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Thomas Seoh
Chief Executive Officer of Kinexum
ThomasSeoh@Kinexum.com
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Welcome to the Summer 2021 edition of Kinexions! In addition to articles by Kinexum oncology experts Peter Lenahan and Jerry Huang, we feature articles on our theme of Metabesity, which focuses on prevention, not just treatment, of chronic diseases...
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How the COVID Pandemic is Transforming Clinical Research & Development
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Peter Lenehan, MD, PhD
Kinexum Consultant
PeterLenehan@Kinexum.com
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The COVID-19 pandemic poses a significant challenge for clinical research and development (R&D), worldwide. Consequent to travel restrictions, social distancing, adherence to personal hygiene, limitations on follow-up visits, personnel’s hospital access, etc., nearly 80% of respondents to a global poll in April 2020 declared that the pandemic adversely affected the initiation of new trials and nearly 70% claimed that it significantly interfered with the conduct of ongoing trials [1]...
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Alzheimer’s disease, a new label extension for diabetes drugs?
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Sam Collaudin, PhD, JMBA
Kinexum Business Strategy Consultant
SamCollaudin@Kinexum.com
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After intensive and successful research leading to new indications for diabetes drugs, such as SGLT-2s and GLP-1s in cardiovascular and kidney diseases in patients with and without diabetes, we start to see a revival of interest in diabetes drugs for neurological diseases, such as Alzheimer’s or Parkinson’s. The recent initiation of a Phase 3 program from Novo Nordisk with their oral semaglutide (Rybelsius®) in Alzheimer’s disease is a key milestone in this direction...
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Symposium Summary: Defining a National Research Vision Targeting the Biology of Aging
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Elijah "EJ" Abass
Kinexum Associate
ElijahAbass@Kinexum.com
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On May 7th, 2021, the Uniformed Services University of Health Sciences (USUHS) held a joint science symposium with the National Institute on Aging (NIA) and the University of South Carolina titled, “Defining a National Research Vision Targeting the Biology of Aging to Optimize Human Performance, Healthspan, and Lifespan.” The workshop brought together those involved in healthcare and therapeutic development, including individuals from academia, government, industry, and the not-for-profit sector...
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Interview with Dr. Sam Collaudin
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Sam Collaudin, PhD, JMBA
Kinexum Business Strategy Consultant
SamCollaudin@Kinexum.com
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Sam Collaudin is a Kinexum business strategist for drug and device biotech companies specialized in diabetes and metabolic diseases. Sam, who is French and based in Germany near the border with France, is trained in mathematics, biology and business. In addition to corporate strategic advice, Sam provides valuations and commercial assessments of product candidates in this space to guide fundraising, portfolio planning and business development for emerging companies. He currently works with different biotech companies and CMOs to help them understand diabetes patient needs, realize forecasting and prepare product launches...
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G. Alexander "Zan" Fleming
Founder & Chairman of Kinexum
ZanFleming@Kinexum.com
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One of the most gratifying developments at Kinexum over the past decade is the firm’s growing involvement in cutting-edge oncology treatments and diagnostics. Articles by two colleagues who have recently joined us reflect this expansion...
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Oncology therapeutic development today: Overcoming the challenges of cancer with science
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Jerry Huang, MD, PhD
Kinexum Consultant
JerryHuang@Kinexum.com
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Cancer remains a deadly disease. In 2021, approximately 1.9 million new cancer cases are expected and about 608,570 Americans are expected to die of cancer (1). Despite the advancement of new anti-cancer drugs, including the next generation of chemotherapy in the form of antibody-drug conjugate (ADC), targeted therapy and immunotherapy, cancer is difficult to treat and cure....
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The Kitalys Institute: Taking the Moonshot for a National Policy on Increased Healthspan for All
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Adriane Berg, JD
Executive Director, Kitalys Institute
AdrianeBerg@Kitalys.org
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From its inception in February 2020, The Kitalys Institute has been touched by history. Days after its launch, Covid-19 forced the world to focus on how to age stronger and prevent the comorbidities that robbed hundreds of thousands of our older citizens of their very lives. The idea of intervening in the aging process itself, rather than treating individual diseases of aging, was long the vision of Dr. Zan Fleming, Founder of Kinexum and the Chairman of Kitalys...
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Webinar Recap: The Dog Aging Project
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Elisabeth "Brontë" Jenkins
Kinexum Associate
BronteJenkins@Kinexum.com
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On Friday, May 7th, the Kitalys Institute hosted a webinar entitled, The Dog Aging Project: extending the lives of “man's best friend” and supporting the quest to increase human healthspan, which featured Matt Kaeberlein, PhD, Professor of Laboratory Medicine and Pathology at the University of Washington (UW) School of Medicine and the Founder and Co-Director of The Dog Aging Project (DAP). DAP aims to understand how genes, lifestyle, and environment influence aging in order to assist both pets and people in increasing their healthspans, the period of life spent free from disease...
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Continuation of the Above Articles
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A Note from the CEO (cont.)
...Sam Collaudin asks whether diabetes drugs that have now shown efficacy in decreasing risk of cardiovascular diseases could be developed for Alzheimer’s disease. We present summaries of our most recent webinar, on the Dog Aging Project, a 10 year study of aging in “man’s best friend,” and agents that may slow their aging, and an important policy colloquium for supporting pursuit of healthy longevity sponsored by the National Institute on Aging and the Uniformed Services University of the Health Sciences, as well as a report on progress at the Kitalys Institute by Executive Director Adriane Berg.
The ‘healthy longevity for all’ movement, of which Kitalys is a part, is entering the zeitgeist. For example, New York Times editorialist David Brooks published a piece on June 3, 2021 providing visibility to advances in geroscience over the past couple decades that are moving, delaying, and even reversing, biological aging from the realm of science fiction into actuality. However, a number of readers commenting on that editorial said ‘no thanks’ to living to an old age in which they are debilitated by multiple serious chronic illnesses. What the public does not yet fully appreciate is that the vision of healthy longevity is not of a nonagenarian in a wheelchair with dementia, but today’s healthy, active 50- or 60-year-old, living an independent, alert, engaged life, until slipping gracefully away while asleep past the century mark.
Achieving ‘healthy longevity for all’ would have major implications for work, personal and public finance, health equity, intergenerational relations and beyond. However, it would also result in vast savings for public and private healthcare expenditures and a huge economic opportunity (to market to a growing segment of active elders), address a root cause of health inequity (differential access and treatment of the disadvantaged for chronic illnesses and conditions), and support a ‘wisdom’ culture that values the elderly as assets, not liabilities. Learn more by attending our virtual Metabesity 2021 conference in October!
- Thomas Seoh
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A Note from the Chairman (cont.)
Drs. Peter Lenehan and Jerry Huang are both physician scientists with decades of experience in wide varieties of oncologic therapeutic areas, in large and smaller organizations. Peter has recently been involved in cancer diagnostics as well as therapeutics. Jerry brings a unique combination of experience in Asia Pacific and western companies, which forms a valuable bridge for global therapeutic development.
Their articles are likewise complementary in addressing two of the major crucibles for oncology therapeutic development—ground-breaking basic science and the Pandemic. The former is revolutionizing how we develop cancer therapies and individualize treatment. The latter has led to changes in how we do clinical trials that benefit all therapeutic areas including, but not limited to, oncology.
Little did my friend and colleague at FDA and fellow Kinexer, Dr. Grant Williams, and I realize in the early 1990’s that our respective fields were about to explode. As clinical reviewers in the oncology and endocrine/metabolic divisions, we had enough time to meet once a week over breakfast with other colleagues to plot ways of advancing drug review at FDA. Many of those efforts resulted in innovations that persist to this day, but that is another story. Our respective FDA divisions subdivided and expanded—pulled along by the proliferation of products yielded by cataclysmic scientific and technological advances.
Today, it is very hard to keep up with all that is going on in the many different areas of oncology therapeutic and diagnostic development. We are delighted to have Jerry and Peter join our oncology practice to help us do that. Kinexers are excited to support programs across the major therapeutic modalities—conventional pharmaceuticals, monoclonal antibodies, advanced therapies, devices, and even nutritional approaches. We are also keenly interested in cancer prevention as part of targeting Metabesity. Cancer, along with the major chronic diseases—diabetes, cardiovascular and neurodegenerative diseases and the aging process itself—form the constellation of conditions that we refer to as Metabesity. Read on!
To your health!
- Zan Fleming
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How the COVID Pandemic is Transforming Clinical Research & Development (cont.)
