Data Coordination Center for Individualized Treatments

The N=1 Collaborative (N1C)

For every rare disease like cystic fibrosis or sickle cell disease, there are dozens of ultra rare diseases defined by unique mutations in obscure genes. This 'long tail' contains the majority of the 8,000+ known rare genetic diseases. Few, if any treatments exist currently, and due to the tiny patient populations within a given disease, biopharma is not incentivized to develop treatments, so there will not be any more treatments, even though collectively these diseases affect millions worldwide. Furthermore, this 'long tail' is expected to continue growing, as advancements in clinical genome sequencing enable diagnosis of genetic disease with greater precision and speed than ever before.

A source of hope in therapies for N-of-few diseases is the maturation of platform therapeutic technologies, such as antisense oligonucleotides (ASOs) and CRISPR genome editing, which can precisely target RNA or DNA to treat genetic conditions at their root cause. Conceptually, after these therapies are developed commercially for common genetic mutations, they can be 'retargeted' to address other severely debilitating/life-threatening genetic disorders without having to start from scratch, offering significant acceleration and efficiency in drug development for rare diseases. Pioneering studies have shown that a custom ASO (Milasen, Kim et al. NEJM 2019) can be developed for a single patient in as little as a single year. The mission of the N=1 Collaborative is how to turn this process of individualized, custom therapeutic development from proof of concept to the standard of care for patients with ultra rare diseases. There exists a future in which individualized genetic interventions for a single patient becomes as routine as lifesaving surgical procedures.

One major challenge to progress is the siloed data collection across each N-of-few treatment: this impedes patient safety, limits the iterative learning necessary to improve future treatments, and ultimately wastes precious resources from desperate rare disease communities. For safety, because N-of-1 therapeutics developed on the same platform are more alike than different, critical learnings from other trials need to be analyzed & actioned in real time to protect patients in active and planned trials. Additionally, the lack of efficient information sharing means re-inventing the wheel, preventing patients from benefiting from the most up to date practices. Despite these needs, knowledge exchange currently happens in ad hoc ways without being broadly accessible or actionable for patients, caregivers, and investigators. Furthermore, the lack of data standardization and aggregation also limits future improvements and regulatory review, especially since emergent properties of platform technologies may only be seen in the aggregate. Overall, this means unnecessary waste of precious contributions from the patients & families who volunteer their lives to push the envelope of drug development. 

The N=1 Collaborative (N1C) is building a Data Coordination Center (DCC) for Individualized Therapies, a global initiative aimed at centralizing and linking preclinical and clinical data captured during the development of custom antisense oligonucleotide (ASO) N-of-few therapies. This enables the easy input and aggregation of data, democratized access to this shared data, and seamless integration for investigators and institutions worldwide, all to serve as a powerful catalyst for advancing the practice of individualized therapies in rare disease. By breaking down silos and promoting collaboration, we aim to improve the safety and efficiency of individualized ASO development, ultimately accelerating the creation of effective genetic treatments across the long tail of rare disease.

The comprehensive solution requires both technological and social innovation. Cutting edge database software and platforms will serve as the backbone of the data coordination, facilitating the seamless collection, integration, curation, and analysis of clinical data from diverse sources with the appropriate patient-specific and site-specific protections. Meanwhile, community alignment on standard operating procedures and robust governance mechanisms are equally necessary in order to ensure high quality data capture, foster collaboration and innovation, all while safeguarding data integrity and privacy.

Clinical data sharing is particularly important for enabling real time safety reporting and allowing investigators to review data across all active and past trials to best inform their practice. Integrating across different diseases, outcome measures, electronic medical record systems, and institutions is challenging but the N1C has identified key collaborators with experience building these such platforms.

Additionally, these clinical data will be linked to preclinical data. Such a pairing provides an unprecedented dataset that captures end-to-end information from preclinical development to their introduction into human trials for multiple treatments, all built by retargeting a common therapeutic platform — this will improve the predictive ability of preclinical data to inform clinical safety and efficacy, thus enhancing our ability to develop effective therapies.

