Galien week of innovation

Climate change is disrupting the contours of human health in ways that are only now being assessed and quantified. The markers of mortality and morbidity are legion, from heat-related illnesses that contribute to edema and cardiovascular failure; respiratory ailments like asthma and allergies from airborne pollutants; fatalities, injuries, mental illness and habitat loss from severe weather events; changes in vector ecology that spread malaria, dengue fever and  a host of other pathogens while enhancing prospects for zoonotic disease transmission; water quality impacts, led by cholera; and increased malnutrition induced by climate pressures on the natural environment, farming and the food supply.

In May, the World Health Assembly (WHO) reiterated its position on climate change as humanity’s single biggest health threat, forecasting 250,000 additional deaths per year worldwide between 2030 and 2050.  The WHO estimates that direct damages to health system infrastructure from extreme weather events alone will total $4bn annually by 2030, a trend destinated to waylay the organization’s plans to introduce a basic global platform of universal health coverage, including access to affordable essential medicines for all, the same year. 

Vulnerable populations like the poor, children and the elderly will be disproportionately affected. Beyond the documented income losses, climate change undermines many of the basic social determinants of health, such as equality and access to care as well as the local community support structures that act as a hedge against economic displacement and mass migration.

Pressure is mounting on business and the private-sector to do more to address climate change.  The Intergovernmental Panel on Climate Change (IPCC) has resolved that, to avert a truly catastrophic trajectory to unsustainable weather patterns, action must be taken now to limit carbon emissions and prevent further rises in global temperature by no more than 1.5 C by 2050. Accomplishing this goal depends heavily on the private-sector to help finance a global “green transition” tied to major new investments in renewable, zero-carbon energy technologies that don’t rely on fossil fuels. The IPCC now estimates $2.4 trillion a year in combined global and country financing/investment commitments will be needed well into the next decade to jump start the transition.   

There is also an expectation that at least a part of this investment be earmarked for countries of the global south, with the preferred vehicle being public-private partnerships involving key multilateral lenders like the World Bank. The idea is to leverage such partnering as a way to “de-risk” the exposure for companies investing in geographies where business confidence is low.

The health impacts of climate change pose particular challenges for the pharma and biotech sector.    The extensive global supply chains that big pharma companies rely on in the manufacture and distribution of medicines have led to scrutiny by climate change advocates, who are demanding a higher level of “resource stewardship” from management. There is also pressure on the shareholder front to ramp up environmental disclosures and compliance under voluntary company ESG commitments.

More important, government regulators like the US Securities and Exchange Commission (SEC) and the European Commission are moving forward with plans for even more transparency on industry actions to address climate change.  The SEC rule mandates public companies to report annually on carbon emissions levels, exposure to risks from global warming and the status of strategies to address it.  The EU rule is more prescriptive and calls for evidence on how the company business model and commercial strategies are compatible with the climate reduction provisions of the 2015 Paris Agreement of the UN Framework Convention on Climate Change, including impacts on atmospheric pollution; water and marine resources; and land-based biodiversity and ecosystems – at every step of the company value chain.   

Overall, climate change makes for more uncertainty for big pharma in operating an essential complex business with numerous customer touchpoints, at scale and across diverse geographies. Extreme weather conditions alone promise supply bottlenecks and product shortages from the loss of manufacturing capacity around temperature-sensitive products with limited shelf life. Long term, the industry will have to confront external demands for changes in its R&D portfolio, in some cases for conditions accentuated by climate change that carry a lower profitability ratio than other disease areas.  Finally, coping with these climate-related risks will require significant new investments in due diligence and hazard avoidance capabilities, extending deep into the third-party supply and support networks where compliance has always been hard to establish. 