... Amongst those pharmaceutical and biotechnology companies that have faired the best over the past year are those that have adopted the concept of ‘Democratization of Research’, i.e., fostering a culture where decisions and clinical trial designs are largely based on potential participant insights [2]. The success of such patient-centered R&D was most prominently displayed by Moderna and Pfizer during the unprecedented rapid development of their respective COVID-19 vaccines. Abandoning the traditional models for conducting clinical research, both companies embraced decentralizing their trials and reducing the complexity of their protocols. These multi-frontal efforts included:
- Streamlining study design by relaxing eligibility criteria and removing ‘nice-to-have’ outcome measures from protocols
- Using central Institutional Review Boards/Ethics Boards that conducted online committee reviews
- Employing electronic consent and patient-reported outcomes (ePRO), including the collection of real-time objective data, e.g., blood pressure, heart/respiratory rates, and ECG, using at-home wearable sensors
- Incorporating remote follow-up visits, i.e., ‘telemedicine’, which helped alleviate the adverse impact of clinic closures
- Allowing remote clinical monitoring
- Creating a hybrid model for data collection, i.e., establishing study sites not only at centralized universities and hospitals, but also in neighborhood clinics, as permitted by what data needed to be collected.
The latter innovation appeared to destigmatize the clinical trials and enhance engagement with socially marginalized groups by fostering interaction with investigators who understood them culturally and community leaders who encouraged participation.
While a sense of urgency during the COVID-19 pandemic likely encouraged the design and conduction of efficient clinical studies, especially for vaccine development, establishing this as the new normal for future clinical research — in a post-COVID world — and in other medical disciplines, demands a focused effort. To this end, the US FDA and Duke University have recently co-founded ‘The Clinical Trial Transformation Initiative’ (CTTI) [3]. Its aim, ‘Transforming Trial 2030’, is to demonstrate and convince stakeholders how clinical trials should be done in 2030. This initiative incorporates 5 pillars and reflects the proven successes achieved during the COVID-19 pandemic:
- Clinical trials are patient-oriented and easily accessible.
- Home trials, hybrid trials, and technologies are maximally used to allow all potential participants to take part regardless of geography and mobility and to maximize efficiency and minimize costs.
- Clinical trials are fully integrated into health processes.
- Healthcare systems and health plans are involved in planning studies and support the integration of trials into regular clinical practice.
- Clinical trials are designed with a quality approach.
- Clinical trials address clear and meaningful scientific questions that are determined with the input and consideration of those who will use the results.
- Innovative trial designs (e.g., statistical approaches) will continue to be developed and used to conduct clinical trials more efficiently and effectively. To this end, especially in oncology, clinical trial efficiency and participation can be enhanced by using ‘umbrella’ and ‘basket’ trial designs [4]. Whereas ‘umbrella’ trials test how well new therapies work in patients with the same type of cancer but with different gene mutations or biomarkers, ‘basket’ trials test how well therapies work in patients with different types of cancers with the same gene mutations or biomarkers.
- Clinical trials maximally leverage available clinical and nonclinical data, including data collected via digital technologies, to minimize collection of necessary trial-specific data.
- Data platforms support multiple clinical trials, rather than being built for individual studies.
- Data standards and definitions are in place within interoperable systems to support integration of data from various sources.
- Clinical trials contribute knowledge about how to prevent, diagnose, and treat disease, and are one of many sources of information that can be acted upon to improve population health.
- New medical products are available to healthcare providers and patients more quickly and efficiently than today.
- With less expensive and more efficient clinical trials, more studies and other types of research are done to answer the questions most important to patients.
Achieving these goals is not without its challenges. Some of these and their possible solutions are detailed in the American Society of Clinical Oncology’s (ASCO’s) 2021 ‘Road to Recovery Report: Learning from the COVID-19 Experience to Improve Clinical Research and Cancer Care’ [5]:
- Telemedicine
- Expanded financial coverage will be required for telemedicine visits that might include the need for certification of professional providers of such services. Notably, in response to the COVID-19 pandemic, the Centers for Medicare and Medicaid Services and some local commercial payers have already proactively modified their payment policies for telemedicine visits [6].
- To help close the ‘digital divide’ between lower and higher income patients, there will need to be a concerted effort, ideally supported by federal legislation, to expand high-speed broadband coverage and help low-income patients gain access to computers and/or smartphones.
- Regulatory Authorities
- Regulatory authorities will need to adopt a sense of flexibility and urgency that is defined by more specific written guidelines as to what will be and what will not be acceptable for approval of a protocol or investigational compound.
- Research & Development (R&D) organizations
- R&D organizations that mounted the most successful responses to the COVID-19 pandemic – and, therefore, will likely to be most competitive going forward post-COVID -- are those that have a flatter structure and, hence, are less hindered by bureaucracy when quick decisions are needed to be made by study teams.
- Access to Clinical Research
- Maximizing the speed of enrollment of a diverse population of patients in clinical studies will necessitate providing a financial safety net for those who would otherwise be excluded. In the US, this includes Medicaid expansion as well as access to affordable and comprehensive insurance plans. ASCO has joined numerous other organizations in urging the US Congress to pass the bipartisan ‘Clinical Treatment Act’ (HR 913 – 116th Congress, 2019-20) which would guarantee coverage of the routine care costs of clinical trial participation for Medicaid enrollees with life-threatening conditions [4].
Predictive analytics
Predictive analytics is the use of data, statistical algorithms, and artificial intelligence (AI) techniques to identify the likelihood of future health outcomes for individuals or populations based on historical patient information. It is amongst the key technologies that are increasingly being used to increase clinical trial efficiency, enable patient-centric R&D, and stay competitive in many therapeutic areas. It is particularly well-positioned to make sense of electronic health records and derive meaningful information in data-rich fields like oncology [7]. As stated in ASCO’s ‘Clinical Cancer Advances 2021: ASCO’s Report on Progress Against Cancer’, the development and integration of artificial intelligence and ‘deep learning’ into cancer research is amongst ASCO’s highest priorities [4].
So… what is AI and why does it garner such high priority? AI leverages computers and robust datasets to enable problem-solving [8]. It encompasses the sub-fields of ‘machine-learning’ and ‘deep learning’, the latter being a subset of machine-learning and comprised of a series of neural networks (see accompanying figure).
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My own research in AI has focused on generating cancer-specific prognostic algorithms derived from genome-wide expression profiles using ‘genetic programming’, an additional subset of machine-learning separate from deep learning. Mimicking Darwinian evolution, a genetic pool of candidate classification programs is created by randomly choosing inputs together with arithmetic and Boolean operators that work with these inputs. Successive generations of classification programs are then evolved through further selection and recombination. Ultimately, evolution is driven to a maximum by improving accuracy to yield results with high sensitivities and specificities. Using this technique, we have successfully generated algorithms that use a minimum number of key genes to predict the risk of recurrence of early-stage colorectal cancer [9] and non-muscle invasive bladder cancer [10].
The ability to risk-stratify patients based on the propensity for recurrence of their cancers will go far for streamlining and expediting clinical trials of investigational agents by targeting those patients who will most benefit from receiving such treatment. AI-enabled technologies will not only benefit oncology but have the potential to offer advantages in a wide variety of therapeutic areas, ranging from quicker and smarter interpretation of radiographs and dermatologic images to generation of smarter wearable sensors that will be needed for one to be competitive in the post-COVID-19 world of personalized medicine.
References
1. Sathian et al. Impact of COVID-19 on clinical trials and clinical research: A systemic review, Nepal J Epidemiol 2020; 10(3):878-887; https://doi.org/10.3126/nje.v10i3.31622
2. Li et al. Digitized adaptation of oncology trials during and after COVID-19. Cancer Cell 2020; 38:148-149; https://doi.org/10.1016/j.ccell.2020.06.018
3. Transforming Trials 2030. Clinical Trials Transformation Initiative; FDA and Duke University; https://www.ctti-clinicaltrials.org/transforming-trials-2030
4. Smith et al. Clinical Cancer Advances 2021: ASCO’s Report on Progress Against Cancer. JCO 39(10):1165-1186; https://doi.org/10.1200/JCO.20.03420
5. Pennell et al. American Society of Clinical Oncology Road to Recovery Report: Learning From the COVID-19 Experience to Improve Clinical Research and Cancer Care. J Clin Oncol 2021; 39:155-169; https://ascopubs.org/doi/10.1200/JCO.20.02953
6. Hollander et al. Virtually perfect? Telemedicine for COVID-19. NEJM 2020; 382(18):1679-1681; https://doi.org/10.1056/NEJMp2003539
7. Parikh et al. Using big data and predictive analytics to determine patient risk in oncology. 2019 ASCO Educational Book; https://ascopubs.org/doi/pdf/10.1200/EDBK_238891
8. IBM Cloud Learn Hub (2020). Artificial Intelligence (AI); https://www.ibm.com/cloud/learn/what-is-artificial-intelligence
9. Lenehan et al. Generation and external validation of a tumor-derived 5-gene prognostic signature for recurrence of lymph node-negative, invasive colorectal carcinoma. Cancer 2012; 118(21):5234-5244; https://doi.org/10.1002/cncr.27628
10. Bartsch et al. Using artificial intelligence and machine learning algorithms with gene expression profiling to predict recurrence of nonmuscle invasive urothelial carcinoma of the bladder at initial presentation. J Urology 2016; 195(2):493-498; https://doi.org/10.1016/j.juro.2015.09.090
- Peter Lenehan
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Oncology therapeutic development today: Overcoming the challenges of cancer with science (cont.)
