Accessibility of Gene Therapies: Exploring the Continuum from Patient-Specific to Market Approved Therapies

At one end of the spectrum lie the diseases with only a handful of patients worldwide. As sequencing technologies have improved and the costs have decreased, more patients (often children) have been diagnosed with unique genetic diseases. While the technology to treat these diseases exists, getting treatments to patients presents various challenges. The n-Lorem foundation, started by Ionis Pharmaceuticals founder Stanley T. Crooke, MD, PhD, aims to address some of these challenges. N-Lorem is based on the antisense technologies (ASOs) pioneered by Ionis. As Joseph Gleeson, MD, chief medical officer of n-Lorem, explained, ASOs have various advantages for treating n of a few diseases: ASOs can treat a variety of different types of mutation, they are inexpensive to manufacture in large quantities, and they can be developed relatively quickly and more cost efficiently than many other technologies. These characteristics make the goal of n-Lorem to develop therapies for n of a few diseases and provide these drugs to patients free for life. In addition, the FDA has signaled its support for such approaches, issuing guidance documents for developers of n of 1 ASOs. However, approaches such as those pioneered by n-Lorem will only go so far. In particular, there are types of mutations and tissues that ASOs cannot yet address and ethical issues involving access to treatment. Furthermore, out of necessity, the foundation and others like it have limited capacity. The model is, therefore, unlikely to fully and sustainably address the problem of developing therapies for n of a few diseases.

While our goal is to ensure that all patients who could benefit from CGTs can access treatment, personalized approaches pose a number of ethical questions. In particular, says Alison Bateman-House, PhD, MPH, questions regarding the equitability of access to treatment. Drugs designed to treat small numbers of patients are subject to different standards than those designed to treat larger patient populations, and because many of these personalized medicines are supported by private, family-run foundations, patients whose families have more resources disproportionally benefit from these approaches. Within the U.S., inequitable access to testing, diagnosis, specialized clinicians, and research amplifies these disparities. The picture globally is even worse, with the current market-driven drug development model failing to address the needs of a number of different types of patients, including patients with diseases that are common in developing countries. Despite contributing disproportionally to the global health burden, these diseases are often left behind. Funding for research and development for these diseases then falls to governments. In terms of societal benefits, this has some advantages, as government funding comes with reporting requirements. These requirements do not exist for research and development funded by private foundations. Dr. Bateman-House suggests that we need to build an ecosystem where we can learn from patient experimentation and use that knowledge to benefit society as a whole.

While Dr. Gleeson and Dr. Bateman-House focused on the development of personalized drugs, expanded access, as detailed by Barry Byrne MD, PhD, provides an opportunity for individual patients to access investigational drugs outside of a clinical trial. According to the FDA, expanded access may be appropriate when a patient has a serious or life-threatening disease with no available treatment alternatives, the patient cannot be enrolled in a clinical trial, the potential benefit outweighs the risks, and providing the product will not interfere with investigational trials that could support the further development or approval of the product. In some cases, manufacturers hesitate to supply an investigational product because of this last stipulation. Despite this, the majority of expanded access requests are granted.

Beyond expanded access, clinical trials for gene therapies often present unique challenges. Conventional clinical trials for gene therapies, Dr. Byrne explains, often are designed to have an initial phase I/II dose escalation study with 2-3 cohorts, followed by dose selection and a phase IIb confirmatory study. In contrast with more conventional drugs, the phase IIb study for gene therapies is often designed as a delayed start placebo-controlled study. This means that participants who initially receive the placebo will later cross over and receive the treatment. For the types of serious diseases that many of these products are intended to treat, there are risks to this design. For example, patients may seroconvert or become ineligible due to the loss of functional capacities that are required to participate in the study. However, there are a variety of reasons to choose this design rather than a concurrent placebo-controlled study, like small patient populations and ethical considerations. Regardless, depending on the characteristics of the disease, the population, or another consideration, alternative controls may be considered.

The small size of many of the patient populations that gene therapies are designed to treat often presents problems for clinical study design, recruitment, and analysis. Demonstrating efficacy or a change from controls is difficult. Very recently, the FDA has signaled they might grant accelerated approval for a surrogate endpoint that could be expected to predict favorable clinical outcomes; however, these outcomes tend to be messy. Alternative clinical trial designs could address some of these challenges. For example, Dr. Byrne suggests that adaptive designs, which allow changes to the design based on accumulating data from the trial might better leverage small patient populations. FDA guidance does address such adaptive designs. These designs can allow access to treatment for populations that are so small that the evidence cannot reach the threshold for marketing approval.

Scientific concerns have also limited potential clinical trial design. For example, there is a belief that once a patient has received an AAV gene therapy, the presence of neutralizing antibodies would preclude ever dosing that patient again. However, significant progress has been made in this regard, and it is now possible in some cases to dose patients repeatedly, allowing sponsors to perform within subject dose escalation. As we accumulate knowledge and listen to patient input, clinical study designs will likely continue to evolve.

Clinical trials can provide patients with early access to potentially life-altering treatments. However, participation in trials is low, particularly in disadvantaged communities. Rae Blaylark, an experienced patient advocate, suggests that there are a number of reasons for this problem. At the most basic level, patients may not be aware that clinical trials exist, and conscious or unconscious bias can affect whether medical professionals educate and inform their patients further. In addition, factors such as a historical lack of trust in medical and research institutions and a lack of representation can drive participation down. Racial and financial minorities may be excluded from clinical trials because they do not satisfy the inclusion criteria; this can be due to environmental factors. Considering who may be left out of clinical trials is one key to improving patient outcomes.

Blaylark suggests the barriers that keep clinical trial participation low may be systemic, organizational, communal, personal, or cultural. On a systemic level, improving clinical trial awareness and participation requires human interaction and engagement, increased representation, and removal of financial barriers. Communication between patients and medical providers requires a common language, free from medical jargon. Clinical trials outreach must also be tailored to communities, which requires an understanding of community structure: where do people get their information and who do they trust? Who are the leaders in the community? Personal barriers to participation might include limited experience with clinical trials and a lack of representation or personal and community biases. To overcome these challenges, we need to create a welcoming, compassionate, and empathetic environment—one that includes a diverse research team and engagement in communities. Engagement, in this case, is more than just approaching the community when we need their help, but being a part of the community in other ways that involve human interaction and understanding struggles and strengths. We need to create safe spaces and ensure accessibility by putting trial sites in the communities and addressing affordability. Doing these things can go a long way toward realizing the potential of CGTs.

The barriers to access do not disappear once a CGT product is approved. Companies have a number of strategies to increase access. Companies like bluebird bio and Bristol Myers Squibb which have approved cell therapies, have various strategies to ameliorate this problem. Clark Paramore, MSPH, (bluebird bio) and Jasmine Greenamyer, MPH, (BMS) detailed some of the steps that their companies are taking. Two of the major hurdles CGTs face are (1) demonstrating value to payers and (2) ensuring access to the communities who would most benefit from the products. Engaging with patient communities and advocating on their behalf is critical to overcoming these barriers. Placing treatment centers within the communities they serve so that patients do not have to travel long distances reduces the burden of treatment by reducing disruptions to the patients’ lives. Community engagement, advocacy, and representation are critical to ensuring access.