Topics for Discussion:

• Current state of academic and institutional research on the relationships between climate change and human health – what does the evidence show? Real world implications for health status, public health provision and disease spread if countries fail to meet UN Paris Convention commitments to limit growth in fossil fuel emissions by 2050.
• Scientific researchers have found a way for plant seeds to effectively fertilize themselves, a discovery with the potential to reduce reliance on fossil fuel-based fertilizers in agriculture. Are there similar impactful innovations underway to address the harmful effects of climate change on disease and other key public health parameters?
• In the US, just under 10% of our national carbon footprint can be attributed to business practices of the health care industry. Is the industry moving at an appropriate pace to lower its carbon profile?  What additional actions can the pharmaceutical and biotech sector take to address the challenge? Do the standardized company reporting guidelines that allow the public to assess and compare progress on climate change act as an incentive or as a burden, in terms of doing more?  
• Is the international negotiating framework now in place for addressing climate change sufficiently enabled to tackle the public health aspects of the threat? Are government negotiators sufficiently aware of the private-sector’s commitment and contributions to meeting climate-related targets?
• Africa is a relatively poor continent which contributes marginally to global warming but whose livelihoods are disproportionally damaged by its effects.  What can the region’s experience tell us about what works and what doesn’t in addressing what is now an existential global challenge?  Is progress simply an issue of extracting more concessional aid through a revamp of the current international financing system?  What can we learn from local approaches built around community awareness and empowerment?  Can the continent achieve a better balance between exploiting abundant extractive industry resources and transitioning to greener, renewable technologies?    

Panel Background:

This pivotal discussion brings together leading experts to explore the transformative potential of immunology in modern medicine.

Immunology and inflammation have emerged as fundamental pillars in how we approach a wide array of human diseases, from cancer to autoimmune disorders. Recent breakthroughs in our understanding of the immune system are leading to revolutionary therapies and opening new frontiers in medical science. Our distinguished panel will delve into the latest advances, current challenges, and future opportunities for harnessing the immune system to combat chronic and inflammatory disorders.

Our panelists will survey cutting-edge research, innovative therapies, and the potential of immunology to revolutionize patient care. They will also discuss how immunological and anti-inflammatory approaches are reshaping our understanding of disease mechanisms and opening new avenues for treatment. These latest developments — from engineered cell therapies to novel immunomodulatory drugs — promise to transform the treatment landscape for millions of patients worldwide.

As we navigate the complexities and promise of immunology, we invite you to engage in this thought-provoking discussion on one of the most promising fields in medical science today.

Topics for Discussion:

• Discuss the current state of scientific understanding surrounding the human immune system and the areas of research that hold the greatest promise over the coming decade to address unmet need in autoimmune disorders, cancer, and other chronic and inflammatory diseases. How close are we to a time where precision medicine approaches (e.g., individual profiling of immune systems) will be widely accessible for informing patient care?
• What therapeutic modalities have emerged, or are on the horizon, that could revolutionize how we target or leverage the human immune system to combat inflammation and disease? Are we closer to achieving true cures for any autoimmune or inflammatory diseases in our lifetime?Highlight the current state of immuno-oncology (IO) research and the broader IO drug development landscape, and examine the impact of immunotherapy on patient care. Has the revolutionary promise of IO lived up to its expectations over the past decade, or has it overpromised and underdelivered? How are AI, big data, and novel computational methods impacting our understanding of the human immune system? Is AI having a broad and meaningful impact on drug development yet, or are we still years (or even decades) away from realizing the real potential of AI on the development of new therapies? Beyond oncology and autoimmunity, how is our evolving understanding of the human immune system shaping therapeutic approaches to other indication areas, such as neuroscience and metabolism? Is the immune system truly the cornerstone of nearly all disease pathology?
• With the cost of and accessibility barriers to novel immunotherapies, will costs to manufacture and scale many next-gen modalities pose a critical challenge to patient access? What measures can regulators take to accelerate the development and approval of new immunotherapies and ensure patient access and affordability?

Background and Topics for Discussion:

Research to understand the complex biologic and lifestyle factors that contribute to chronic disease is opening new doors for medicines linked to the human condition known as metabolic syndrome. The syndrome underlies or contributes to numerous debilitating diseases which often appear in patients simultaneously, making research, diagnosis and treatment more challenging. 