We have currently prototyped this database across multiple individualized ASO programs and patients at Boston Children's Hospital, a pioneering institution for individualized medicines. This database has already yielded important learnings on both drug development and data workflows. We aim to expand and enhance this prototype database to encompass protocols from multiple clinical sites, ensuring a diverse and representative dataset that captures the nuances of ASO therapies across different patient populations and disease contexts.

The establishment of the N1C Data Coordination Center seeds the necessary infrastructure for the future advancement of the field. The continuing growth of a high quality, structured database will enable future machine learning algorithms to uncover additional insights for improving drug design. Additionally, while the initial trials focus on ASOs as a drug platform, this establishes the precedents that are relevant to other emerging platform therapeutics such as CRISPR gene editing, RNA editing, and beyond.This data infrastructure will be designed from the start to accommodate these new modalities. Our proposal represents a significant step forward in advancing individualized medicines, fostering collaborative research, and driving transformative change in the field of rare disease therapeutics.

Our solution first and foremost serves rare disease patients and their care providers. For most, no treatments exist today, and developing a customized therapeutic offers hope for targeted treatment in many ultra rare diseases otherwise ignored by commercial drug development, while able to be completed in time to actually help the patient suffering today. The N1C Data Coordination Center aims in the short term to provide the best chance of success for the initial patients being treated today, while enabling data-driven scaling of this pathway to serve many more patients tomorrow.

There are two time horizons on which the N1C Data Coordination Center will serve patients:

• Short term (next few years), this database ensures that patients and their treating physicians have access to the broadest data set of individualized treatments to best plan and manage their approach. This informs the decision to undergo treatment, enables therapeutic development according to data-driven best practices, while also being an important resource during active treatment to manage any safety events possible with such new therapies. Overall, the Data Coordination Center will help optimize the benefit/risk profile of individualized medicines for patients.
• Long term (next decade), the goal is for such a curated and high quality database to inform an expedited regulatory path for individualized medicines to ultimately enable greater access to all patients diagnosed with rare disease. Regulatory agencies require data in order to make thoughtful decisions regarding new treatment pathways, particularly in establishing safety guidelines and evaluating clinical outcomes to determine acceptable benefit/risk. Streamlined guidances would enable accelerated therapeutic development to help patients in need, and well-defined regulatory support would permit better payor ability fund such individualized treatments. Altogether, this would enable the goal to scale and standardize individualized medicines to become a standard of care for those with amenable rare genetic diseases.

Beyond patients, treating physicians, investigators, and drug developers will all benefit from a high quality database of platform treatments and patient outcomes for both improving drug platforms and learning about disease processes. Key expected learnings include platform-wide safety and efficacy profiles, dosing protocols, impact of retargeting on platform biodistribution and pharmacology, reversibility of disease pathology, relevant biomarkers and clinical outcome measures — all of which will be critical for iteratively improving the future generation of drugs for both rare disease patients and more common diseases treated using the same therapeutic platforms. 

The current data coordination center has been designed and developed by the Data Coordination Workgroup within the N=1 Collaborative, and has built a pilot database (v1.0) at Boston Children's Hospital that incorporates the clinical data from all ASO programs and patients initiated at Boston Children's Hospital. Based initially on the OpenClinica platform, the aggregation of longitudinal clinical data across 3 diseases and 4 patients (which includes 5+ years of data in the longest N-of-1 trial), we were able to determine clinical database needs across a heterogeneous mix of diseases (e.g., Case Report Forms, data fields and requirements), regulatory and legal requirements, and basic use cases such as in safety evaluation and data visualizations. From this resource, exports have been sent to by partners in industry and numerous academic investigators for use in designing their future N-of-1 trials, and we are currently gathering feedback. Across the total N=1 Collaborative membership of 600, we have provided more than 30 investigators and patient groups the N1C's protocols, data, regulatory documents, enabling more and more such treatments globally. We are currently working on the v1.5 database build, in which we are partnering with 2 additional institutions beyond Boston Children's in order to establish data infrastructure needs to accommodate patients across multiple sites.

