precision medicine

Personalized Medicine in the Trump Era with Edward Abrahams

The Personalized Medicine Coalition advocates for a wide group of constituents, including scientists, health care providers, entrepreneurs, payers, and patients. Which is why we’ve often wondered how the organization can be absolutely clear in their priorities.

Today, PMC President Edward Abrahams joins us to answer that question.

For example, take the topic of laboratory developed tests. The country is currently experimenting with an anti-regulatory political direction. Is Ed happy that the FDA has dropped their guidance for LDT regulation? With such a disparate constituency, what does he think is the best way forward? What about the CMS announcement recently that there wouldn’t be any reimbursement for diagnostic tests that weren’t FDA approved (isn’t this at odds with anti-regulatory policies?)—does Ed have any insight here? Also, is the current boom in direct-to-consumer testing a boon or bane for the industry?

When Obama’s Precision Medicine Initiative was launched, many organizations which had been using “personalized medicine” in their nomenclature were pressured to change their names. Ed says he’s still happy with the old term and in fact is working in congress to create the first Personalized Medicine Caucus.

We come in at around 27 min today with one of those unique industry veterans who can talk science with scientists, can talk real with patients, and carries clout on The Hill.

Going Beyond the Liver with RNAi: Chris Anzalone of Arrowhead Pharma

Fifteen years ago, folks in the industry were buzzing about RNAi the way they talk about CRISPR today. Then things went quiet for the technology, at least in the news. Until last year.

In September of 2017, Alnylam Pharmaceuticals, the leader in the RNAi space, announced such positive phase III study results that most experts in the business expect an FDA approval soon. It will be the first for an RNAi drug.

So what took the technology so long, and what was the key to the great results? These are questions we ask today of Chris Anzalone, the CEO of Arrowhead Pharmaceuticals, another runner in the RNAi race. Arrowhead scooped up various RNAi programs from some of the big pharma giants, including Roche and Novartis, during the "quiet" years. Coupling these assets with some of their own technology, they are going after not just some of the esoteric diseases we've come to expect from a new platform first proving itself, but are also targeting the very recognizable Hepatitis B.

How does Arrowhead plan to further differentiate themselves from Alnylam?

“One of our great contributions to the field and, frankly, to world health, is our ability to bring this outside the liver,” says Chris.

So far, the major programs from RNAi companies like Alnylam are all limited to liver diseases. Arrowhead is the first to have drug candidates which go after non-liver diseases. It's a major step forward for this RNAi technology.

How we will know when RNAi has matured, we ask Chris at the end.

Vice Chancellor Keith Yamamoto on UCSF’s Role in Medicine Today

A major chapter in the history of medicine has been written by UC San Francisco. They are writing the next for precision medicine.

Keith Yamamoto is in both chapters. Since the 1970s, he has been a researcher of cellular and molecular biology at UCSF and now serves as Vice Chancellor of Science Policy and Strategy as well. His career has always had these two parallel tracks of scientist and policy administrator. He has sat on various review boards at the NIH and chaired the Board of Life Sciences at the National Academy of Sciences where he worked with a group that would stimulate President Obama to launch his Precision Medicine Initiative (PMI) back in 2015. Today he shares with us what that was like for him.

Though the political wind blows a different direction at the national level these days, the momentum continues for the PMI at NIH, funded, as Keith points out, by congress with the Faster Cures bill for ten years.

And at UCSF? They are just getting started in precision medicine. With an illustrious history in medicine, an enviable location at the tech hub of the world, and resourced to the gills—the university can boast its sixth year in a row of being the top recipient of NIH funds, and rides around the top of the list for private contributions--UCSF is also one of the hosting universities for California’s own Precision Medicine Initiative, which just a few days ago received a huge boost from Governor Brown's new budget.

What is the university doing with all this gold? Keith says UCSF is building a machine, a precision medicine platform, that brings together data from all the disparate places we’ve talked about here on the program—the omics data, wearables information, electronic health records, etc—into an information commons similar to Google Maps, creating a "knowledge network." It’s a story we’re all familiar with, and if anyone can do it, certainly this is the place.

In addition, Keith describes one of the many collaborations UCSF is involved in called ATOM, or Accelerating Therapeutics for Opportunities in Medicine, a public-private consortium that brings the idea of big data sharing to drug discovery at the pre competitive level.

“What we’re moving is the starting line, rather than the finish line", says Keith.

The NIH has spearheaded similar efforts before. Perhaps with UCSF’s star computer science power this effort will go new places.

For those in our audience attending next week’s Precision Medicine World Conference in Silicon Valley, you can hear Keith talk on Accelerating Cancer Therapies and Exploiting Longitudinal Patient Data: Partnering to Achieve Precision Medicine.

Seattle Startup Takes Precision Oncology to the Next Step: Carla Grandori, CEO, SEngine

Carla Grandori was for thirty years a cancer researcher most recently at the Fred Hutch in Seattle. She had her personal reasons for working on cancer, she tells us in today’s show. Now, she’s the CEO and founder of SEngine, a startup offering something completely new for oncologists around the country.