A prominent example of clinical progress in this area is a new generation of incretin hormones (GLP-1 receptor agonists, dual (GLP-1 and GIP) agonists, and other combinations) medicines originally developed to improve glucose control in diabetes that now show much broader efficacy as pharmacologic approaches to overweight and obesity. The fact that obesity is a foundational condition associated with diverse health risks beyond diabetes (as many as 200, according to some estimates) means these new drug classes – and potentially others on the horizon – will add to our therapeutic armamentarium against metabolic syndrome. Even modest research breakthroughs in this area not only will contribute to improved health for individual patients but have the potential to contribute to improvements in population-wide health outcomes as well as easing the burden metabolic diseases place on scarce health resources.

Today’s panel focuses on a proliferating but still “under the radar” liver disorder, Metabolic Dysfunction-Associated Steatohepatitis (MASH). It’s a new name (replaceing the term NASH) for an existing condition that is both deadly and largely asymptomatic. Patients with MASH experience a progressive metabolically driven build-up of excess fat in the liver, resulting in inflammation and cell death that progresses to fibrosis and scarring that can lead to cirrhosis. Advanced cirrhosis may eventually necessitate a transplant as the only option remaining to prevent death. Today, an estimated 22 million US adults are living with MASH and its related stages and co-morbidities. A large proportion of victims have yet to be formally diagnosed or are not receiving treatment. Awareness of MASH as a mortality risk and public health threat remains low, an unfortunate situation because the disease can often be prevented entirely through lifestyle changes and behaviors before the need for pharmacologic intervention. 

With such statistics in mind, clinicians are working to clarify the nomenclature for diagnosing and managing this disease. In 2023, a joint collaboration between hepatology clinicians and patient groups proposed that the disease’s existing name, Non-Alcoholic Steatohepatitis (NASH) be dropped, on grounds that the “non-alcoholic” label failed to accurately define the disease as the “hepatic manifestation of metabolic syndrome.” MASH (and its accompanying label for less severe forms of the disease, Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) also removes the “stigmatization” linked to the previous label’s indirect reference to excess consumption of alcohol. Likewise, the existing shorthand characterizing a milder version of this disease, Non-Alcoholic “Fatty Liver” Disease (NAFLD) was abandoned for seemingly targeting obese patients to the exclusion of others who might benefit from treatment. 

The new designations mark a turning point in securing greater awareness among patients, clinicians and the public about the many dangers of MASH and the burden it imposes on the health system. MASH is the leading cause of the steep rise in costly liver transplants in the US: more than 10,000 were performed in 2023 alone. More important, seemingly unrelated co-morbidities from MASH ranging from heart disease, type 2 diabetes, solid tumor cancers and even neurocognitive decline also can result in death. In fact, patients with MASH/MASLD are twice as likely to die of cardiovascular diseases (CVD) than from liver failure. 

In recent years, the complexity of MASH as a research target and the challenges of clinical development programs persuaded a number of leading drugmakers to abandon development programs in this disease area, with numerous candidates failing in early development. This situation now is changing as the insights around metabolic signaling derived from the GLP-1 agonist class bear fruit. 

In March, the FDA granted the small biotech Madrigal Pharmaceuticals conditional approval to Rezdiffra (resmetirom), a thyroid hormone beta receptor agonist for adults with noncirrhotic non-alcoholic steatohepatitis characterized by moderate to advanced liver scarring (fibrosis). The first treatment that directly addresses the liver damage that can lead to liver failure and death, Rezdiffra bears a requirement for use only in conjunction with a lifestyle regimen of diet and exercise; clinical benefit must also be reaffirmed on completion of another 54-month clinical trial. Multiple other biotechnology and biopharmaceutical companies including three represented on this panel (Boehringer-Ingelheim, Eli Lilly & Co. and Novo-Nordisk A/S) have MASH candidates in development , all of which build on the potential of their vastly successful GLP-1 weight loss molecules. 