...Hanahan and Weinberg (2) described the 10 hallmarks of cancer cells, which make cancer a daunting target:
1. Sustaining proliferative signaling
2. Evading growth suppressors
3. Resisting cell death
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Activating invasion and metastasis
7. Deregulating cellular energetics
8. Evading immune destruction
9. Genomic instability
10. Tumor promoting inflammation
In addition, there is substantial crosstalk between cancer cells and a complex mixture of signals from other cells in the tumor microenvironment. Any genetic aberrations, such as mutation, amplification and translocation, may lead to the deregulation of one or multiple intracellular signaling pathways.
The complexity of cancer biology is reflected in the low success rate of 3.4% for an oncology drug from first-in-human clinical trial to regulatory approval compared to the overall success rate of 13.8% in other therapeutic areas (3). Started in the late 1990s, biomarker-driven targeted therapy has taken center stage in oncology drug development. From tamoxifen and aromatase inhibitors in ER over-overexpression breast cancer; trastuzumab and lapatinib in HER2 amplified breast cancer; cetuximab and panitumumab in colorectal cancer with wild type KRAS; to gefitinib and erlotinib in NSCLC with EGFR amplified or mutation. This type of personalized or precision medicine has been a game-changer in the field of oncology drug development and cancer patient care. It aims the right medicine for the right patient at the right time.
In recent years, oncology drugs in tissue agnostic therapies that target multiple tumor types with unique key oncogenic drivers have received FDA approval, including pembrolizumab for multiple tumor types with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017; larotrectinib for NTRK gene fusion tumors in 2018; and entrectinib in adult and adolescent cancer patients with NTRK gene fusion in 2019. These innovative approaches have transformed patient selection in oncology drug development and cancer treatment. The success of precision medicine depends on the nature of the biomarker and the validity of the diagnostic. Whether the biomarker is an oncogenic driver versus a passenger gene or whether the gene aberration represents overexpression, amplification, mutation or fusion, the selected biomarker is the key for the development of the cancer drug and the companion diagnostic assay or device. Another key ingredient for success is to identify early in clinical development the partner for co-development who can achieve concurrent regulatory approval of the companion diagnostic device (CDx) and the therapeutic.
The impact of molecular biomarker testing is growing in the oncology therapeutics market. Biomarker-driven drugs in development pipelines are increasing. Many breakthrough therapies and breakthrough device designations are in oncology. In the US, precision medicines represented 5% of new therapy approvals in 2005. That proportion increased to 25% in 2019 (4). Some CDxs for anti-cancer drugs are listed in the Table:
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Advances in technologies and clinical science have created opportunities to tailor health care and guide treatment decisions for each patient. Oncology drug development and cancer treatment continue to evolve from a single treatment regimen for patients with the same diagnosis to personalized medicine, based on specific genotypes or other markers, resulting in greater benefit to each patient.
References:
1. Cancer facts & figures 2021. American Cancer Society.
2. Hanahan and Weinberg. 2011. Cell. Hallmarks of Cancer.
3. Chi Heem Wong, Kien Wei Siah, Andrew W Lo. "Estimation of clinical trial success rates and related parameters." Biostatistics 20(2): April 2019, Pages 273-286. Published online: 31 January 2018.
4. The Personalized Medicine Report. 2017. Opportunity, Challenges, and the Future.
- Jerry Huang
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Alzheimer’s disease, a new label extension for diabetes drugs? (cont.)
...Alzheimer's is the most common cause of dementia (about 60-80% of dementia cases) which affects memory, thinking, and behaviour to a point that can interfere with daily tasks and lead to death. It is known to be the 6th cause of death in the United States (diabetes is the 7th) [1]. Type 2 diabetes (T2D) and related diseases such as NASH and obesity are known to be linked with an increased risk of Alzheimer’s [2-5]. T2D and Alzheimer’s also have common features, including the accumulation amyloid-beta (Aβ) plaques and hyperphosphorylation of tau in, respectively, the pancreas and the brain inducing inflammation [6]. These common features between diabetes and Alzheimer’s lead researchers to call Alzheimer’s disease ‘Type 3 Diabetes’ [7]. Alzheimer’s is maybe not seen as an important comorbidity for diabetes patients today, but it is a significant disease with little to no efficient treatments. It could become a differentiation factor for certain diabetes drugs or class of drugs, and a way to expand the use of these drugs as it is the case today with cardiovascular and renal label extensions for SGLT-2s and GLP-1s.
Alzheimer’s treatments: many drugs failed to demonstrate medical benefit during late clinical development.
What causes Alzheimer’s disease (AD) is not well known, but numerous research studies correlate AD with the formation of amyloid-beta plaques that can disrupt neural cell functions and the accumulation of the protein tau forming neurofibrillary tangles. Today, no efficient treatments are on the market, and pharmaceutical and biotech companies are trying to develop new treatments with mixed results. The main strategy of the past decades was to target beta-amyloid plaques; however, it resulted in almost no success in Phase 3 clinical trials. Both Eli Lilly with solanezumab and Pfizer with bapineuzumab failed to show significant improvement in Phase 3. Moreover, Biogen finished FDA submission last summer of aducanumab following mixed results of their Phase 3 program. This drug is still in the FDA review process, but received a strong disapproval from the FDA advisory committee the 6th of November, 2020 and the PDUFA date was recently postponed to the 7th of June, 2021. Other projects are in development that target beta-amyloid plaques, tau proteins, or other pathways, but for many reasons, the threshold to demonstrate significant clinical benefit is high. A Dartmouth College, Emergency Medicine physician wrote an opinion piece on why he believes it is difficult to develop a new treatment for AD (https://massivesci.com/articles/alzheimers-cure-lifetime-brain-neuro-mind-control-amyloid-tau/).
Another project came from vTv, who is developing an oral molecule called azeliragon that inhibits the receptor for advanced glycation end products (RAGE). RAGE is an immunoglobulin-like cell surface receptor that is overexpressed in brain tissues of patients with AD, both linked to diabetes complications and beta-amyloid plaques. vTv first failed to demonstrate positive medical benefit of azeliragon in a general mild AD population during the STEADFAST clinical trial [8]. In a subgroup analysis, they identified potential benefit in patients with both AD and T2D, and started a Phase 2 trial in patients with mild AD and T2D, but recently released mixed results. There was also a 6 month placebo-controlled trial in n=43 patients, with a decline from baseline of the ADAS-cog14 assessment scale of 1.8 point with 5mg of daily azeliragon vs 0.35 point for placebo, without statistical significant difference. The program was discontinued for Alzheimer’s, and vTv is currently looking at new indications including prevention of T1D [9].
Interest in diabetes drugs to slow down Alzheimer’s progression.
Novo Nordisk is not the first one to study the potential effect of a diabetes drug in AD. Below, I will review a few ongoing or past clinical research programs with PPAR-gamma, metformin, pramlintide and GLP-1s.
PPAR-gamma
GSK did a large Phase 3 program called REFLECT with rosiglitazone, in patients with mild to moderate AD starting in 2006 [10-12]. Rosiglitazone, commercialized under the name of Avandia®, was largely used in the early 2000s before the demonstration of a potential increase of heart attacks. The reasoning behind this research was that insulin resistance is proposed as a potential underlying mechanism leading to AD and that PPAR-gamma increases glucose sensitivity [13]. Another argument was that rosiglitazone effect was linked to apolipoprotein E e4 allele status, suggesting the potential effect of rosiglitazone on a genetically defined subset of patients with mild to moderate AD [14]. The Phase 3 program was also based on a positive pilot study conducted by Watson et al [15]. However, all three trials could not demonstrate statistically significant improvement of cognition and further development was stopped [16, 17].
The National Institute on Aging, in collaboration with Takeda, also investigated the potential benefit of another PPAR-gamma, pioglitazone (Actos®) in a Phase 2 trial [18] with no significant treatment effects [19].
Metformin
Columbia University started to investigate the effect of metformin on cognitive impairment with a Phase 2 trial in 2008 [20]. They based their research on the link between hyperinsulinism and AD, and the known effect of metformin on reducing hyperinsulinism. This small trial couldn't demonstrate statistical benefit of metformin, possibly because of the small size of the trial (n=80) [21]. They concluded with the need to do a larger clinical trial that started in March 2021, results are expected in April 2025 [22].
