Pharma and patient advocacy: Allies in the quest to develop rare disease cures

Many of the rare disease treatments currently on the market would not be there without the dedicated work of patient advocacy groups (PAGs). These groups are often spearheaded by individuals deeply connected to the cause, such as parents of children diagnosed with genetic conditions like Angelman syndrome, Duchenne muscular dystrophy or FOXG1 syndrome. PAGs provide several vital services that help bridge the gap between patients, providers and manufacturers by amplifying the patient voice while speaking the language of pharma.

In the first installment of our two-part series on rare diseases, we highlighted the significant role and impact of PAGs on the path to commercializing treatments for rare diseases. As important as they are to the commercial side of pharma, research and development (R&D) is where they can really move the needle and serve as the catalyst for groundbreaking advances, and that’s our focus here. Historically, patient groups have taken part in everything from funding scientific research to exploring disease mechanisms to developing animal models of disease for study.

Given the urgency to develop new products for the estimated 400 million people around the world affected by rare diseases, it’s imperative that pharma companies engage with PAGs earlier to foster closer, more frequent and more comprehensive collaborations. This approach is essential to accelerate the development of new therapies and to ensure that the voices of those most affected by these conditions are heard throughout the pharmaceutical value chain.

One of the primary challenges of rare disease treatment is a lack of understanding of certain diseases’ natural history. There is an urgent need for a concerted effort to contextualize rare diseases and their causative genes. This endeavor calls for collaboration from researchers, pharmaceutical companies and regulatory bodies to develop standardized, validated models for studying disease biology and quantitatively assessing disease impact over time. Such models are vital in ensuring a thorough understanding of disease mechanisms before selecting therapeutic treatments, especially in gene therapy, which involves DNA manipulation.

PAGs play a crucial role in this process, often leading the way in establishing patient registries, biobanking programs and identifying research gaps. Unfortunately, the challenge of data fragmentation complicates the scenario, as decentralized data sources hamper the effectiveness of these programs due to the small and incomplete nature of datasets. More robust advocacy from commercial stakeholders is also needed to amplify these efforts, mobilize greater resources and bring attention to the unmet needs of patients.

Despite the preponderance of data sharing initiatives, concerns linger regarding how patient data is accessed and used. Rare disease patients may be reluctant to share their data if they’re worried insurance companies will use it to drive up premiums. What’s more, data collection challenges such as accurately capturing data from genetic tests and the results of invasive, confirmatory procedures can hinder the effective application of advanced data analytics in the rare disease field.

Pharmaceutical companies stand at the forefront of ensuring data privacy in the rare disease drug discovery process. Establishing robust data sharing frameworks is critical for protecting patient privacy while fostering the ethical use of information. Additionally, investment in AI and machine learning (ML) training programs and the creation of innovative solutions like patient-level blockchain tokenization, can significantly improve the utilization of these technologies, improving data privacy while potentially revealing deeper insights into the genetic underpinnings of rare diseases.

Successfully accelerating the identification of treatments for rare diseases depends on how well pharma companies foster collaboration, ensure precision and commit to long-term strategic planning. A companies’ ability to understand the downstream impacts and the sustainability of responses to treatments is a gradual process that hinges on comprehensive studies of disease biology. This involves quantifying the disease’s impact over time and gaining a sound understanding of its mechanisms before selecting therapeutic treatments, particularly in gene therapy.

Many companies are investing in advanced AI-driven translational science programs to more efficiently define targets and design therapeutics to meet these needs. While AI-driven drug discovery is promising, multiple products using this technology have failed to meet clinical endpoints over the past year. Coupling AI’s power with scientific expertise to hasten the drug discovery process and find quicker solutions will be critical to pharma’s ability to advance drug development.

One approach that’s helped speed up discovery in recent years is drug repurposing. This is a developmental strategy in which existing drugs, such as those already approved for one disease, are tested for their efficacy in treating other conditions.

While there’s significant promise with this approach, especially considering 505(b)(2) pathway benefits, identifying new indications for an existing drug requires robust scientific evidence and faces several challenges, including inadequate investment and issues in accessing appropriate on-label or discontinued therapeutics. For example, Catalyst Pharma identified the potential value of leveraging Firdapse, or amifampridine, for Lambert-Eaton Myasthenic Syndrome through biomedical research.

Initially used to treat congenital myasthenic syndromes, Firdapse received FDA approval in late 2019 after a confirmatory study proved it to be valuable. Creating a centralized information repository could further streamline the sharing of knowledge and resources, facilitating quicker access to potential treatment options. Moreover, the advent of advanced genetic medicines, such as CRISPR gene editing, highlights the need for continued investment and monitoring due to concerns over off-target effects.

While the recent regulatory approval of exa-cel (formerly CTX001, in sickle cell disease) in December 2023 by Vertex and CRISPR Therapeutics represents a meaningful scientific breakthrough. Concerns over off-target effects means that the continued exploration of more advanced genetic medicines will require meaningful investment for future success.

Ultimately, these combined efforts in advancing technology, enhancing collaboration, and investing in long-term research and monitoring are key to overcoming the challenges associated with the speed of treatment identification for rare diseases.