Topics our six-member expert panel may address include: 

• Identify and assess the most promising biologic pathways toward treating and curing MASH/MASLD. Is big pharma and biotech on course to “crack the code” on metabolic syndrome? 
• Define the principal barriers to the approval of novel drug therapies for MASH/MASLD from a discovery, development, regulatory and patient access perspective. Do the potential financial returns justify the investments in R&D? 
• Identify the challenges in providing better diagnostics to screen, identify and track MASH/MASLD. Are current clinical practice guidelines adequate to the task of differentiating among the many facets of this condition?
• What strategies are necessary to build awareness of MASH/MASLD and assure patient behavior changes are introduced early enough to prevent liver failure as the ultimate end point of disease? Is losing weight the single best response to reversing the course of disease? 

Panel Background:

The frontier of medicine in the 21^st century is being driven by two groundbreaking therapeutic platforms – mRNA and gene editing – that target the underlying biology of diseases once deemed untreatable. Both rely on the manipulation of individual genetic material, but in different ways: only gene therapy is designed specifically to permanently alter a patient’s DNA “script” by creating a functional copy of a gene, editing or disabling a defective gene, or preventing gene activation.

mRNA, in contrast, is not the powerhouse of genetic information like DNA, but serves as an intermediary “messenger” to pass on instructions to the cells in activating proteins that enable the body’s own immune system against any number of invasive threats – in essence, the job of mRNA is teaching the body to make its own medicine.  mRNA also benefits from its simple design; short development cycle; and high target specificity, applicable to a wide variety of conditions. But like all medicines, mRNA’s molecular payload is transitory, not permanent, as is the case of an edited gene. mRNA degrades quickly after an immune response is recorded; its fragility is underscored by the need to encase the inscription in a soluble, fatty lipid nano-particle to ensure potency on delivery.

Gene therapy carries its own calculus of benefits and risks. It offers the promise of durable, effective treatment for many rare and inherited diseases that currently provide few options for patients. Applied at an early stage, there is a possibility to reverse disease progression and even initiate a cure. Gene platforms like CRISPR and CAR-T are also customized around individual genetic drivers of disease causation – an exemplar of precision medicine.   At present, however, delivery of a gene-based therapy can carry significant risk of an adverse immune system response and other side-effects, some which are life-threatening. The necessity to take precautions also drives up the cost, complexity and duration of treatment, which in turn limits access to many patients who need gene therapy the most.  

Where the two platforms do complement each other is in the saga of a small cohort of “true believers” who pursued the potential of mRNA and gene editing against the indifference of the experts. Gene therapy began moving forward in the clinic after a decade of public massive investments in sequencing the human genome, in 2003. A patient payout from the 1961 discovery of mRNA became apparent only in 2020, when its swift deployment as an effective vaccine against COVID-19 led to it being designated by the World Health Organization (WHO) as the source of one of history’s most successful public health interventions. The unprecedented speed in which mRNA vaccine technology passed muster from regulators has also raised the bar on what the pharmaceutical industry is capable of in capturing and commercializing the therapeutic secrets contained within the human genetic code.

Today, researchers are pursuing a widening set of opportunities in both platforms. Since March 2021, the FDA has approved some 36 gene-based therapies and more are expected into 2025 and beyond. In turn, success of the mRNA model for vaccines has prompted investigation of a broader range of RNA-based therapy types. As of April 2024, the FDA has approved more than 20 such therapies; studies are underway in areas of long-term potential, such as vaccines for cancer and multiple infectious conditions like TB and malaria; single gene (monogenic) inherited conditions like cystic fibrosis and hemophilia; and various metabolic and immune system disorders.

Regardless of their different set of strengths and weaknesses, there is no doubt that drug discovery and development in both platforms are moving forward at warp speed. Each will play a significant role in the evolution of drug discovery for the remainder of this decade. And, as always, the market – and the waiting patient – will decide what comes next.

