Susan M. Manzi, MD

	Lupus is one of the most complex and unpredictable diseases of the modern medical era. Despite the estimated 5 million people around the world affected by this autoimmune disease, and the 24,000 new cases reported each year in the U.S. alone, the disease remains elusive in many ways.

 The underlying cause of the autoimmune disease remains unknown, and because of its wildly variable-even volatile- symptomology and heterogeneous organ manifestations, it’s an inherently multidimensional and mutable disease. Many of the symptoms are non-specific and may overlap with other diseases, while some critically ill patients exhibit no notable signs of sickness at all, making lupus tremendously difficult to diagnose, research, and treat.

	Progress has been made in improving our clinical understanding and treatment of the disease, yet considerable hurdles remain. Challenges associated with lupus heterogeneity have permeated into and continue to stymie drug development, clinical care, and access. Over the past 60 years, only one lupus-specific treatment, Benlysta

 (belimumab), has received regulatory approvals.

 While upwards of 30 companies currently work to produce new pharmacotherapies and promise hope for the future, these efforts remain vulnerable to late-stage clinical failure if we do not address the field’s most obstructive barriers.

	The lupus community has been voicing its challenges for well over a decade but has not had the opportunity to come together and, with one voice, provide the evidence to support them. And with disease rates on the rise globally, and mortality rates from lupus consistently three times as high as the general population, the need to advance lupus science is apparent and pressing. This is why the Lupus Foundation of America (LFA), researchers at the Center for the Study of Drug Development at Tufts University School of Medicine (Tufts CSDD) and a Global Advisory Committee (GAC) of 13 lupus experts collaborated to launch the ALPHA Project.

	Global expert consensus and collaboration are essential to determine a clear course of action for the lupus community and its scientific advancement. Historically, global efforts have focused largely on removing barriers specific to drug development and have had limited success. However, the goal of the Addressing Lupus Pillars for Health Advancement (ALPHA) Project, as well as the approach to reach that goal, is different. Led by the LFA, Tufts CSDD, and GAC, the ALPHA Project aims to identify the most fundamental barriers, or knowledge gaps, in this disease area, gain global consensus on those barriers, and prioritize the most critical issues that must be tackled first by all lupus stakeholder groups.

	This is the first time the international lupus community has been given the opportunity to come together to look holistically at the comprehensive set of issues the lupus field faces. By engaging with lupus thought leaders in research, clinical practice, industry, government, and patient advocacy across 20 countries, the project provides a truly global perspective on the state of the science, treatment, and care. ALPHA’s ultimate goal is to develop and implement targeted tactical plans to improve the diagnosis, treatment, and systems of care for those with the disease.

	It’s an incredibly energizing moment for the lupus community, signaling exciting progress to come.

	Consensus around the most fundamental challenges was clear. In fact, differences in respondents’ location, years of experience, or amount of time spent in direct care for individuals with lupus did not translate into significant differences in perceived priority areas. Sub-groups were aligned on the most pressing barriers to drug development, clinical care, and access and value, validating agreement despite geography or experience.

	The study validated known challenges in lupus, identifying lupus heterogeneity as the primary barrier impeding drug development, clinical care, and access. Additionally, experts agreed upon the following as the top barriers to improving outcomes in lupus: 

		Lack of diagnostic, predictive, and prognostic biomarkers for lupus and lack of biomarkers to predict drug response in clinical trials

		Lack of access to clinicians familiar with lupus/limited awareness of lupus among non-expert medical professionals

		Barriers to effective management of lupus due to social determinants of care in predominantly lower socioeconomic status areas

	At last guided by global alignment, the lupus community’s most prominent obstacles now represent our most urgent opportunities. Fundamental challenges prove to be consistent across the globe. ALPHA builds on many existing efforts, but underscores that a disease as multifaceted as lupus requires a unified effort to identify and address priorities common across global lupus research, care, and access.

	Meanwhile, while biomarker research has been prolific in the last decade, the ALPHA Project’s findings double down on the research community’s call for more concerted, longitudinal efforts to identify and validate biomarker candidates and move toward precision medicine and more practical aspects of clinical care. Addressing flawed clinical trial design is of paramount importance as they are currently undermined by factors such as common comorbidities, background medications, non-adherence, and underrepresented study populations.

	This is just the beginning. As a next step, the ALPHA team will continue to engage stakeholders and support further research endeavors to characterize key barriers and further explore and conceptualize the lupus spectrum. An international stakeholder meeting has been set for January 2020 to develop a global roadmap of specific recommendations to address the top challenges identified. Recommendations may include multi-pronged strategies involving regulatory and advocacy efforts, scientific consensus building, and concerted communication programs. We also recognize targeted approaches may be needed to address specific populations, such as children with lupus.

	1. Lupus Foundation of America. What is lupus?  Updated: July 31, 2013. Accessed: June 21, 2019. 

https://www.lupus.org/resources/what-is-lupus

	2. U.S. Food and Drug Administration. Lupus Therapies Continue to Evolve. Published May 18, 2017. Accessed July, 15, 2019. 

https://www.fda.gov/consumers/consumer-updates/lupus-therapies-continue-evolve

	3. The Lewin Group, Inc. Overcoming barriers to drug development in lupus. 2009:1-16. 

https://www.lupus.org/s3fspublic/documents/Overcoming_Barriers_to_Drug_Development_in_Lupus.pdf

MPH, Board Chair, Medical Director, Lupus Foundation of America;

MBA, Director of Sponsored Research Programs & Research Associate Professor, Tufts University School of Medicine Center for the Study of Drug Development

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Global experts collaborate to form the Addressing Lupus Pillars for Health Advancement (ALPHA) Project in order to combat challenges in lupus drug development.

Susan M. Manzi, MD

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