Investment in disease areas with blockbuster potential, such as Alzheimer’s and obesity, is overshadowing the needs of rare disease research. To address this imbalance, regulatory bodies must play a pivotal role in encouraging a more diversified investment landscape by offering incentives for R&D in overlooked therapeutic areas. Direct financial incentives, such as grants, subsidies and tax credits, or regulatory mechanisms, such as priority review vouchers or reduced regulatory fees, can encourage companies to invest in areas that might not otherwise be considered financially viable due to smaller patient populations or higher uncertainty.

Additionally, pharma companies and PAGs can collaborate to leverage nontraditional funding sources, such as philanthropic venture capital, and establish strategic partnerships to de-risk the development process in these less ventured areas and advance rare disease research. This collaboration can take various forms and serves to pool resources, expertise and networks to drive forward the development of new treatments.

One of the significant hurdles in rare disease R&D is the lack of streamlined regulatory pathways, coupled with the slow adaptation of approval processes, which often disincentivizes the pursuit of innovative treatments. To overcome this, there is a need for more transparent communication between industry players and regulatory bodies. Furthermore, the establishment of adaptive regulatory frameworks can facilitate quicker and more efficient development cycles, helping to land “more shots on goal.” Again, the most effective changes come when these groups work together. Establishing a shared responsibility requires coordinated efforts from all stakeholders involved in drug development and regulatory processes. While regulatory bodies have the primary responsibility for creating, implementing and adapting regulatory frameworks, pharma is at the forefront of developing new treatments, and PAGs play a critical role in advocating the voice of the patient.

Implementing industrywide standards for platform development approaches could also streamline the R&D process, allowing for a more cohesive and effective strategy in tackling rare diseases. If stakeholders adopt these and other measures, they can transform the R&D landscape for rare diseases into a more fertile ground for innovative treatments and therapies.

It’s essential that pharma companies pursue efficient and innovative approaches to clinical development when working to obtain timely regulatory approval in rare diseases. The small patient populations characteristic of these diseases make traditional study designs significantly more challenging, particularly in patient recruitment. With patient populations sometimes as small as 50 patients worldwide, traditional study designs like placebo-controlled trials can make it difficult to recruit patients. But this is another area where pharma can collaborate with PAGs. These groups have deep experience developing patient registries, which can streamline the identification and recruitment of eligible participants, and that can make the trial process more efficient.

Another approach pharma should consider is using retrospective natural history studies as comparators in clinical trials. A well-executed natural history study can prepare a group for a clinical trial by characterizing the natural course of a disease over time. Success stories like Zolgensma in spinal muscle atrophy or Rocket Pharma in Danon disease show the feasibility of leveraging historical control data in studies to replace a concurrent control. By reducing the number of required patients, historical controls may make enrollment of rare disease clinical trials more feasible.

However, this approach requires a deep understanding of clinical endpoints and natural history. Alternative approaches may allow treatments to bypass traditional phase 1 and 2 studies under the 505(b)(2) pathway. To ensure the effectiveness and credibility of these studies, it is vital to establish clear guidelines and standards. These standards should focus on the use of retrospective studies as comparators, emphasizing transparency and reliability in the process.

The U.S. Food and Drug Administration has demonstrated that it’s open to reviewing new trial designs, including the use of surrogate endpoints, but this requires early engagement from developers and the provision of substantial evidence to support these innovative methodologies. Encouraging the sharing of successful case studies can play a crucial role in building confidence in nontraditional trial methodologies. Such shared knowledge can help pave the way for more flexible and effective regulatory processes, ultimately speeding up the path to approval for new treatments in rare diseases. Adopting these strategies can transform the regulatory landscape, making it more conducive to the unique challenges posed by rare disease drug development.

Pharma companies also need to make meaningful investments in AI and ML tools to improve site selection and recruitment timelines.

Ensuring long-term safety of a therapy, particularly in advanced treatments like CAR-T and gene therapy trials, remains a prevalent concern in rare disease. One proposed approach to address this challenge has been to design advanced vector systems, such as more sophisticated delivery mechanisms used in gene therapy to transport genetic material into patient cells to treat or prevent disease. While next-generation vectors have the potential to enhance safety profiles and capacity, control gene expression and minimize risk, they also pose practical challenges. Industry stakeholders are often deeply invested in existing commercial products, which makes it difficult to integrate new vectors into current pipelines.

What’s more, patients with unmet needs require solutions that are both accessible and effective without undue delay. Therefore, our focus must include not only the exploration of new scientific possibilities but also the diligent optimization of existing therapies. Pharma should continue to optimize and refine existing therapies alongside early-stage scientific exploration of new vectors. This dual approach aligns with the immediate and long-term needs of the patients.

As a second option, leveraging biomarkers or proteomics for precise patient identification can significantly enhance safety. By identifying patients who are most likely to benefit from specific therapies and those at risk for adverse reactions, treatments can be tailored more effectively. This precision medicine approach not only improves the safety profiles of therapies but also ensures that patients receive the most suitable treatment based on their unique genetic makeup and disease characteristics. To ensure long-term safety is a priority for rare disease therapies, pharma will need to work collaboratively across the research, clinical and regulatory landscapes.

Despite the very real barriers to rare disease R&D, a collaborative effort between PAGs, pharma companies and regulatory bodies is valuable. By leveraging patient registries, AI-powered drug discovery and innovative clinical trial designs, stakeholders can accelerate the identification and approval of new treatments. Continued investment in long-term research alongside the optimization of existing therapies ensures a future where patients with rare diseases have timely access to safe and effective treatments.