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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.

This material is based upon work supported by the National Science Foundation and the National Institute of General Medical Sciences under Grant No. 2122350 and 1 R25 GM139147. Any opinion, finding, conclusion, or recommendation expressed in these videos are solely those of the speakers and do not necessarily represent the views of the Science Communication Lab/iBiology, the National Science Foundation, the National Institutes of Health, or other Science Communication Lab funders.

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