Interview Questions for Michael E. Phelps, UCLA

Question 1:

Given the significant advancements in PET radiopharmaceuticals over the past decade, what do you see as the most promising areas for future development? How do you envision these new radiotracers enhancing the diagnostic capabilities and clinical utility of PET imaging?

Answer:

During the last 10 years there has been an ever-accelerating growth in academic discoveries and inventions, and in capitalization of the number of companies in Theranostics. The focus of this is integration of molecular imaging with PET to image and measure the biology of disease and phenotype disease cells throughout the body to have or not have the therapeutic protein target and to image and measure therapeutic responses. Theranostics focuses on the use of two versions of radiolabeled molecular probes. One uses the probe labeled with positron emitting radioisotopes like ¹⁸F, ⁶⁸Ga and ⁸⁹Zr, for the imaging assays of the protein therapeutic target, and the other for therapy where the probe is labeled with radioisotopes that emit beta or alpha particles, like ¹⁷⁷Lu or ²²⁵Ac, to radio-ablate disease cells that have the protein target. Each of these labeled probes are injected through IV, carried throughout the body by the bloodstream and cross into tissues in search of the protein target. Because of remarkable therapeutic responses with minor and manageable side effects with the initial probes, they moved quickly through FDA approval, reimbursement and adoption worldwide. This is illustrated by the diagnostic of ⁶⁸Ga-DOTATATE and the therapeutic of ¹⁷⁷Lu-DOTATATE for neuroendocrine tumors and the corresponding combination of ⁶⁸Ga-PSMA-11or [¹⁸F]PSMA and ¹⁷⁷Lu or ²²⁵Ac-PSMA for prostate cancer.

An imaging example below illustrates this Theranostic approach:

These successes have led to a rapid expansion of molecular probes for PET imaging assays and phenotyping, and therapeutics for a wide array of protein targets and in a wide array of diseases, although continuing to expand the number of different cancers that are targeted.

Question 2:

What are principles that differentiate Theranostics from other imaging diagnosis to aid therapeutic approaches?

Answer:

A)    In Theranostics, the imaging part of this diagnostic and therapeutic partnership, the PET molecular imaging probes specifically target proteins involved in the biology of diseases that are therapeutic targets, and from this, to phenotype diseased cells throughout the body to determine if patients have the therapeutic protein target or not. The same, or similar molecular probe, is used for imaging and therapy. From this, you can use the imaging probe to safely determine the time course of the tissue distribution of the probe in patients to provide the analogous information for the therapy probe, and to assay the amount (dose) of the probe on the target. You can achieve this in a safe and effective manner since the imaging version of the probe is given in trace amounts with little to no significant pharmacologic or mass effects.

B)    These PET imaging probes are part of what are called biomarkers of disease that are companion diagnostics to therapeutics in the world of precision medicine. Let’s examine the importance of imaging biomarkers coupled to therapy in Theranostics to put this in perspective. To do this, let’s examine the effect of PET molecular imaging and phenotyping of disease cells in a Signal to Noise analysis, where the signal is responders to therapy and noise is the non-responders, and ask the question, “What are the relative number of patients required in therapy trials for a given outcome with % changes in responders?” In the case of 20% responders to treatment (average response in drug trials), this requires 100 patients. If the responders were increased to 40% and 80% by a biomarker patient selection approach, the relative number of patients required would be 25 and 7, respectively. This produces corresponding reductions in costs, time and the number of patients taking the risk of clinical trials without adding to the desired result. Theranostics provides a demonstration of this principle in trials that is passed on to their use in healthcare.

C)   The expanding number of academic and commercial research and development programs throughout the world are focused on the development of many new Theranostic combinations of PET biomarkers and therapies in an increasing number of diseases.

D)   While initial successes in Theranostics are driven by successes where the therapeutic is radio-ablation of disease cells, the principles apply not only to radioablation therapy, but also to drug and cell-based therapies, although one must keep in mind the mild and manageable side effects in the radioablation therapy. The principles of Theranostics are establishing a fundamentally new and effective example of precision medicine.