Simultaneously, we have evaluated technology platforms and providers that can help the N1C scale this data model. Given the numerous existing data sharing platforms in rare disease, we first conducted a needs assessment and overview of available platforms and concluded that our unique use case of "near real-time" clinical data sharing across multiple sites and investigators required technical and operational innovations beyond the current platforms. We determined key pieces of technology that are particularly versatile and well suited to the needs of the N1C Data Coordination Center: Across Healthcare's Matrix Platform, the Broad Institute's Terra and DUOS (Data Use Oversight System) platforms. We have already drafted a Scope of Work so that learnings from the inter-institution, v1.5 build can be rapidly followed up by a more full-featured v2.0, federated database and data governance system built on the new platform. Additionally, we have also partnered with a leading preclinical ASO design platform by La Jolla Labs to bring their team's decades of experience in drug design to best inform what 'features' of the drug and clinical outcomes should be linked for maximum value.
As mentioned, the comprehensive solution requires both technological and social innovation. For the latter, the N=1 Collaborative, since its founding in 2021, has been promoting the value of data sharing in drug design. We have over 600 members worldwide, consisting of many of leading academics, patient advocates and families, and industry experts who understand the value of data sharing and the unique opportunity for impact within ultra rare diseases. We also have an initial Data Sharing Agreement, signed by 8 institutions from across the globe (including Boston Children's Hospital, Leiden University Medical Center, NIH, University of Colorado, Tokyo Medical and Dental University, National University of Singapore), providing a legal framework to facilitate data sharing for individualized medicines across these institutions.

 
This is just the start, but we believe that the momentum built across both technical and collaborative aspects will catalyze further growth of individualized medicines as a therapeutic approach for many rare diseases. 

"Breaking down data silos" is a frequent refrain in drug development with clear benefits, but few solutions have been durable. There are several key facets of the N=1 Collaborative's Data Coordination Center that enable an unique toehold in this challenging space:

• The intentional initial focus on ultra rare diseases with no current commercial prospects promotes collaboration for the sake of patients while circumventing complex financial incentives. Well-defined financial incentive structures are critical for the long term success of individualized medicines, but in the short term they can actively sabotage collaborative efforts.
• Most of the initial individualized medicines are being developed by academic investigators working closely with families and patient advocates, who are more incentivized to share data so that they can provide the best possible care to their patients.
• The N=1 Collaborative, as an independent nonprofit organization, is building and hosting the Data Coordination Center, providing a neutral, transparent data steward and standards body. 
• We are drawing upon substantial existing precedents and existing technologies, just combining them in a new way — we are not seeking innovation for the sake of innovation alone. In a highly regulated environment like drug development, precedents can be critical for stakeholder acceptance: we have methodically built upon existing practices and precedents, and are filling gaps with familiar technologies and experts so that a final solution, while innovative, is familiar and readily endorsed.

That said, the very practice of creating these individualized genetic interventions is new. For decades, the vision of truly personalized medicine, in which a custom therapeutic can be tailored to an individual's genetic condition, was more fantasy than reality — only in recent years have the technological, scientific, and medical advances have made this a real possibility. The rapid pace of change has meant that most clinical and drug development infrastructure today is ill suited to the unique needs of individualized medicines, where platform-wide data sharing will be essential for safe treatments and rapid iterative improvements over time. Breaking down data silos with our Data Coordination Center is necessary to ensure that the fullest impact can be realized with greatest speed, all for rare disease patients in need. 