Carla says she was motivated to step out of the research lab when two patients came to her personally and asked her, “can you study my cancer?”

“When I heard that second request, a light went off. I had thought maybe in 10 years the research would be useful. But then this patient made me think, ‘no, I think we can help now.' When I realized the potential of our technology to help patients immediately, I saw no more boundaries. I said, 'we have to get there.’"

What is this technology? And if it’s so powerful, why hasn’t it been offered before?

SEngine's (think Search Engine) new test, called PARIS, screens individual patient tumor cells onsite against a complete library of over a hundred and fifty cancer drugs. Before now with say, Foundation Medicine, there has been much progress in sequencing tumors and offering lots of omics data virtually. But the PARIS test goes a step further, screening a patient’s actual cells in real time while also combing through accompanying omics data. Until now we didn’t have the technology to deal with the samples with enough precision and in small enough quantities, nor the necessary robotics and software.

The company received CLIA certification back in June and the test is for sale to oncologists now. The next step for SEngine is to build up a major clinical utility validation.

Immuno Oncology 2017: Looking Back, Looking Forward with Rachel Laing and Olivier Lesueur

Immuno oncology is now the dominant topic at Mendelspod. From shows with CEOs presenting new panels of predictive biomarker tests, to the firsts at the FDA with the CAR-T approvals as well as the first approval of a drug (Merck’s Keytruda) based on a common biomarker (MSI) rather than on a tumor type, to scientists discussing rare cells of the immune system, we had more podcasts on this topic than any other in 2017.

Rachel Laing and Olivier Lesueur are partners at Bionest, a global life science consulting firm. They work with companies on both the drug and the diagnostic sides of immuno oncology and are at ease switching back and forth between the two in today's discussion.

Complexity is the key word, says Rachel. Immuno oncology has turned the development of biomarkers on its head. Whereas formerly with a simple companion diagnostic, one starts with a very specific biomarker develops from there.

“With immuno oncology, it’s very different from that,” she says. "You’re not just dealing with a tumor cell and the signaling that goes on there, you’re dealing with the immune system. And there’s a lot of interplay between the tumor, the microenvironment, and the immune system. It’s unrealistic to think you could get away with just measuring one biomarker.”

What are the challenges for diagnostics companies in commercializing various biomarkers into ongoing testing for the same patient, or what’s becoming known as “real time oncology?”

Olivier addresses the great reimbursement irony in the field of drugs and diagnostics. Without the biomarker tests, the drugs may not work for the right patients. Yet the diagnostics companies receive pennies while the drug makers are getting away with— well, we all know that issue. Olivier says one drug maker recently preempted this problem by offering to just pay for the diagnostic up front in geographies where the diagnostic reimbursement was being questioned, which is good for everyone, including the patients, and shows some vision. This problem of undervaluing diagnostics has bedeviled our industry for a long time and becomes especially crucial with immuno therapies that rely on patient stratification and ongoing profiling.

In our final question about what we’ll see in the year ahead, it’s cautioned that though patients are seeing more and new therapy options, the complexity of treatment is becoming ever more demanding on some people who are already pretty sick.

Huh? 30 Million Americans Have a Rare Disease? Howard Jacob on the State of Clinical Sequencing

Here’s a title for you. Chief Genomics Officer. Today’s guest is also the VP of Genomic Medicine and a faculty investigator at the HudsonAlpha Institute for Biotechnology.

He launched the world’s first genomic medicine program becoming the first person in history to use genome sequencing to diagnose, treat, and cure a patient. Few people exude the sheer force and vision for the future of genomic medicine that comes from Howard Jacob. We’re very pleased to have him on Mendelspod for the first time to talk about progress with rare disease, sequencing technology, and how he would teach genomic medicine to young people today . . . And of course, that genomic age old question: the exome or the whole genome?

With their Own Manufacturing Facility, Seattle Children’s Goes Big into CAR-T, Rare Disease

The past few months have seen the first approvals at the FDA for CAR-T cancer therapies. But trials have been going on for years. And not just by big pharma.

Today’s guest, Dr. Michael Jensen, is a researcher at Seattle Children’s Hospital and started his first CAR-T cell trial back in 2002.

“It’s been a long road to get to the point where we understand enough about the science and physiology of this technology to make it work int he clinic," he tells us in today's interview.

Seattle Children’s has set out a tremendously bold vision: think hybrid academic center and biotech company. They are currently building a $350 million, half a million square foot research tower along with a 30,000 square foot GMP manufacturing facility--all under the non-profit umbrella. This is an upgrade on the current GMP facility and will be one of the biggest such facilities of its kind in academia.

Michael says that the center is out ahead of big pharma with CAR-T therapies because they are not going for big drug approvals, but rather focused on early proof of concept work.

“Our role is to innovate in early phase studies with the hope that positive data will result in a Novartis or Gilead or Juno or Bluebird coming in and taking it across the finish line.”