Pramlintide
Some research works have demonstrated that Alzheimer’s disease is correlated with a lower plasma concentration of human amylin. Based on these observations, pre-clinical work has been done to understand the potential neuroprotector effects of amylin analogues, such as pramlintide, and their effect on beta-amyloid plaque accumulation [23]. Amylin analogues are part of new R&D projects to improve diabetes control and induce weight loss, with different programs of insulin and pramlintide fixed combinations (i.e., by Adocia, Arecor and Xeris) or with long acting amylin analogues such as Cagrilintide from Novo Nordisk. Adocia is the only company that publicly showed an interest in studying the potential benefits of its drugs in Alzheimer’s patients.
GLP-1
Different studies have been done to try to demonstrate the positive effect of GLP-1 in AD with different GLP-1s, such as exenatide and liraglutide.
The National Institute on Aging started a Phase 2 trial in 2016 to study the potential benefit of exenatide in AD [24]. It has been demonstrated in pre-clinical studies that exenatide could prevent the development of Alzheimer’s, particularly by decreasing levels of hippocampal IRS-1pSer and activated JNK that are induced by Aβ plaques accumulation. During this trial (n=21 patients with early stage AD or mild cognitive impairment, double-blind, placebo-controlled, during 18 months), they couldn't demonstrate cognitive improvement nor other clinical indicators expecting a significant reduction of Aβ42 in extracellular vesicles [25].
The University of Aarhus did another pilot clinical trial with liraglutide [26] in n=38 patients with AD, placebo-controlled, during 26 weeks. They demonstrated the prevention of CMRglc decline, a marker of AD progression, but couldn't demonstrate benefit on cognition nor on Aβ load [27]. In parallel, the Imperial College of London studied the impact of liraglutide in patients with mild-AD in the Phase 2b ELAD study [28, 29] with more patients (n=204), double-blind, placebo-controlled, during 12 months. This study finished in early 2020, with first results presented at the CTAD meeting in November 2020. The trial didn't show differences on the cerebral glucose metabolic rates, but some other markers were numerically better [30].
Despite ELAD results, and based on real-world data and post-hoc analysis of large CV trials with liraglutide and semaglutide, Novo Nordisk recently initiated a Phase 3a clinical trials program to test their oral semaglutide (Rybelsius) in AD patients (EVOKE and EVOKE Plus trials) [31-33]. They expect to recruit 3,680 patients with early AD that will be treated with 14 mg of oral semaglutide or placebo during about 2 years with an extension phase of 1 year. The only differences between the two studies are the addition of two secondary outcomes in EVOKE Plus to measure AD progression (ADAS-Cog-13 and MoCA) and one less exclusion criteria. Results are expected between 2024 and 2025. These first major clinical trials with a GLP1 should help the community have better knowledge of the impact of such drugs on AD.
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Other diabetes drugs could also be interesting in helping prevent AD. For instance, the use of insulin through nasal spray with ongoing work [34].
Today, only Novo Nordisk is strongly committed to studying their drugs in Alzheimer’s patients, but it may open a new dynamic of research and influence other companies with similar drugs, such as Eli Lilly, to do the same.
*Addendum following breaking development while this article was in press:
Aduhelm (aducanumab) has been approved to treat patients with Alzheimer's disease by the FDA on the 7th of June under the accelerated approval pathway. It is the first therapy approved for patients with Alzheimer's disease since 2003. In a press release, the FDA recognized the mixed results obtained during the Phase 3 program but mentioned that these trials demonstrate that aducanumab reduces amyloid plaques and that "this reduction in plaques is reasonably likely to result in clinical benefit". This approval has been seen by part of the community as a positive sign for treatments targeting amyloid plaques, for instance, Eli Lilly's shares, which is developing a similar drug, increased by more than 10%. Nevertheless, regulatory approval is not a clinical validation of the amyloid approach. The FDA clearly announced that Biogen needs to conduct additional post-approval studies to verify aducanumab's "anticipated clinical benefit". Biogen announced that the drug will be priced at about $56,000 per year; with this relatively high price, it is difficult today to estimate its adoption, or its effect on the urgency for other approaches to Alzheimer's disease.
References:
1. National Vital Statistics Reports. CDC. 2017
2. Crane PK et al. Glucose levels and risk of dementia. N Engl J Med. 2013
3. Loef & Walach. Midlife obesity and dementia: meta-analysis and adjusted forecast of dementia prevalence in the United States and China. Obesity. 2013
4. Estrada et al. Liver Dysfunction as a Novel Player in Alzheimer’s Progression: Looking Outside the Brain. Front Aging Neurosci. 2019
5. Mondal et al. Lipocalin 2 induces neuroinflammation and blood-brain barrier dysfunction through liver-brain axis in murine model of nonalcoholic steatohepatitis. J Neuroinflammation. 2020
6. Miklossy et al. Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes. Neurobiol Aging. 2008
7. Kandimalla et al. Is Alzheimer’s disease a Type 3 Diabetes? A critical appraisal. Biochimica et Biophysica Acta. 2017
8. https://clinicaltrials.gov/ct2/show/NCT02080364
9. https://www.globenewswire.com/news-release/2020/12/15/2145823/0/en/vTv-Therapeutics-Announces-Topline-Results-of-Phase-2-Elevage-Study-of-Azeliragon-in-Patients-with-Mild-Alzheimer-s-Disease-and-Type-2-Diabetes.html
10. https://clinicaltrials.gov/ct2/show/NCT00428090
11. https://clinicaltrials.gov/ct2/show/NCT00348309
12. https://clinicaltrials.gov/ct2/show/NCT00348140
13. de la Monte SM. Insulin resistance and Alzheimer's disease. BMB. 2009
14. Risner ME et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 2006
15. Watson GS et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry. 2005
16. Harrington et al. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. Curr Alzheimer Res. 2011
17. Gold et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010
18. https://clinicaltrials.gov/ct2/show/NCT00982202
19. Geldmacher DS et al. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol. 2011.
20. https://clinicaltrials.gov/ct2/show/NCT00620191
21. Luchsinger et al. Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J Alzheimers Dis. 2016.
22. https://clinicaltrials.gov/ct2/show/NCT04098666
23. Adler et al. Neuroprotective effects of the amylin analogue pramlintide on Alzheimer's disease pathogenesis and cognition. Neurobiol Aging. 2014
24. https://clinicaltrials.gov/ct2/show/study/NCT01255163
25. Mullins RJ et al. A Pilot Study of Exenatide Actions in Alzheimer's Disease. Curr Alzheimer Res. 2019.
26. https://clinicaltrials.gov/ct2/show/NCT01469351
27. Gejl M et al. In Alzheimer's Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front Aging Neurosci. 2016.
28. https://clinicaltrials.gov/ct2/show/NCT01843075
29. Femminella GD et al. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study). Trials. 2019
30. https://www.evaluate.com/vantage/articles/news/snippets/ctad-2020-elad-fails-glp-1s-could-still-have-future-alzheimers
31. https://clinicaltrials.gov/ct2/show/NCT04777396
32. https://clinicaltrials.gov/ct2/show/NCT04777409
33. https://www.novonordisk.com/content/dam/nncorp/global/en/investors/irmaterial/investor_presentations/2020/AD-conference-call-16-December-2020.pdf
34. https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-minute-is-alzheimers-type-3-diabetes/
- Sam Collaudin
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The Kitalys Institute: Taking the Moonshot for a National Policy on Increased Healthspan for All (cont.)
...However, Covid-19 provided the tipping point needed to escalate that vision to a national effort.
The Kitalys Mission is to translate the acceleration of scientific breakthroughs into public policies that will increase our healthy years, not just our longevity. We see a future with fewer of us suffering from chronic diseases or withdrawing into continued decline.
When the Institute was launched, Kinexum had already organized two successful Targeting Metabesity Conferences in 2017 in London and 2019 in Washington DC. These conferences furthered the goal of healthy longevity by bringing together geroscientists, payers, policymakers, academics, and many other stakeholders in healthy longevity to break down silos among them and promote the conversation on Healthspan.
Our fledgling organization was on the verge of duplicating these established events for 2020 when COVID-19 struck, and everything changed. Despite an utter lack of experience with virtual events, we achieved a significant turnout of 1000 attendees, 80 speakers, and four jam-packed programming days. We also added a fourth day for the Emerging Company Showcase, during which 25 presenters dazzled us with their breakthroughs.
