Richard Horgan

COVID-19 has radically transformed society and has especially transformed the potential for drug development’s acceleration. For rare and ultra-rare disease populations, the pandemic has shown these groups the potential to create, test and conditionally approve an effective therapeutic for a disease that’s killed over 400,000

 Americans as of January 2021. While an infectious disease is biologically different from a genetic disease, the framework of rapid development, testing and conditional approval is one that can be used by society to advance therapeutics for orphan and
rare diseases.

The concept of rapid prototyping, testing and approval for small populations is one that Cure Rare Disease has pursued for its rare and ultra-rare disease patients who lack effective treatments since its start in 2018. Cure Rare Disease is a unique organization–a nonprofit biotechnology company dedicated to creating an ecosystem supportive of N=1 (or a few) drug development–an ecosystem including payer reimbursement and clear guidelines from our regulators.

Key to this ecosystem’s development is the interdisciplinary collaborative network that Cure Rare Disease forged. A collaboration that includes leading academic investigators, preclinical, regulatory and manufacturing expertise alongside disease luminaries. Rather than traditional clinical trials with a varying number of patients, the therapeutics under development are designed to remedy the individual’s genetic mutation–starting with the neuromuscular disease class. These N=1 (or a few) trials will forgo the traditional placebo–a questionable practice for fatal pediatric diseases with well-established natural history–and instead treat the pre-treated individual as a control when combined with rich natural history data. Improvements or stabilization of the disease’s progression are the ultimate determinants of success and are driven by both biomarker and functional endpoints based on the individual. This means that for non-ambulatory patients there will be no exclusion from participation but rather a trial whose endpoints are centered on upper-limb improvements and pulmonary capacities alongside increases in dystrophin (in the case of Duchenne muscular dystrophy) protein. The freedom to experiment with new and potentially impactful endpoints is an advantage of nonprofit drug development–a chance to experiment with the status quo in hopes of finding a better alternative that allows more patients to participate rather than be excluded based on factors out of their
own control.

As a lean organization, the power of collaboration has continued to catalyze the speed of therapeutic development. An example of this is the ability of the team to understand how one’s role as a collaborator contributes to the primary mission downstream rather than a more traditional silo structure of talent with barriers separating discovery to preclinical development and beyond. Through a collaborative structure, individual therapeutics are designed in a holistic manner with inputs from downstream processes such as manufacturing and regulatory support inputted into the initial construct design aimed at avoiding pitfalls further down the development path and ultimately save the most precious resource to patients: time.

Though a young organization, Cure Rare Disease is preparing for its first clinical trial in 2021–a single patient CRISPR-based transcriptional activator targeted to rare mutation on the dystrophin gene for a 25-year-old patient. As a first-in-human for this therapeutic modality, the speed with which this drug was designed is notable. The approach began in 2018 with an initial muscle biopsy. By 2019, proof of principle was established and by 2020 proof of efficacy was shown in-vivo. Engaging the FDA from an early time point helped to paint a confident development roadmap as did the trailblazing work from an earlier program led by Dr. Timothy Yu at Boston Children’s Hospital.

 Through this collaboration, a new way of advancing life-saving medicine is born–a furthering of the template first forged by Dr. Yu in an effort to define a path for families, academics and clinicians to treat even a single patient impacted by a genetic disease.

Behind the first patient are several other patients with varying genetic deletions and duplications –primarily on the dystrophin gene but not exclusively. In using the first patient as a proof of concept for not only the modality but for the framework, Cure Rare Disease marches forward with a trove of experience and insights regarding the development of tailor-made (mutation-specific) therapeutics. It would be a disservice to the collaborative network not to mention the lengths to which these collaborators are willing to go to support this vision–all giving some to support the growing realityof customized therapeutics.

The collaboration has led to additional questions that seek to challenge the status quo regarding the potential for investigators and drug developers to innovate in how preclinical testing and development are done. Concepts from as the potential for 2D and 3D tissue modeling in lieu of an animal model to test efficacy to common delivery platforms in the case of AAV reducing the need for repetitive vector toxicology. These concepts are those that the regulators and NIH are now considering

 and concepts that Cure Rare Disease is putting into action to shift from the theoretical to the practical.

Essential to a patient-centric collaboration is the patient and patient family. Through Cure Rare Disease’s drug development program, the patient and patient family are key contributors to enabling the successful development of a customized therapeutic. Patient families are required to contribute biological samples to enable the research team to understand the mutation, its break points and other aspects as if a custom drug is to be developed, the target needs to be well defined and characterized. Beyond the contribution of biological samples, the patient and patient families are kept frequently informed of progress in an effort to reduce the anxiety and uncertainty that families face in the race to develop a therapeutic. Ultimately, the goal is to have an aligned team aware of the challenges and unified around the singular goal of developing a customized drug.

