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?    

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?