What the non-profit center is able to do that big pharma never will be able to, therefore, is to go after all cancers and pediatric diseases, no matter how rare.

We begin the interview with a rundown on the ongoing CAR-T trials at Seattle Children's and their plans to translate success in blood cancers to solid tumor cancers.

With Immuno Oncology Comes a New Focus on Rare Cells

Modena, Italy is the town where one of the world's rarest cars were first developed and built: the Ferrari sports car. It’s also home to one of the world’s oldest universities where today’s guest spends his time studying rare human cells.

Andrea Cossarizza is Professor of Pathology at the University of Modena and Reggio Emilia School of Medicine and the President Elect of ISAC, or the International Society for the Advancement of Cytometry. He joins us today to talk about the role that improved cytometry technologies are playing in detecting rare cells and how this is being translated into better treatments for patients with cancer and other diseases such as immune disorders.

With the advent of immuno therapy has come a renewed interest in rare cells, or cells that occur with less frequency than 1 in 1000. Rare cells include the antigen specific T cells that we hear so much about with immuno oncology. But rare cells are also studied in many immune and inflammatory diseases such as HIV.

“This is a very new and interesting field which will have enormous importance in the future,” says Andrea, who wrote the chapter on rare cells in a new book on single cell analysis.

Andrea says that though new immuno therapies have shown such enormous promise, they only work on about half the patients. Being able to detect rare immune cells in advance of treatment will help clinicians to know which patients will respond.

What are the challenges that are emerging in this new field? When should the patient be tested? How does rare cell detection technology need to develop?

Join us as we lift the hood on the future of rare cell detection.

Why Childhood Cancers Need Their Own Gene Panel: Tim Triche

When we first talked with Tim Triche of LA Children's Hospital, we found out he was a bit of an outlier among cancer researchers. He was an advocate for poking around in the non-coding RNA.

Today we welcome Tim back to the show to talk about a new gene panel that he has designed specifically for childhood cancers. It’s a first of its kind and was modeled quite closely on the gene panel for the NCI’s MATCH trial. The new panel has both a DNA and an RNA component, and the RNA side is by far the biggest.

"There are 1,400 different amplicons on this panel looking for RNA fusions. Thermo Fisher tells me it’s the most ambitious RNA panel that they’ve ever undertaken," Tim says in today's interview.

"When 100 cancer patients walk in your office, then 100 cancer patients walk in your office," says Tim, quoting a common line in the field that points to the uniqueness of every cancer.

Yet even though every cancer is different, certain biological commonalities combined with better sequencing tools is enabling the design of new gene panels to guide in diagnosis and treatment. More and more a cancer is looked at based on the drug that might treat it rather than the organ in which it grows. The new panel can guide this treatment.

Some of the most important targets on the panel are RNA fusion transcripts. What are they, and why are they so important for helping kids?

Childhood cancers come from inherited mutations, whereas most adult cancers have to do with the skin or the linings of the organs due to mutations caused by environmental impacts. Fusion transcripts are very common in the youth cancers and have been a big part of routine diagnostics.

If a mutation is there early in life, is it likely to turn into cancer sooner rather than later? Yes, says Tim.

“If you look at the incidence of childhood tumors, there’s a big bump in the first months or year or two of life, and then they disappear thereafter."

Additional benefits from these new next gen sequencing panels are that they can work with very small “real world” samples of tumor tissue, and they can also be used as discovery tools. Tim says the panel, called OncoKids, is ready to go for frontline therapy, and is hoping to get the word out to oncologists everywhere.

Exploring the Exome and the Future of Genomics with Jay Shendure

Back in 2009, University of Washington professor, Jay Shendure, wrote a definitive paper offering up a roadmap for exome sequencing. Since then, the cost of sequencing has come down so far that many have debated whether or not to do whole genome sequencing vs. just the exome.  

As it turns out, the exome, as a unit, has been very fruitful for both clinicians and scientists, particularly in the area of rare disease discovery and diagnosis. Most genetic testing companies these days have the exome on their product lists.

In today's program, Jay says that we are still in the heyday of the exome; there is still much low hanging fruit.   However, some eight years after his landmark paper, he warns we will soon come to the end of that cycle.

“There clearly is a lot that we haven’t explained. But doing the same thing over and over again isn’t going to get us there. We’ve got to take a step back and systematically investigate the various explanations for the keys that aren’t clearly labeled and not under the lamppost.”

What are some examples of new hypotheses for decoding the genome? Jay points to searching in non-coding regions, epigenetic mechanisms, somatic mosaisicm, and di-genic mutations.

As we go ever deeper into the genome, what are Jay's thoughts on the need for going wider with lots of genomes? And is he on the same page with his UW colleague, Evan Eichler, when it comes to long reads?

Jay is a scientist's scientist. Coming out of George Church's lab at Harvard, he's worked over the years on new methods for genomicists. One of his latest projects dives into developmental biology. He says we've spent a lot of time looking at the "what" of genomics. Now it's time to look at the “how” and “why."

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