Dr. Fleming had long ago coined the word “Metabesity” to refer to the common causes of aging—inflammation, immune system decline, cell death, mitochondria weakening, and other measurable conditions—that cause major diseases and chronic illnesses. Our Metabesity approach calls upon targeting interventions that can delay or prevent these common causes rather than taking a disease-by-disease approach. There is no doubt that the ravages of Covid-19 were the catalyst to looking for a new way to solve infirmities of aging.
In less than one year, the Institute evolved from a brand-new nonprofit with a single annual event to a juggernaut for establishing a National Healthspan Policy in the United States. In this regard, we collaborate with multiple well-established and larger organizations such as the GSA, AFAR, Longevity Technology, Longevity UK, Life Extension Advocacy Foundation, American Mexican Retirement Association, NGO on Aging for the UN, Kings College London, Aging Analytics, Collider Health, Age Wave and many more.
Our Project Healthspan is slated for a Congressional Briefing, and we have made associations on both sides of the aisle for a significant push for a Healthspan policy. The goal of Project Healthspan is to develop clarity on the solutions to challenges of increased healthspan and help formulate regulatory and legislative packages that can be adopted in a bipartisan spirit. During COVID-19, it became clear there is a vast divide in accessibility to healthcare, nutrition, technology, and digital health that made a difference in how well individuals could manage the pandemic and keep their lives and health intact. The Kitalys Institute realized that if our Mission of increased healthspan was reached, this health boon must be available to everyone. We responded with a seemingly minor change in our Mission Statement. We added to our mission the simple words, “FOR ALL,” making our stated mission: To Take the Moonshot for Healthy Longevity For All.
With this in mind, we began two ambitious projects. We offer a slate of free webcasts that educate on various healthspan topics, including Covid-19 and aging, mitochondria, exercise, and more. Also, we are inviting all stakeholders to a Virtual Campus built to provide a private HIPPA compliant platform to network, collaborate and expose the essential issues that form barriers to greater healthspan and offer joint solutions.
On October 11-14th, we hold our next Virtual Conference, which along with the Campus are handmaidens of collaboration to achieve our mission. Register FREE at www.metabesity2021.org, and you will be eligible for admission to the Campus free of charge. The first three days will be organized around the issues that form barriers to a Healthspan Policy and the solutions. We are creating a virtual think tank for contributions from our eminent speakers and attendees alike. We are continuing the fourth day with an expanded Emerging Company Showcase and curated poster sessions. All registrants will be eligible to join our Virtual Campus, including forums and special interest groups, for year-long continued dialogue and collaboration. Our Campus has a curated library, free and open to all. We include video, audio, print, augmented reality, and graphic materials that shed light on Metabesity and related topics and move the needle toward our mission.
We say that we are taking a “Moonshot.” Why so dramatic? Currently, we approach diseases as separate and distinct events like cancer, heart attacks, and diabetes. It will be a revolutionary change in thinking and medical education to shift the view to prevention, holism, and the optimistic idea that diseases of aging often have a common cause in which we can intervene before they take hold. The mission is as much a Moonshot in changing long-held beliefs and the protocols which follow, as was reaching outer space before the first Moon landing.
We need your help. Please visit www.kitalys.org and listen to the eleven-minute video made by Dr. Fleming. It will inspire you to support us. There are several ways to do so. We offer sponsorships to our Conference and Campus at all levels of contribution; we seek volunteers with social media and press relations savvy; and we aim to expand our Collaborations to increase members of our Campus and attendees of our Conferences. We also happily accept direct donations no matter how small through our crowdfunding site found on www.kitalys.org. To learn more about sponsorship of our Conference, visit www.metabesity2021.org. And please reach out to me personally at adrianeberg@kitalys.org.
Let us take the Moonshot together.
- Adriane Berg
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Symposium Summary: Defining a National Research Vision Targeting the Biology of Aging (cont.)
...These parties discussed the advances and shortcomings within the aging biology field, as well as a potential research agenda aimed at accelerating the translation of such findings into tractable interventions for U.S. citizens. The entire recorded program is found at the conference website. As part of developing the symposium, the organizing committee, which included Kinexum’s Dr. Alexander Fleming, authored a white paper Defining a National Research Vision Utilizing the Biology of Aging to Optimize Human Performance, Healthspan and Lifespan.
The session opened with an address from Senator Chris Van Hollen of Maryland. He discussed the unity and speed of the nation’s COVID-19 mobilization effort and how the pandemic highlighted the need for improving quality of life for seniors, a demographic that composes an increasing proportion of our population. Building on current efforts, however, will require collaboration from the public, private, and non-profit sectors. A few weeks prior, Senator Van Hollen attended a bipartisan discussion hosted by President Biden covering the creation of the Health Advanced Research Projects Agency (ARPA-H), an organization that could help propel the advancement of solutions to major healthcare challenges, such as the epidemic rates of chronic disease in our country.
Dr. Charlotte Yeh, Chief Medical Officer of the American Association of Retired Persons
(AARP), then provided a patient advocate perspective on the issue of aging and healthspan, the period of life free of chronic diseases. As the nation’s largest nonprofit, AARP focuses on issues affecting those over 50 years of age, including health security, financial stability, and personal fulfillment. Dr. Yeh therefore voiced her excitement and interest in the many initiatives aimed at promoting healthy aging. Society perceives aging as a period of decline and increased dependency, and according to recent studies, greater than one-third of older adults internalize these negative stereotypes. Despite our negative conception of aging, age comes with benefits such as protection against self-reported anxiety and depression levels. Thus, AARP strives to increase the positive factors associated with aging while decreasing the negative outcomes. Such a movement provides economic benefits, as studies show that each additional protective outcome correlates with an incremental $1,356 reduction in healthcare expenditures per person. Dr. Yeh ended with a call to change the perception of aging because we should all aim to thrive in motion rather than age in place.
Dr. Ana Maria Cuervo, Chair for the Study of Neurodegenerative Diseases at Albert Einstein School of Medicine, continued the discussion with her research on autophagy, the process by which our cells degrade unnecessary or damaged components, and its role in pathogenesis of neurodegenerative disorders, primarily Alzheimer’s disease (AD). Dr. Cuervo and her team created a mathematical model that measures an individual’s rate of autophagy, and using said index, found that the rate of autophagy within mice naturally decreases with age. To their surprise, her lab found a similar reduction in mouse models with AD, suggesting that the process plays a potential role in humans’ increased susceptibility to the disease as we age. Therefore, Dr. Cuervo conducted an experiment in which she used gene therapy to preserve autophagy function in mice, and after doing so, found that it both extended their lifespan and mitigated the onset of AD. In regard to the latter, Dr. Cuervo hypothesizes that autophagy activation helps to “clean the brain” by targeting the accumulation of tau proteins. Though far from translating these findings to humans, Dr. Cuervo sees great promise in the potential of this intervention as a treatment for neurodegenerative diseases.
Next, Tom Kalil, who serves as Chief Innovation Officer at Schmidt Futures and worked within the Obama and Clinton administrations to help design and launch numerous National Science & Technology Initiatives (NSTIs), focused on the potential for geroscience to use NSTIs to create a federal healthspan agenda and accelerate the development of healthy longevity products. NSTIs traditionally act as mechanisms for setting priorities and guiding federal R&D investment to solve key economic and societal issues. A prime example of a successful NSTI is the National Nanotechnology Initiative launched in 2000, which has garnered over $31 billion in funding over the years. This substantial investment led to the technology’s application across a wide range of uses, such as semiconductors, energy storage, displays, sensors, and health. In order to create an NSTI for healthspan, Mr. Kalil emphasized some key considerations for the geroscience field. The proposal must strike a balance between setting ambitious goals that will generate excitement without overhyping the promise and potential benefits. Additionally, stakeholders must lay out numerous sub-goals for the initiative, such as discovering and validating biomarkers that act as surrogate endpoints for large clinical trials. The field should further decide in what ways government agencies, such as NIH and FDA, can assist them in propelling healthspan research and projects (e.g., in basic/clinical/ translational research and regulatory science) forward. Moreover, healthspan stakeholders will need to engage other key funders and supporters within philanthropic organizations, patient groups, and the private sector by raising awareness about the many developments within the aging biology field and their potential implications.
The conversation on the government’s role in the progression of aging biology continued with Mike Stebbins, Former Assistant Director for Biotechnology in the Obama Administration’s Office of Science and Technology, who discussed the creation of ARPA-H. Despite the recent strides in modern medicine, the U.S. only has about 500 interventions for the estimated 10,000 known human diseases. The slow progress of therapeutic discovery highlights how current federal investment strategies cannot address the market failures of the biomedical research enterprise. The U.S. healthcare sector relies heavily on private companies to develop therapeutics and given that these institutions avoid investing in diseases with low profit potential, these conditions remain largely overlooked. Therefore, ARPA-H will serve as a catalyst for medical innovation by providing cutting-edge approaches and essential guidance to the development of new platform technologies. By providing direct investments in “low-profit” diseases, ARPA-H will facilitate therapeutic development in these areas and benefit patients throughout the country. In this respect, the organization would act as the health sector analog of DARPA (Defense Advanced Research Projects Agency), whose formation allowed for the development of landmark innovations, such as the Internet and the Moderna vaccine.