Topics for discussion:

• What are the unique issues that mRNA and gene therapy confront in securing timely regulatory approvals and gaining access from insurers at a price that society and patients can bear? What’s the right business model to prevail in a more challenging medicines market characterized by strained drugs budgets and tougher coverage criteria – all in the context of higher post-Covid expectations of health as a public good?
• What can the FDA and other major regulators like the EMA do to address the technical complexity, safety and cost aspect of bringing new gene and RNA-based therapies to market?   Is there any ”perverse incentive” issue at work here?
• Highlight key areas of research progress in these two areas that will lead to groundbreaking advances in patient care and disease outcomes over the remainder of the decade.
  • What is the state of science and commercial prospects for the new “bridge RNA” tool to promote large- scale human gene modifications at lower cost?
  • What’s next for new mRNA vaccines in infectious diseases, especially in light of the steep variations in demand and shifting government contract positions that led to strategic uncertainty around Covid-19 vaccine sales during and after the pandemic?  

Panel Background:

The market for health care investment in AI is forecast to increase from $14 bn in 2022 to $164 bn in 2029. Currently, much of this is being spent on AI-assisted clinical screening and development of highly focused algorithms to help narrow the astronomical range of proteins and molecules that have medicinal properties in humans. As of May 2024, the US FDA has authorized 882 AI/ML-enabled medical devices, up from less than 20 in 2020. In April, US biotech Insilico Medicine scored a first by securing Investigational New Drug (IND) approval from the FDA to commence clinical trials for one of its promising cancer compounds. Many more such approvals are expected to follow in both the US and Europe. Beyond basic research, industry is exploring AI applications in making clinical trial management more efficient and less costly; creating better, more targeted diagnostics; improving manufacturing quality standards; helping supply chains adapt to a more complex and personalized approach to drug treatment; and promoting prescription optimization and adherence, linked to better patient outcomes.

However, achieving demonstrable results in these – and other – areas face numerous barriers. The most important of these are the need for AI users to apply massive stores of curated (and energy-intensive) data to “train” systems that can learn, identify and solve problems. Risk mitigation issues in AI are becoming more prominent, led by concerns about fairness, bias and accountability in yielding conclusions from data that can be harmful to individuals or entire populations. Skeptics of AI-generated problem-solving point to the “black box” phenomena, in which an AI system’s inputs and operations produce results without being able to explain precisely how it did so. This can expose the originators of such data to claims around errors or even outright disinformation.  

The question – can we trust the data? – is one reason why government efforts to evaluate the merits of AI as a decision tool will grow, particularly in biopharma and med devices which already face intense public scrutiny.   The EU Commission has finalized a three-part regulatory risk standard for AI, and the UK has a new National AI Strategy focusing on governance to ensure patient privacy and protections against bias in health research derived through AI- and ML-generated data sets.

In addition, the FDA has signaled it is ready to move beyond its current focus on AI/ML software in medical devices to drug development itself. In March, the Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) issued a paper announcing the FDA would follow four priorities in their approach to AI/ML, covering domestic and international collaborations on AI/ML to safeguard public health; promoting medically useful medicines innovations; establishing internal performance targets on ML and AI applicable to all phases of the medical product life cycle, from ethics and regulatory transparency to safety, cybersecurity, quality assurance and risk mitigation; and criteria for establishing multiple demonstration projects based on these other priorities. Implementation will be the responsibility of a new FDA Quantitative Medicine (QM) Center for Excellence, which draws on extensive work already in place on the role of digital science in FDA’s mandate and mission.

• Review industry progress in integrating AI and Machine Learning (ML) capabilities and prioritizing these throughout the biopharma enterprise;
• Identify key internal and external barriers to take-up of AI and how to solve them;
• Share viewpoints on AI/ML among external stakeholders, including patients and regulators;
• Assess continuing advances in the theoretical underpinnings of AI at the academic level [i.e. unsupervised learning, vision and natural language processing];
• Examine issues in AI/ML governance and public interest positioning [i.e. Responsible AI];
• Understanding the importance of distinguishing artificial from human intelligence – a critical viability issue for medical publishing;
• With 60 countries now actively struggling with ways to address these precedent-setting technologies, predicting the state of AI/ML capabilities in health care by end-decade and beyond: how goes the road to singularity?