We are seeking the visibility and access to expert networks if given the opportunity to present as a finalist at the Concordia Annual Summit, and if awarded the Amgen Prize. Spreading the "why" of data sharing in ultra rare disease is as important as the "how" of building the technical solution, so engaging business, government, and nonprofit leaders with the desire to create positive social impact will be catalytic to our work.

The named sponsor of Amgen is also important — as a pioneer in genetic technology and a leader in biotech, the support of Amgen and access to any resources through them would be transformative. While individualized medicines are primarily driven by academic investigators at present, industry participation is critical to scale these efforts, leveraging biopharma's deep experience in drug design, development, manufacturing, and distribution. Specifically, the N1C would like to creatively brainstorm new business models for individualized medicines with a partner like Amgen — is there a world in which a company can be successful by hitting many singles versus a few home runs, e.g., selling thousands of individualized medicines across many diseases, rather than developing singular "billion dollar molecules" for just a few diseases? Working together with a biotech leader like Amgen would be important for establishing credibility and sketching a path to commercialization (and scale/access) for individualized medicines as rare disease therapies.

The N1C was founded by representatives from two core constituencies: the expert scientific and clinical investigators that developed the first N-of-1 treatments and trials, and the patients and caretakers who such treatments benefit. It has now grown to over 600 members—clinicians, researchers, manufacturing experts, toxicologists, regulators, patient groups, industry representatives—dedicated to advancing the science and clinical practice of individualized medicine. Amongst our group are the investigators that organized the first three personalized antisense oligonucleotide trials (milasen, jacifusen, and afinersen, for Batten disease, FUS ALS, and C9ORF72 ALS), as well as others from over 30 institutions worldwide. The core operational team and Board of Directors of the N1C consists of members personally impacted by rare disease (Operations Manager, Program Manager, 1/6 Board Member) and those who actively work in treating rare disease patients or rare disease drug development (Team Lead, 5/6 Board Members). 

This is the larger organization that is available to support the Data Coordination Workgroup, who works closely with the core operational team and leadership to design, plan, and build the N1C Data Coordination Center. The workgroup contains industry experts on database technology and legal/regulatory needs to complement the investigators and patient advocates as the key end-users of this project. We believe that our open membership and intentional inclusion of patients, investigators, and industry will build a stronger solution that incorporates all of their needs from the beginning.

For the N=1 Collaborative, our goals for the next year fall on 4 pillars:

• Align & Share Best Practices: to establish standards & consistency across diversity of individualized treatment programs worldwide
  • This involves sharing via seminars, summarization on our website, detailed descriptions in peer reviewed publications, and hosting our first N1C Annual Meeting.
• Expand the Data Coordination Center: continue expanding the pilot, collect critical mass of data for improved safety/efficacy and ultimately support regulatory decision making
• Enable the N1C Member Exchange: build communication platform to provide resources, referrals, and support between N1C members to reduce redundant "backroom" discussions and increase sharing.
• Build Financial and Operational Sustainability: build a business model and financial runway for the sustainable operation of the N1C as a nonprofit to support individualized medicines for years to come. 

Within the next 5 years, we want to have:

• Industry/academia model for long term sustainability: established a valuable enough pathway that we have built a symbiotic industry/academic business model to deliver custom individualized medicines, much like how surgeons at major academic centers still deliver complex operations (e.g., transplants) but industry supplies the tools and technologies (e.g., catheters, devices) to enable the operation. 
• Regulatory streamlining: provide evidence to regulatory agencies to accelerate the development process for individualized treatments, eventually moving towards a 'process approval' for investigational new agents instead of a per-treatment approval. 
• Enable the growth of patients treated with individualized medicines approaches: this is really the only metric that counts — we want to track using our database how many patients are treated per year, how many benefit, and ensure that we are on the path towards treating the millions worldwide within the long tail of rare disease. 

The N1C Data Coordination Center (DCC) will standardize the development of individualized medicine and aggregate high quality data on treatment development and clinical benefit. 