Dr. Luigi Ferrucci, Scientific Director of the National Institute on Aging (NIA), provided a geroscience perspective on approaching the issue of increasing healthspan. Although we frequently associate aging with the elderly, aging results from the accumulation of damage throughout one’s lifespan. We must therefore examine healthspan through a life course approach, in which interventions are administered early in one’s life to prevent issues, such as age-related chronic diseases, down the road. The traditional approach of treating specific diseases fails because the elimination of one disease comes with the inevitable rise of another. Rather than adopting a disease-specific approach, the NIA looks to target the fundamental mechanisms of aging, which represent the strongest risk factors for developing debilitating chronic diseases such as diabetes and cardiovascular disease. The Interventions Testing Program investigates the potential for easily administrable drugs to increase healthspan in mammals. Compounds, such as rapamycin and metformin, demonstrate the ability to delay the onset of chronic disease in mice models and therefore, show great promise in doing the same in humans. Dr. Ferrucci hopes that this research will drive the field towards his goal of providing five additional years of healthy, independent life for U.S. citizens by 2035 while significantly narrowing healthspan disparities between disadvantaged groups and the general population.
Addressing health disparities also represents a central issue in the future of aging biology research. This portion of the symposium began with a presentation by Dr. Patricia Jones, Director of the Office of Special Populations at NIA, whose research focuses addressing health disparities through both basic and social/behavioral science. Geroscientists must consider contextual factors (i.e., causal factors related to health and illness that are external to the individual) influencing health outcomes. These determinants (e.g., housing, discrimination, and income) can create “syndemics”, in which they interact with health issues to give rise to additional diseases in a population. Based on these considerations, the NIA developed a Health Disparities Framework that takes into account the diversity of patient populations in terms of factors such as race/ethnicity, sexual orientation, geographic location, and allows researchers to analyze the influence of these factors on pathways of interest. Dr. Jones ended with a call for team science that integrates community engagement into the research process and encourages collaboration among academics, scientists, community members, patients, and other stakeholders.
Building off of Dr. Jones’ presentation, Dr. Rory Cooper of the University of Pittsburgh examined healthspan and health disparities in the context of those with disabilities. Not only do those with disabilities constitute the largest minority population in the country, but people become more likely to enter this population as they age. He highlighted the substantial disparities in access to life-changing technologies, programs, and general healthcare for those with disabilities. Dr. Cooper stressed the need to shrink this gap in medical care, as interventions such as sports and recreational programs improve both physical and mental health outcomes in those with disabilities as these patients adjust to new versions of themselves. Therefore, he called for the consideration of this population in future healthspan research, initiatives, and potential legislation.
Similarly, Dr. Elizabeth Calhoun, Associate Dean for Population Health at the University of Kansas, discussed the public health and economic implications of our country’s health disparities. As the healthspan field accelerates, its stakeholders must consider the disparities in chronic disease prevalence and lifespan between minorities and the general population, especially given that minorities will compose greater than half of the nation’s population by 2050. Addressing these issues should lie at the heart of the push to increase healthspan. Mitigating health disparities will have a tremendous impact on the economic health of the country, given that the U.S. healthcare spending per capita eclipses that of all other comparably developed nations (we lead the next highest spender, Switzerland, by 42%).
Dr. Alexander (Zan) Fleming, Executive Chairman of Kinexum and Chairman of the Kitalys Institute, moderated the closing session of the symposium, which featured Dr. Ellis Unger, Director of FDA’s Office of Cardiology, Hematology, Endocrinology, and Nephrology (OCHEN). Dr. Fleming recognized Dr. Unger as having key regulatory insight on the advancement of healthspan therapeutics given his responsibilities for most divisions at the Center for Drug Evaluation and Research (CDER) that review chronic disease therapies. Dr. Unger began his discussion by acknowledging the growing relevance of geroscience and the crucial regulatory questions that come with the emergence of healthspan therapeutic development. Recognizing that healthspan interventions must address conditions whose prevalence increases with age and decreases quality of life, he began by asking: If a drug helps prevent heart attacks or hip fractures, would they qualify as aging treatments? Even though they target age-associated outcomes, he believes these interventions do not target aging per se. Because aging is a systemic process occurring within multiple organ systems, creating a successful aging intervention would require validation from a wide range of parameters proven to relate to aging. This necessitates the validation of surrogate endpoints and biomarkers that accurately predict clinical endpoints of aging, which takes time. However, Dr. Unger stated that composite endpoints represent a promising avenue for healthspan trials. He also emphasized that a drug only needs to show clinical efficacy to receive a health claim, regardless of whether it targets aging per se. For example, if a drug shows it can delay the onset of cardiovascular disease and Alzheimer’s disease, then it will receive approval for both, separately. In the discussion that followed Dr. Unger’s presentation, Dr. Unger offered specific suggestions for developing novel clinical endpoints and trial design. He also observed that if an intervention affects a critical mass of endpoints that relate to aging, then the data may convince the FDA to award such an indication.
- Elijah Abass
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Webinar Recap: The Dog Aging Project (cont.)
...DAP studies aging in dogs due to the difficulty and cost of conducting trials in humans. Even though dogs age more rapidly than humans, they acquire the same age-related diseases, have genetic diversity, and share our environment. DAP’s efforts will not only guide our understanding of aging biology in companion dogs, but will potentially help dogs and people live longer, healthier lives.
The traditional approach to healthcare primarily centers around treating individual diseases as they arise. However, this method requires that individuals become sick before receiving treatment or, as is more typical with chronic diseases, alleviating their symptoms. In recent years, science has shown that aging represents the greatest risk factor for all major chronic diseases and may underlie the onset of these conditions. While the mechanisms of aging are not fully understood, scientists know enough to begin outlining clinical trials. By targeting aging itself, humans may be able to delay the onset of chronic diseases and increase healthspan, an approach that Dr. Kaeberlein calls “21st century medicine.”
DAP studies companion dogs for a variety of reasons: 1. They age in a similar fashion to humans; 2. They experience the same functional decline and diseases associated with aging as people; 3. It’s feasible to study aging in dogs due to their compressed lifespans (i.e., can study 21 years of human aging in a 3 year trial with dogs); 4. Like humans, dogs have extreme genetic and phenotypic diversity; and 5. Companion dogs share the same environment as humans. Regarding the last point, DAP collects the zip codes of dogs and their owners, which enables the researchers to study various environmental factors, including air and water quality. Dr. Kaeberlein calls the study an example of citizen science, as it engages participants in the research process and creates a community among dog owners and their dogs as they work towards the common goal of increasing healthspan.
DAP consists of two components: The first part, the Longitudinal Study of Aging, is completely observational and aims to understand the most important genetic and environmental factors influencing healthy aging in dogs. The second, the Intervention Trials, looks to determine whether interventions shown to target aging in laboratories slow aging in companion dogs. The first intervention being tested is the human immunosuppressant drug, rapamycin (see below), but Dr. Kaeberlein intends to test various other agents as well. The structure of The Dog Aging Project is as follows:
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All the dogs within the study form the DAP pack, which is at about 30,000 dogs currently, and Dr. Kaeberlein hopes to reach 100,000 dogs. The DAP pack is currently limited to dogs in the United States and owners can only nominate one dog from their household for data quality reasons. The dogs within the Foundation cohort receive genetic tests in which their genomes are sequenced to map genotypes to phenotypes, with respect to lifespan and age-related health outcomes. The Precision cohort focuses on systems biology. Data such as blood metabolome, fecal microbiome, blood epigenome, blood chemistry, and veterinary visit information are collected annually on the dogs within the cohort. The Centenarian cohort studies dogs that live longer than expected based on size.
Dr. Kaeberlein stresses that the DAP pack data is all owner-reported and independent from veterinarian electronic medical records. While the DAP pack has a sizable distribution of ages, sizes and sexes, Dr. Kaeberlein noted that they could use more puppies and intact (i.e., not sterilized) male and female dogs. Daniel Promislow published data suggesting that intact and sterilized dogs tend to die from different diseases. Therefore, dogs essentially have four sexes: intact males, intact females, sterilized males, and sterilized females. Since owner-reported walk speed trends downwards with age (similar to humans), Dr. Kaeberlein and his team are working to incorporate activity monitoring into the various cohorts. Additionally, dog owners report a range of diseases across many tissues and organ systems. As dogs in the pack get older, there will likely be a shift in health distribution data and multi-morbidity networks will demonstrate which diseases of aging could be linked.