Question 3

What has been the commercial and academic responses to the growing success to the precision medicine approach of Theranostics?

 Answer:

           Success in academic research in Theranostics is producing investments commercially.  Commercial success increases academic investments and the cycle repeats. As I mentioned, in Theranostics there is an accelerating increase in commercial capitalization and an accelerating increase in start-ups, mid-size and corporations in imaging, biotechnology, biopharma and pharma. In the last 10 years, the number of new companies in Theranostics has grown to over 50 companies on the therapeutic side of Theranostics including large pharma like Norvartis, Lilly, Bristol Myers Squibb, AstroZenca and Sanofi, and importantly, a growing number of small and mid-size companies that drive innovation and discovery and move successes to larger companies through mergers and acquisition with biopharma and pharma companies.

On the molecular imaging diagnostics and phenotyping of cells throughout the body there are many innovation-driven small, mid-size and large imaging companies like GE Healthcare and Siemens Healthineers, who are aggressively moving to Theranostics by building internal programs, partnerships and acquisitions.

Question 4:

Beyond the value of PET imaging diagnostics of the biochemistry and biology of disease and phenotyping disease cells, what are the technology advances that are occurring in PET scanners and their integration with CT and MRI?

Answer:

PET, MRI, CT and ultrasound all provide valuable information in healthcare. Each provides different information by the origin of the signals used to form their images. In this array of imaging technologies, there are advances occurring for each technology, as well as combining them into single scanners such as PET/CT and PET/MRI to combine their individual source of information in the same patient examination.

PET is a technology that uses labeled molecules to assay proteins involved in metabolism, cell signaling, gene expression, immune system functions, etc. that were originally developed by biochemists, biologists and pharmacologists to study and understand these processes in vitro in health and disease. PET transfers these assays to the in vivo setting of the only true model of human disease – patients. PET does this in safe and effective ways because the imaging probes are used in trace amounts (they are called tracers) that exert no significant pharmacologic or mass effects on the biology of the body.

PET is intrinsically a whole-body imaging technology because the tracers are injected intravenously, move throughout the body with the bloodstream and are transported or diffuse into tissues of the body to search for and engage the protein target for which they are designed. PET is also an analytical imaging technology to quantify proteins and the functions they perform.

PET is fundamentally different than CT, MRI and Ultrasound, although they all provide remarkable access to disease in the body though images. PET provides measures of the biochemistry and biology of disease as the critical information in understanding, diagnosing and treating the biology of disease, and it does this safely and effectively in patients.

Academic and commercial PET scanners are being invented to improve spatial resolution,image quality and shorten the scan time. The invention of the EXPLORER Total-Body PET/CT scanner by Simon Cherry and Ramsey Badawi at UC Davis has been commercialized by a Chinese company, United Imaging Healthcare. This system provides dramatic increases in detection efficiency, spatial resolution, short scan times, and allows the entire human body to be imaged at once. Their initial commercial system developed in 2019, and was 40 times more efficient than other commercial PET/CT scanners available at that time. The United Imaging system is now FDA-approved and can provide images of the total body in a matter of a few seconds to minutes. This has inspired GE Healthcare and Siemen Healthineers to also develop new PET/CT scanners with increased body coverage, higher efficiency and spatial resolution and shortened scan times.

Interview Questions for Kári Stefánsson, CEO of deCODE Genetics

1. Focus on Ongoing Projects:

Can you share details about a current project at deCODE that excites you the most, whether in multiomics or another area of research? What specific findings or innovations do you think will have the biggest impact on clinical practice in the near future?

