Rare Diseases: Reverse Engineering for Drug Development

main_img

Monica Weldon draws on her own experience as a rare disease patient advocacy group CEO to outline how such groups can work collaboratively with other stakeholders in drug development to better target funding and create a more patient-centric drug development process that ultimately gets better drugs to rare disease patients more quickly.

 

How did we do it?

Collaboration and education are the keys to accelerating treatments in the rare disease community. There must be a concerted effort to partner with patient advocacy groups in academia and the clinical world of research. As our foundation grows, we quickly adopted the model of leveraging partnerships to drive analysis using real-world data and other methods that accelerated research and available funding in both the private and public sectors.

Many advocacy leaders have approached me and asked how our organisation has expedited to get to where we are. We have been incredibly fortunate to have 20 years’ worth of animal model data that has been studied and accumulated over that period, giving us an upward advantage of being closer to translational science than most newly discovered genetic diseases.

We built this model with our scientific advisory board, which is the most critical component of an organisation to meet short- and long-term goals. Many rare disease organisations struggle to find direction and specific goals to achieve while moving at an accelerated pace. The key is selecting specific targets and growing that focus. This concept, in many similar ways, parallels how precision medicine works.

 

Strategy is everything!

The landscape of research is changing, and so is the role of the patients and caregivers. Due to the inherent challenges facing rare disease communities, such as relatively few patients spread across a large geographic area, few scientists, and clinicians familiar with disease biology, all stakeholders must work together for the best strategic outcome. We found ways to leverage our assets (data) and community engagement to help support our scientific adviser’s endeavours. Organisations like ours, the SYNGAP1 Foundation stewarding our patient databases, have put the patient community at the centre of all drug development.

Why? Because in the past, traditionally, the common trend was keeping patients outside the circle of drug development. Instead, academic institutions, hospital systems, drug developers, and regulators decided on how and in what direction drug development should occur without considering the value of patients and their caregivers living the experience at the grassroots level. Creating a more patient-centric model can help de-risk drug development in ways that were not done before. Adding patient and caregiver experience to every step of drug development can help coordinate a focus on the reality of how they lived and coped daily with the disease that will most benefit their quality of life while advancing translational research, creating more efficient Natural History Studies, and much better designed clinical trials.  We learned that the value of intertwining academia and clinical worlds of study is much more attractive to outside investors and pharmaceutical companies in the future once a possible treatment comes available.

Strategic planning can only occur with a good understanding of the rare disease landscape. Investing time and education and knowing the stages of research and drug development fitting into where we were was the most critical part. That came from attending many conferences and meetings that focused on various areas of drug development, from clinical trial design to registries, the types of Natural Histories, as well as regulatory policy and how it affected everything else. This phase takes nearly two full years of constant immersion within drug development from beginning to end to understand the full scope of barriers in the rare disease landscape. One of the most critical steps we made was engaging with the Food and Drug Administration (FDA) to learn more about the types of paths, how drugs were approved, and the best application of those paths to a clinical trial. We need to know what the test covers to understand how to put together our goals and activities to get there.

 

Achieving Better Business Goal Outcomes

Once a clear picture of how all the moving parts work emerges, an organisation has a much clearer picture of where its focus needs to lie. You can’t do everything at once, but you can utilise resources and common sense to move in the direction you need to be more effective. It’s not just money that makes things faster. When patients and caregivers are desperate, it is easy to grasp onto anything that appears to be hope. However, without an understanding of the moving parts within research, money invested can easily be wasted on projects unlikely to move to the clinical stage.

Many organisations give money to any researcher with their hand out, thinking they will get a cure-all, and in some cases are just funding junk science. Additionally, start-ups that prey off families willing to do anything to have a “mouse” created for precision medicine often pop up, despite the fact that moving to even an N=1 cannot be achieved due to there being no natural history study completed, validated endpoints, outcomes measures, or biomarkers. This leaves desperate families with empty bank accounts, drained of hope, while for-profit companies line their pockets.

Therefore, it is important to know the difference. There is a more specific order to follow when getting to treatments. Many hours of listening to experts speaking about the things to focus on is crucial. There can be no shortcuts. Shortcuts can cost valuable time and money and force you to return to redo what you missed. Many factors must be considered when an organisation needs to get all the necessary pieces in place and at the right time.

 

Timing is everything, and there is no downtime

Advocacy organisations are sometimes not treated as businesses. However, it is a significant business, and managing it correctly is vital. The stereotype that is very common amongst the public is that non-profits should not have paid employees. I beg to differ. The old saying, “you get what you pay for,” is true. Getting the desired outcome will take experts when dealing with such a complex and long-term goal. Experts in all reality will not work out of the “goodness of their heart.” Don’t buy into that. It won’t work, and your programs will end up just like that high school group project you were in, where “you” ended up doing all the work while the others sat back and directed traffic or only showed up for the presentation and claimed all the credit.

 

Understand All Moving Parts of Drug Development

There are several moving parts an organisation must consider. The most important is how you will increase growth, NOT just increase finances. Being frugal when you have nothing is probably the best growth you will ever have. “Necessity is the mother of invention.” This is true, and you learn to be careful and aware of every next move. It would help if you imagined your moves two to three steps in advance. This is a risk assessment. You have plan A, but before moving forward, plan for the curve balls that life throws you and be ready to adjust if necessary. Many organisations make that their one fatal flaw when strategising. Have a backup plan for everything. Every aspect of your organisation, such as advocacy and awareness, patient engagement, development, and research, must simultaneously work to grow your mission. Still, with careful planning, it takes a lot of time.