The outbreak of COVID initially forced drug makers to shift R&D focus and delay non-COVID clinical trials even though disease progression does not slow. Now almost a year later, the drug development industry has become far better at managing development and clinical trials that are in-part remotely conducted. For Cure Rare Disease, which began as a virtual company, the segue into a forced virtual environment was a relatively seamless one as it relates to preclinical development. Rather than conducting efficacy studies through our academic collaborators, it became essential to shift these studies to facilities deemed exempt in order to maintain continuity of research. Zoom and Microsoft Teams became even more essential technologies to allow our multi-national collaboration to continue to drive progress.

While preclinical development was able to be shifted with limited impact, two areas that were not as fortunate in the current climate are logistics and clinical operations. In shipping high-value materials domestically and internationally, the already-stressed shipping channels proved to be challenging. It was here that extreme attention to detail became especially important. For Cure Rare Disease, this meant continuously tracking various shipments in coordination with the recipient party and even a Christmas Eve FedEx handoff to ensure material integrity. As the world begins to return to “normal”, issues surrounding shipping and logistics will likely be reduced but the learnings remain that contingency plans are critical when time-sensitive materials are on the move–insurance, extra packaging, dedicated resources to tracking and resolving issues as they arise and a clear line of communication between the senders and recipients.

Beyond the logistical challenges that COVID-19 has brought came the potentially larger challenge of conducting clinical trials. For Cure Rare Disease, patients undergo immune suppression to enable the delivery of AAV-mediated therapeutic. Therapeutic administration is conducted in either the PICU or the ICU. During the height of COVID-19, ICUs across the US became inundated with COVID-19 patients thereby forcing the delay of gene and cell therapy trials. A recent report by McKinsey cited that 45% of respondents (cell and gene therapy companies) expected delays of 3-6 months on average for development programs.

 Diving into the details, delays regarding site activation for clinical trials, patient recruitment for trials and follow up appointments of enrolled patients were top areas of delays with 55% of respondents citing these three areas as delayed.

While these delays are temporary, the lessons learned from the COVID-19 experience are not. Lessons such as allowing virtual trials visits informed by diagnostic tests being done locally rather than having the patient go to a clinical trial site thereby limiting visits, trial burden and potential exposure (even in a post-COVID world). For instance, to what degree is it possible to have trial participants have diagnostic scans and blood draws done in their hometown (or nearby city), and then have that information transmitted to the trial site for accumulation for the trial sponsor? This is known as decentralizing clinical trials. This suggested change may ultimately benefit the trial sponsor in enabling greater enrollment for families who previously would not enroll due to the trial burden and traveling. Only time will tell but COVID has brought an opportunity to challenge traditional status quos.

In the same light as modifying clinical trials so too is the need to discuss the advancement of regulatory thinking as it relates to therapeutic development. With overlapping phased trials and streamlined preclinical development conducted for COVID-19 vaccine trials–to what degree can we apply these lessons to future efforts that are not directed at infectious diseases but rather genetic diseases? A piece of the answer lies with the flexibility that the incoming FDA commissioner will have vs. his or her predecessors. Under Commissioner Scott Gottlieb, MD, the FDA approved a record number of novel drugs, especially for orphan indications. Several of the learnings from COVID-19 will likely not be applicable to drug development such as the parallel tracking of clinical trials; however, components such as regulatory flexibility are ingredients that may well be applicable to rare disease broadly to help speed development, especially as it relates to bespoke drug development (N=1). Another aspect that could be considered for adoption is the increased leveraging of real-world evidence (RWE) by analyzing real-world data sources as was seen with COVID therapeutic and vaccine development and accelerating this initiative. These learnings present only a subset of the opportunities available for implementation into non COVID-19 drug development efforts moving forward.

Ultimately, COVID-19 has presented an opportunity for drug development to reimagine the status quo. As the saying goes, necessity breeds innovation and society stands at a cross roads now to conduct business as usual or attempt to adopt these painfully garnered learnings to improve the speed with which drugs are developed, tested
and approved.

https://www.nytimes.com/interactive/2020/us/coronavirus-us-cases.html

https://cen.acs.org/business/Milasen-drug-idea-injection-10/97/i42

https://fnih.org/what-we-do/programs/bespoke-gene-therapy-consortium

https://www.mckinsey.com/industries/
pharmaceuticals-and-medical-products/our-insights/
covid-19-and-cell-and-gene-therapy-how-to-keep-innovation-on-track

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