Our general approach to the study of human health and disease has been to focus the biological foundations of human diversity. Human diversity begins with the diversity in the sequence of nucleotides in the genome but the environment makes significant contributions to it, not only through the selection component of evolution but also by interacting with the genomes of individuals from their conceptions to their deaths. Recently we have been putting emphasis on the study of interactions of variants in the sequence of the genome with other variants in the sequence (epistasis) as well as with environmental factors. It has proven difficult to document these interactions that are inevitable in part because of lack of power. We have however found a way that makes it easier at least for some categories of interactions and it goes as follows: Usually when people are searching for variants in the sequence that correlate with quantitative traits they look for variants that correlate with the mean. If instead of that you look for variants that correlate with variance in the quantitative trait (some with the allele have low value and others have high value) it inevitably means that the variant is interacting with something else, either another variant or a component of the environment. This approach has allowed us to find variants in the genome that interact with components of food that through the interaction influence risk of diseases. We have, for example, found a variant in the sequence that interacts with a diet item that is called oily fish in the UK biobank in such a way that if you carry the minor allele it leads to elevation in cholesterol but does not affect it if you are a non-carrier. We have also found a variant in an other gene that interacts with alcohol in such a way that if you are a carrier your level of non-HDL cholesterol and hence your risk of coronary artery disease is inversely correlated with your alcohol consumption. I believe that our ability to map in detail the interactions between the genome and environment (food and othe lifestyle) is going to have a major impact on clinical practice in the near future. It is going to allow us to use the sequence of our genomes to craft a personal lifestyle that is good for our health.

2. Addressing Current Challenges:

deCODE’s work in population genetics has been groundbreaking, but translating population-level insights into individual treatments can be complex. What is one specific challenge you’re addressing in this area, and what solutions or methodologies are you exploring to overcome it?

I do not disagree with the opinion that it is a formidable task to translate insights from population level genetics into individual treatments. However there are no other types of insights that offer more opportunities to do so. When we find an association of a variant in the sequence of a gene that affects the risk of a disease and we can determine whether the risk allele is a gain or a loss of function the gene product is a reasonable candidate for a drug target. When we find a target in this way and we combine the genetics with proteomics and/or transcriptomic it almost invariably comes with  biomarkers of target engagement, pharmacodynamic effect, and disease progression that can become a biomarker of regression upon treatment. We have already discovered such targets that are engaged by compounds that are now in clinical development. The limiting resource in this work is access to large enough amount of sequence data to allow for the discovery of very rare variants and access to sequence data from other populations than the ones of European descent. We are relentlessly sequencing genomes from extremely well phenotyped populations and we have begun sequencing large number of African genomes.

3. Data Scalability and Clinical Translation:

deCODE has access to one of the most comprehensive genetic databases. How are you leveraging this vast amount of data to accelerate the clinical translation of genetic research into real-world healthcare? Are there any specific tools or frameworks you’re developing to ensure scalability and practical implementation in clinical settings?

We are participating in an attempt to use all of the genetic data we have generated on Icelanders that includes insight into genotypes of the entire nation and whole genome sequence of a large proportion of the nation in the implementation of precision medicine. This could be looked upon as a clinical trial of the translation of genetic reserch into real-world healthcare.

4. Future Visionary Direction:

Looking ahead 5-10 years, which emerging technologies or methodologies in genetic research are you most excited about, and how do you see them shaping the future of precision medicine?

The amount of genetic data that will be available in 5 to 10 years will dramatically change the nature of the field. The application of artificial intelegence (AI) to the analysis of data on sequences of millions of genomes, and of transcriptomics and proteomics data  from tens of millions of serial samples with focus on multimodal analysis will be a game changer.  Furthermore, AI analysis of clinical images will allow for the discovery of much more phenotypic details from both normal tissues and tissues undergoing pathogenesis of diseases. All of this is going to lead to avalanches of discoveries and much more accurate understanding of the contribution of genetics versus environment (lifestyle) in the pathogenesis of diseases and maintenance of health. I also expect that within this time frame the application of multiomic understanding of disease and health will have made it into the delivery of healthcare. The most effective way to accomplish this will be through aps that allow the individual to download all of the information available on their own healthcare (electronic medical records, data from wearable devices etc) and provides the option to buy genomic sequencing and transcriptomics and proteomics measurements. This would be accompanied by analytical software to turn these data into risk assessments. This would not only allow for the application of genetics to healthcare but empower the individual to become her or his own primary healthcare provider. The data generated thorough this type of healthcare would allow for much more specific genetic research into both heath and disease.