 

Our Strategic Steps

Before moving into our strategic plan, our organisation consulted our medical advisory board to determine where they were in the research, discussing what they knew and what more important questions they had been asking. To better understand what was happening, we planned a stakeholder meeting. This meeting included researchers, clinicians, and patient families, taking the guesswork out and focusing on what was essential to the families while putting a face to the disorder for the researchers who had never met a patient. The conference helped pinpoint the areas our organisation needed to fill in as priorities.

The next focus was creating a registry database related to providing the information needed to help scientists understand how the gene was working. If there is an understanding of the gene’s function, it puts us on the path to targeting possible drug candidates for treatments. Effective patient engagement strategies will produce valuable gains in accelerating treatments while building beneficial collaborations that support it in the rare disease space.

The other added benefit of sharing information was the fostering of a more significant interest in our rare disorder. Our experience is that this level of cooperation will improve outcomes for everyone involved. Discussing strategies, creating solutions, and implementing programs designed by and for the specific population that needs them, is how we plan to move forward as a community.

The benefits of collaboration with vested groups of rare disease experts and the patients and organisations that support their research will expedite treatments. The patient organisation must understand the rare disorder research landscape and the emerging standards for clinical care. This level of understanding will facilitate the construction of programs that fulfil both scientific and patient needs. This synchronising of research priorities with foundation programs will help drive and accelerate the process of finding answers to many questions, especially if the organisation is in translational science and drug discovery. We have seen that by maintaining an open dialogue with our scientific advisory board and outside interested researchers, we can directly reshape the landscape of the rare disease space while setting standards for clinical care and possible therapeutic solutions.

 

Our Model Works

Our organisation started the work to find the current ASO therapy in pre-clinical development in 2016. In five years, we were able to target funding streams through government funding and create a robust longitudinal natural history study that provides the needed observable recorded outcomes or Real-World Data. The most significant step was obtaining our database platform through the IAMRARE® Registry Program with the National Organisation of Rare Disorders, initially funded by the Food and Drug Administration (FDA) in 2015.

In tandem, the collaborations between researchers and clinicians began. This resulted in building off the current twenty years of basic science on SYNGAP1, gathering clinical data, and intertwining data from the SYNGAP1 (MRD5) Natural History Study and Registry. By combining our efforts with these collaborations, we could harness several significant awards for our partnering researchers by providing letters of support for their work. Our first dated August 14, 2015, to evaluate mechanisms in repurposed molecules to determine targets by narrowing down the field using the self-reported data from SYNGAP1 caregivers. This information provided valuable insights to the basic scientists that used it to design their research studies better and begin the translation of mechanisms in the SynGAP protein. The advances not only opened doors to finding therapies but also the needed outcome measures, biomarkers, and endpoint discovery to begin the pursuit of capturing the pharmaceutical and biotech world but also building capacity bringing other interested researchers to the forefront. Additional letters of support from our work helped fund the discovery of the Sensory Processing Disorder mechanism published in Nature Neuroscience linked to autism and several biomarkers and endpoints from the SYNGAP (MRD5) Natural History Study and Registry. A letter of support was submitted to the grant awarded by the National Institutes of Health (NIH) on February 11, 2017, in the amount of USD 3.6 million.

These small building blocks of information led our organisation to coordinate a small cohort of SYNGAP1 patients in July of 2017. Each patient and one neurotypical fraternal twin acted as the control and provided blood samples, converting them to neurons in apheresis. The iPSC stem cell lines were delivered to Scripps, where drug assays were conducted, resulting in the ASO studies being researching the ASO studies being investigated now. The National Institutes of Health awarded 2M dollars million dollars by the National Institutes of Health for drug assays studies. The molecule was then pitched to companies to help develop therapies for patients with SYNGAP1.

Our combined efforts led to Molecular Neuropsychiatry which led to the first potential therapy for SYNGAP1 patients in less than five years.

 

Grit!

It takes grit to achieve this, and we did it on a slim budget. Most of the money comes from tax dollars, and small community-funded seed grants went to the needed funding to support this effort through the government. Our organisation has to date secured over USD 25 million with our multi-pronged approach. We have a validated endpoint, potential biomarkers, and outcome measures for clinical trials and the steps around natural history studies help ensure access to a drug when it becomes available. We are risking a failed attempt that we have been working so hard towards without comparison to judge a drug’s effectiveness in improving quality of life. Natural history studies provide that, using real-world data and making patients the centre of research, the chances of clinical trials failing are much higher. Without good regulatory and legislative policies in place, we may have an available drug, and the worst case would be our patients do not have access to it.

There are so many things to prepare for to move the needle. Our model is reproducible ONLY if everyone works together for the common goal, STRATEGICALLY. We are a decade ahead of most diseases in drug development, beginning to end; it took five years for a drug molecule to develop—the work we did as an organisation we strategised alone. It can be done. It will take rolling up your sleeves, having grit, perseverance, tenacity, and a will to get things done regardless of your challenges. Learn from those who went before you and anticipate troubled waters ahead. No path is easy for a pioneer because they always take the arrows.


Related Content


Latest Report