Two interesting areas of study when analyzing companion dogs are dietary interventions and dementia. For dietary interventions, dogs demonstrate a natural model of time-restricted feeding because owners feed their dogs once, twice or three times a day, or ad libitum (i.e., constant access to food). Tracking this information along with other health data could provide insight into how various dietary interventions affect people. Since it is possible to clinically diagnose dogs with dementia and owner questionnaire results match very well with veterinarian canine cognitive dysfunction diagnosis, DAP uses a Canine Social and Learned Behavior (CSLB) survey to determine whether a dog has dementia, with a score above 50 being indicative of dementia. Based on the data collected so far, CSLB scores increase with increasing age.
In the clinical Test of Rapamycin in Aging Dogs (TRIAD) group, dogs are given rapamycin to test whether the drug slows aging. Rapamycin was selected because it is to date the most effective and reproducible longevity drug in laboratory animals. In mice, many labs have shown that rapamycin consistently slows aging and increases lifespan. Dr. Kaeberlein’s laboratory conducted a study where they administered 20-month-old mice either a control or rapamycin for three months. The mice that received rapamycin for three months lived about 60% longer after the treatment period ended, which has tremendous implications if translatable to companion dogs and humans.
TRIAD is a double-blind placebo-controlled study with 350 dogs equally randomized between placebo and rapamycin. The dogs are brought to the veterinarian every six months over a three-year period, but the treatment period is only one year. To participate, owners must be willing to bring their dogs to one of seven veterinary teaching hospitals every six months over the course of the study. The treatment is 0.15 mg/kg doses of generic rapamycin with an enteric coating provided once per week by the owner. The goal is to have 100 dogs randomized by the end of 2021 and all of the dogs randomized by 2022. Since aging interventions target middle-aged populations, an entry criterion for the study is that the dog must be at least seven years old. Also, dogs must weigh between 40 and 100 pounds due to the correlation between dog size and lifespan. The third criterion is that dogs must be of normal health status for their age. Safety is a top priority of TRIAD, so all precautions are taken to ensure the health and well-being of the dogs participating. The study has an animal board as well as a NIH mandated data safety monitoring board, and two preliminary clinical trials have been completed to test safety. The first one was a 10-week clinical trial that showed no evidence for side effects and a potential improvement in cardiac function. Additionally, dogs treated with rapamycin that started out with low or lower function were the ones where the most benefit was seen. While lifespan is the primary endpoint of the trial, multiple secondary endpoints are being examined to assess the drug’s effects on healthspan, including heart function, disease incidents, and cognitive function activity.
After Dr. Kaeberlein’s discussion on the DAP program and its current status, Ron Kohanski, PhD, the Director of the Division of Aging Biology at the National Institute on Aging (NIA), commented on DAP and its NIA funding for which he helped approve. Dr. Kohanski characterized the conception of DAP as ‘brilliant’ in terms of elucidating the biology of aging in a higher mammal that shares many features of aging with humans. Dr. Kohanski expressed optimism that the project may produce promising insights into aging that can be translated into the extension of healthspan in humans.
Since the Dog Aging Project is an open science project, the data collected will be available to the scientific community and general public to expand the research. For the longitudinal study, data will be accessible annually. However, for TRIAD, data will not be released until the end of the study because the trial must remain blinded. To sign your dog up to be a part of the DAP pack, click here.
- Brontë Jenkins
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Interview with Dr. Sam Collaudin (cont.)
*The questions and answers have been edited for length and clarity.
Since you have experienced different cultures and have been trained and educated in different countries, how would you describe your intellectual and personal formation?
I have been to different countries, but I spent most of my studies in France. I came from France and I only started going to Germany to do research at the end of my bachelors degree and during my PhD. I am spending most of my time between these two countries.
I started my studies in mathematics because I was good in mathematics. My father was also a professor in mathematics, so I studied fundamental mathematics at a young age. I probably studied with one of the best fundamental masters in France and in the world. It was going very well; however, I wanted to apply mathematics to a less abstract subject because it was far from being applied to anything that we could think of in the field that we were studying. Therefore, I started to study applied mathematics in biology. I did an internship in Heidelberg, where I started to understand that the worlds between mathematics and biology were completely different. I remember a meeting between my professor in mathematics and a professor in biology, and it was as if they were talking in different languages. They were trying to work together, but they couldn't understand each other. This meeting is where I got the idea that maybe I could be a bridge between mathematics and biology. That's why I started to think of studying biology. When you try to study some biomathematics papers, they are often quite far from application, from the real problem. The last conference I did on my PhD was a conference in biomathematics in Poland; I was invited there. It was quite striking to see people demonstrating very beautiful mathematical theories and in the last five minutes trying to find the biological problems that could be applied to the mathematics system. They were so far away from the biological problems they were trying to solve.
What do you do differently that's fixing the problem you witnessed in Poland?
I think it's what is seen in the research we are doing with artificial pancreas, but they are still a bit in between. When you understand the biology behind the problem, you can use the mathematics as a tool and you don't try to get a beautiful mathematic theory with very beautiful equations. Instead, you have both an idea of the biological problem and how the mathematics can help you to solve the biological problem. This way you can work much faster because you know when you write the equation that it will work or it will not work since you already have the mathematical intuition. You can do a quick analysis of the equation and think, "Yes, I see that there is a solution or there is a type of equation that could help us understand the problem." It was quite a good experience to really be in the middle of the two fields.
Can you elaborate and explain why these mathematical equations are necessary and very helpful for understanding and then solving some of the biological problems associated with creating a device beneficial to patients?
From what I see in the artificial pancreas, they really used a full mathematical theory, partly developed by Roman Hovorka and his team. The goal was really trying to understand how insulin and how glucose control works in the body. I think all the theories that were developed in the '80s, '90s and all these equations that are now used in some artificial pancreas programs, really helped the research communities to have a better understanding of what part of the reaction of insulins are important in regulating glucose. For instance, how insulin diffuses in the different tissues of the human body, how it interacts with glucose, how it is degraded… These models are at the basis of our current insulin PK/PD models. That's really the most important part of biomathematics—it's really a tool to help you better understand the system you are studying (i.e., the interaction between two proteins) in order to conduct research before doing any clinical trials. I think the immediate application is to use mathematics in devices, such as the artificial pancreas, because when you are able to really model a system, then you can improve the use of drugs and the use of insulin. That’s quite powerful.
How does this background tie into what you're doing now?
It helped me a lot when I was studying and when I was working on insulin programs. I worked on insulin and on combination of insulin and pramlintide. It's very interesting to try to understand how all the different pancreases that are in development are working and to see if they could work with the insulin that we were developing. For instance, trying to understand how the algorithms working with a combination of insulin and pramlintide helps you to know how to develop your project and which insulin to choose to combine with pramlintide. There is all this ongoing discussion of whether you should use a natural insulin or human insulin, etc. It’s different if you use an insulin pen or if you use an artificial pancreas, and it’s different in various types of populations. My background helped me to understand the different algorithms, and helped the development team to adapt to these different systems and design clinical trials. My background also allows me to be good with numbers, which helps a lot with analysis and forecasting. Without necessarily building models, you can already do a lot of work with just numbers.
Have you worked on applying analytics and artificial intelligence to biological systems or product development?
Since I left Adocia, I haven't really worked on artificial intelligence. During my PhD, I developed equations, like genetic networks, to understand the problem and did some modeling etc. Now, I mostly do data analysis and valuation. I worked a lot on the T1D Exchange database, for instance, trying to extract some interesting information on patients, how a patient behaves with CGM or with pumps, how many patients are stopping or starting using pumps, and seeing the dynamic between the different databases. I built a full SQL database system to really track the patients. All of this can also give you quite interesting information.
I've been studying research mainly, leading to a PhD in biology and biomathematics, followed by a junior MBA. Ironically, I always consider that half of the things I learned during my studies were outside of my studies. I was really not the most present student; I would miss a lot of lessons because I would spend most of my time in different volunteer activities. I was part of different student associations, but I also spent a lot of time as a member of the University Board. I was also part of some national unions, was vice president of the Federal University, and was part of advisory boards for the Higher Education Ministry. I worked on different projects including the financial management of the university and on lobbying for the students. I definitely created a good number of things and lead some of these projects. I learned a lot from these activities.
What motivated you to take part in these activities?
I like to do different things. I can't focus on just one project and I like my time to be useful. Plus, I find it very important to help others and have some volunteer activities, like working for not-for-profit companies, in which I also have a lot of activities in today. Additionally, I like business, lobbying, and management. And so, I also like to do these activities outside of my work. I took advantage of these opportunities and learned a lot of things, met a lot of people, and built an important network in France.
