beauty of Herceptin was that this monoclonal antibody 00:06:06.15 was humanized. Most of the antibody, greater than 90% 00:06:11.14 was human. Less than 10%, and in fact in this case, 7% 00:06:16.03 was murine. And that meant that unlike some of the early antibodies 00:06:20.20 human beings didn't reject the antibody as foreign. 00:06:24.11 So Herceptin was a humanized monoclonal antibody 00:06:28.25 that specifically targeted HER2, 00:06:32.07 allowing us to test the hypothesis, if we direct an antibody 00:06:36.01 against HER2 can we improve outcomes in women with HER2 positive breast cancer. 00:06:43.10 So this is a slide that shows you the development timeline for Herceptin. 00:06:48.14 And a couple points I want to make on this slide, 00:06:51.00 you notice the slide is a very long timeline. 00:06:53.22 It takes a lot of time to do great drug development. 00:06:56.15 and that is because each step along the way you ask and answer 00:07:01.09 specific questions. Now the first study 00:07:04.08 of Herceptin was all the way back in 1991. 00:07:07.24 And that is when the investigational new drug 00:07:11.01 or IND was filed to ask the FDA, we want to do clinical trials 00:07:15.03 with this new concept for patients in the clinic. 00:07:18.06 By 1994, the phase 2 studies were being done 00:07:23.16 based on an early rating that this was safe enough to give patients. 00:07:27.04 In phase 2 you ask, is this medicine going to help patients? 00:07:33.04 Does it look promising? And you start to figure out the dose 00:07:36.10 for which you are going to do the most important phase of testing, 00:07:39.20 or Phase 3, which opened up in 1995. 00:07:42.25 The other things that are shown in this slide as we get into the late 90s 00:07:48.10 and then into the 2000s are a series of steps with the regulators. 00:07:52.26 With the US regulators in terms of filing 00:07:56.23 a BLA or a biologic license application, 00:07:59.18 and with the ex-US regulators and what this shows is that something 00:08:04.09 had to be done that is special with a targeted therapy 00:08:07.13 and that special thing is filing both Herceptin, 00:08:11.09 or Trastuzumab approval, and HercepTest. 00:08:14.04 This makes drug development even more challenging. 00:08:17.25 You have to ask for approval of your product, 00:08:21.17 Herceptin, and simultaneously ask for approval for your diagnostic, HercepTest. 00:08:27.02 These were both concurrently approved in 1998 00:08:30.14 in the metastatic setting or breast cancer that has spread. 00:08:36.00 And then not until 2005 did FDA approve Herceptin in the adjuvant setting, 00:08:42.26 or following primary surgery as adjunctive to standard chemotherapy. 00:08:47.08 Now the HER2 testing part of the Herceptin 00:08:53.04 experience was a critical part of the lessons that I learned 00:08:56.28 about product development when I worked on Herceptin. 00:08:59.15 And what this slide shows you is a great example 00:09:02.28 of why a diagnostic matters so much. 00:09:06.03 It actually makes drug development cheaper 00:09:09.05 and faster. And why is that? Well, this is a 00:09:13.00 statistical representation of what might have been with the Herceptin study. 00:09:18.04 In patients whose breast cancer has spread, 00:09:21.20 metastatic breast cancer, or MBC, 00:09:23.16 we knew before Herceptin median survival was 22 months. 00:09:28.09 So 50% of patients had died by 22 months 00:09:32.05 when you studied first line metastatic breast cancer. 00:09:35.19 Let's say that we expected the benefit of Herceptin to be to extend that 00:09:39.23 survival from 22 months to 27 months, 00:09:43.15 or a 5 month improvement in survival. 00:09:46.06 Well if everyone in the study, or 100% of the patients, 00:09:49.29 were HER2 positive, that 5 month difference would 00:09:53.27 take about 1250 patients and 52 months duration of study. 00:09:59.17 If we didn't have the diagnostic test, 00:10:02.28 and the truth was that only 25% of our study population had 00:10:07.12 HER2 over expression, that study would have shown 00:10:10.20 a 1.25 month difference, and taken 349 months, 00:10:16.10 and 11,000 patients. We couldn't have done that study. 00:10:20.01 That study wasn't possible. 00:10:21.11 So the diagnostic allowed for a smaller patient 00:10:23.27 group and a faster study. 00:10:26.12 And here is the answer to the question, 00:10:29.12 does Herceptin help women with metastatic breast cancer? 00:10:32.15 The great news is that the answer is yes. 00:10:34.22 In fact, as we had predicted, 00:10:38.11 the median survival extended from 20.3 00:10:41.18 months to 25.4 months, a 25% improvement 00:10:46.13 in survival in women with metastatic breast cancer, 00:10:50.11 all of whom were HER2 positive, when treated with Herceptin. 00:10:53.15 Even better news came when we studied Herceptin early on 00:10:58.25 in the adjuvant setting. The time 00:11:00.29 to first distant recurrence doubled. 00:11:04.23 The time that women stayed in remission doubled 00:11:07.02 when Herceptin was given just after surgery. 00:11:10.12 And this news was so dramatic that it got a standing ovation 00:11:13.25 when it was presented for the first time. 00:11:15.18 In my experience the first time I have ever seen a standing O at a medical meeting. 00:11:20.00 Great news for patients treated with Herceptin. 00:11:24.19 Here is the New England Journal article 00:11:26.23 that talked about that great news for women 00:11:30.05 in the adjuvant setting, HER2 positive, treated with Herceptin. 00:11:33.24 And the most important thing that I want to point out 00:11:36.20 in this New England Journal article is 00:11:38.17 the last line: "This will completely alter our approach 00:11:42.20 to the treatment of breast cancer." 00:11:44.25 Now you have to ask: is the patient HER2 positive? 00:11:48.09 Can you help women by targeting 00:11:52.00 this scientifically based new therapy 00:11:54.17 at what could become the Achilles' heel of the cancer? 00:11:57.17 And the answer was yes. 00:11:58.25 So let me come back to the key things. 00:12:03.04 We understood the science. We had the right drug. 00:12:06.03 We targeted the right patients, set a high bar (survival in the clinic) 00:12:10.11 and we worked all the way along the line with Food and Drug Administration. 00:12:15.05 And the best thing about working on Herceptin 00:12:18.21 and the experience that I had was that I know now 00:12:21.12 hundreds of thousands of patients 00:12:23.01 are going to benefit from this work. 00:12:25.15 And that's the best news of all in great drug development.