First, even as the database is in its infancy, the aims to align and share best practices to reinforce standardized ways of data collection. 

This leads to higher quality data sets due to uniformity of data.

These emerging data can enable iterative learnings for drug developers, treating physicians, and investigators to improve safety and efficacy of drug development. 

The N1C helps convene these discussions at a regular cadence, which then will be used to update best practices in a virtuous cycle. 

After a few iterative cycles, these data-driven best practices and aggregated data on safety and efficacy can inform regulatory (e.g., FDA, MHRA, EMA) conversations aimed at streamlining processes and expanding regulatory approval for these investigational agents.

Efficacy data would also help payors (e.g., government, insurance companies) to justify cost reimbursement for the development and delivery of individualized medicines, unlocking business opportunities. 

Regulatory streamlining can speed up drug development timelines and reduce overall cost, which combined with modular platform therapies, can dramatically reduce Cost of Goods Sold (COGS) for new rare disease therapeutics. 

This incentivizes greater industry participation, increasing scale, and likely further driving down COGS, creating more treatments that are based on validated platforms and practices for safety and efficacy. A part of the regulatory requirements is to deposit future pre-clinical, manufacturing, and clinical data in the N1C DCC to continue the cycles of iterative learning.

Increased scale and reduced costs ultimately expands access for these treatments to more rare disease patients worldwide, particularly in ultra-rare indications for which traditional drug development is not incentivized. 

For the Data Coordination Center, the N=1 Collaborative has available:

• 2 Full Time Employees
• 2 Part Time Paid Consultants
• 5 Part Time Unpaid Volunteers (~10h/week)
• 14 members of the Data Coordination Workgroup

Across the organization, we have:

• 600+ Members
• 65 active volunteers across workgroups
• 6 Board Members

1.5 years

Rare disease knows no borders so our team is intentionally global, open to membership, and has no barriers to engagement. That said, we recognize that caring for an individual affected by rare disease is a full time role in addition to needing to provide for one's family; thus, actively seeking out the perspectives and needs for those who may not have the time to engage with this community is important to make sure that their needs are met. While our team currently has strong representation across genders and developed countries, we are aware that rare genetic diseases can disproportionately affect developing countries due to social practices and large families — our goal is that once these processes are established, that we increase our outreach to both physicians and patient groups in those geographies to help build a solution that is 'right-sized' for their country. 

In the meantime, we strive to make our resources as accessible as possible, such as recording our seminar series for later review and making publicly available guidelines and resources from the N1C. 

We have initially raise funds from government grants, foundations, and corporate sponsorships to bootstrap the first build of the Data Coordination Center. As the practice of individualized medicines emerges, it is important to set a precedent for data sharing and have the infrastructure available to support this practice. 

The goal is then to supplement financing from grants with a membership-based business model for both individual participants (e.g., investigators, drug developers) and institution membership for larger entities such as academic hospital centers or biopharma drug developers. The relevant precedents are public private partnerships on platform technologies such as the Bespoke Gene Therapy Consortium, as well as treatment databases to support quality programs in medical specialties such as the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. 

The progress of the N1C to date has been generously supported by the Chan Zuckerberg Initiative, with an initial grant of ~$300,000 supporting the establishing of the N1C in Sep 2021, with a follow-on for building a pilot Data Coordination Center (~$700,000) in Nov 2022. 

In addition, we have been building a corporate sponsorship program since 2023, and in the first year have received ~$130,000 in direct ($116,000) and in-kind donations (~$15,000) to support N1C activities. We anticipate that as our programmatic activities increase and our outreach expands, we will be able to further engage more corporate partners with both financial and in-kind donations to support our work. It is clear that as a therapeutic paradigm, individualized medicines for rare diseases is an area of significant interest amongst academic investigators, patient advocacy groups, and the biopharma industry, and we aim to leverage this interest towards greater revenue through grants and support in the future.