Do you have any interest in politics?
Not a lot, I've done my part in the national lobbying. Now, I'm much more interested in getting back to local things and working on concrete projects.
How did you come to be a prolific follower of the field of therapeutic interventions in diabetes and metabolism and what do you do in the field?
I came into diabetes purely by opportunity, but it fit completely with what I was looking for. When I was doing my junior MBA, I was looking for a company to work with and had some contact with Adocia, who was very interested in my profile. I really like chronic diseases, especially where prevention has a strong impact. Diabetes was good for that and I liked the field because it's one of the fields where the human is important in the treatment. Trying to understand how people are behaving with treatments, why they're taking a treatment or not, and trying to understand the life of a diabetes patient is so important in the development of drugs.
I like chronic diseases, not necessarily only diabetes, but also obesity and NASH. My work is both: 1. trying to understand the science, since I'm a researcher by training—I'm always interested in reading scientific papers and seeing where we are going in terms of developments; and 2. trying to study patients to see how we can help them the best. I would say that’s been a good part of my work for the past years. The other part of my work being the financial valuation side. I love numbers and it's natural for me. I can spend a few days in front of a very complex excel sheet and be very happy.
Please talk about the regular updates you write for Steve Daly and others.
It's something I started to do during my PhD. We shouldn't redo what others have already done and I realized that some people around me were doing research without really looking around at what had previously been done. Therefore, when I was doing my PhD, I would start every morning by reading new articles in my feed for one hour. I have kept it up for the past 10 years. I started to track different news, first for my PhD and then in diabetes when I started working for Adocia. Today, each time I see something interesting, I write a line in my file and include the link. Then, at the end of the quarter, I spend some time redacting the documents. It's also a way for me to have a synthesis of all this news because I use it a lot or realize I need it later for my work. I would say doing this task is something important for my work, to really know what's happening and being able to find it quite easily.
Once I did this document, it was natural to share it with my network, my clients and more largely with the community, and Steve was great help in doing so. The next natural step was to share it the Kinexum community. Additionally, I often go to or follow important diabetes conferences and at the end of the conference, I do a report of what could be interesting for some of my clients. When I find an interesting conference, I write a summary of the main information and transfer it to different interested people.
[Note from Kinexum: Steve Daly is Chief Commercial Officer of Modular Medical, and has previously held commercial posts with Adocia, Halozyme and Amylin. Sam has started to prepare his quarterly reports under the title of KINEXUM QUARTERLY REPORT.]
What do you want to accomplish over the next few decades?
What I have in mind can always change, but my goal right now is to really understand the most, to learn a lot on how drug development is working, and to gather different experiences. I'm mainly interested in working for small to midsize biotech companies, but I'm also interested to know more about big pharma companies. At some point, I’d like to get back to very early projects that are at the border between universities and new companies, and really help universities and researchers to see the value of their research. In the future, I want to work for incubators or to transfer technologies, but I need experience in biotech companies to be able to really advise academic researchers, universities, or incubators in the best way possible. That's what I want to do in the future.
How would you characterize the impact that you'd like to have contributed?
For the past 10 years, I would say my main focus was in health. A lot of my activities are on health and developing drugs, but I also have a lot of activities in prevention and I'm also chairing not-for-profit healthcare insurance companies that are targeting students mainly. I have done a lot of activities with students—how to eat properly, alcohol prevention, etc. I always had these activities in mind and when I was a student, I also spent a lot of time on these topics. My other focus is around education and ecology. I would say educate the population about the ecology, the ethics, and trying to transform the world in a better way. From my different experiences, I find that local activities and projects have a much stronger impact than simply doing something at a big national level, such as doing national lobbying in politics, etc. Today, I feel I can have impact in helping different local projects around me.
Would you say mathematics is your hobby, as well as the main element of your training? Or do you have other hobbies?
It was. I spend much less time on mathematics today. The mathematics I use is mainly in finance. My hobbies are a crazy amount of sports in fact. I do a lot of outdoor sports, especially in the mountains. I like trail running, biking, hiking, and climbing. Also, I spend a lot of time in my volunteer activities. I have two main volunteer activities today. One, I have spent a lot of time on for about a year now. In France, we have this kind of small club of people from the same village that put their money together to invest in very local companies in the social economy, such as financing a zero waste shop or financing a small place for people to gather. Some projects are much more ecological oriented. I created a club with a group of friends from my former foundations. There is an regional foundation that brings all of these different clubs together and I'm the president of the foundation now, so I spend basically a day per week working on this foundation. I spend a lot of energy to partly teach the population about this ethical financing, and the way that you could also involve yourself in the local community and help or assist a project around you.
What are some formative books that you've read that explain who you are today?
I read a lot of historical books. I’m starting to study ancient Greek, its role in the history of mathematics, and geometry. Also, I'm trying to understand the bigger world, so I spend a lot of time reading different philosophers. I read a lot in my childhood, my father had a library of about 5000 books and all the classical books were there. I spent a lot of time reading many classical books, like Descartes and Platon, to try to understand a bit of how human life and our philosophy evolved and what bring us where we are today.
Which ones stand out to you? If you have to go to a desert island and have three books with you, what would they be and why?
Hard question because I read very different books. One of the books I really liked is a French book you could translate to The Parrot’s Theorem. It is a book explaining the history of mathematics between Greece and North Africa, and also a history of philosophy. All these parts were very interesting for me. It's a book I read when I was maybe 12 years old, and it's probably one of the books that gave me the interest for science and interest to understand the meaning of why we are here today.
What's a book you've read in the last year that you got very excited about and you would recommend to other people?
I read a few of Ken Follet’s books last year and the beginning of this year. I really enjoyed reading them. It was interesting to be inside the period, the different eras that were covered by his books and trying to understand a bit of the life at this time.
Do you follow other popular culture at all? Theater, movies, songs?
I spend some time in theaters and museums because I like to see a bit of culture. I like some independent movies once in a while, but I spend a lot of time reading.
What is something not a lot of people know about you?
I think the interest I have for history, history of science, and understanding the world is something that not a lot of people know about me. Also, I’m very interested in the study of civilization. A few years ago, I was studying the Phoenician civilization, for instance. I spent some time studying Japanese civilization these last few years.
Tell us about your family.
I have two brothers. One that is one year younger than me and he's a sport teacher in France. He also reads a lot, more than me. I think we were both highly influenced by our father. I have a second brother that's seven years younger than me and he's in cultural project management. He's currently working on opening a music museum for the Philharmonic of Paris. During our childhood, we spent a lot of time outside in a very small village in the countryside in the middle of France, so we did a lot of gardening, taking care of the house, etc.
How would you describe your family? Are they French?
Yes, French. I'm the only one that goes to Germany once in a while. I have no family roots in Germany. We have quite a big family, both on my mother’s and father’s side, with many cousins, aunts and uncles that are close and help each other.
Have you done any population genetics research into your family background?
No. Some of my great uncles do genealogy work and so we have a general tree for some of the branch of the family that dates back to the end of the 18th century, or even younger than that.
Have you traveled a lot? And if so, what was your favorite place that you visited?
I have traveled a bit, mainly to European countries. When I was a student, it was easier and less expensive to travel around and there are so many things to discover. I'm someone that really likes mountains, so I can spend a few weeks just hiking in some new mountains. I've visited a lot of European countries, but probably the most striking and interesting trip I did was in Chile. I spent some time in the Atacama Desert and that was a really beautiful place. I really like nature, so when I visit places, I don't go to visit cities, but I go to visit around.
What sort of work and value can you offer as a Kinexum consultant to potential clients?
Valuation is definitely one thing. I have a good capacity and am able to understand the market very well in terms of the patients, developments, problems, etc. Additionally, I can build very good models for new drugs, especially in the diabetes, obesity and NASH domain, but I can also work on other domains. The different models I've built in the past were very well recognized, both inside the companies, but also externally when we were presenting the models to potential investors or banks.
I usually do models for early stage companies. The idea is to have them as an internal tool to know what could be the potential market volumes, so how do you prepare your development, your CMC work, etc. or how do you negotiate contract with potential suppliers? It's also a tool to prepare a discussion with potential investors or partners. I'm not at a level where you prepare a model to enter on the market, where you need a team of specialists to be very precise. The work that I do is forecasting, volume forecasting, values forecasting, development of a full cost models, NPV. I spend a lot of time with people inside companies to really gather the different costs and build the full model.
I can also help companies to make good strategic decisions, by analyzing markets, doing program review, discussing with KOLs, conducting market research with external vendors, and helping develop a partnering strategy or an investment one.
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Have ideas for other articles you would like to read?
Please submit suggestions to brontejenkins@kinexum.com or elijahabass@kinexum.com
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