Basic Science Research as the Pillar for NDD Drug Development

Background

In the last decade, there has been a significant increase in the prevalence of neurodegenerative diseases (NDD) in the United States, affecting approximately 10.5 million individuals. This number is predicted to triple in the next 30 years.¹However, in comparison to other disease areas such as oncology, the approval of NDD drugs has been relatively limited. Our team has explored the NDD drug development ecosystem from three perspectives: stakeholders, funding, and policy. This article summarizes our key findings and presents a case study to suggest that the scarcity of new drug development may be attributable to insufficient basic scientific research. Finally, we outline our objectives for the upcoming semester.

Stakeholders

The drug discovery and development process is intricate, with multiple stages and stakeholder interests. Our preliminary analysis reveals five key challenges:

Deficiency of basic science research: There is relatively little investment in studying the basic pathophysiology of NDDs, hindering the development of targeted therapies and considerably impeding the drug development process's efficiency.
Inefficient approaches to basic science research: Out-of-the-box approaches to basic science research receive little incentive. Although most basic science research is conducted in government labs or government-sponsored academic institutions, academics must apply for grants to run their labs, through what is referred to as Investigator-initiated studies. The grant application process emphasizes publication counts, and requires substantial proof-of-concept data, creating a vicious cycle that offers little freedom, provides unclear deadlines and timelines, and results in a potentially inefficient use of time.
Lack of market accountability for drug approval and value: The inherently costly and risky nature of researching and developing medications alters drug development companies' incentives. To minimize risks and maximize returns, companies are encouraged to lower their research endpoint to obtain drug approval. Moreover, since the medication faces limited competition in treating the specific disease, companies can charge above-market prices for products that may not meet market standards, leading to economic inefficiency.
Lack of innovative financial vehicles: The lack of basic science research into the underlying pathophysiology of NDDs increases investment risk, particularly in the early stages of NDD drug development. Private investors seek to maximize profits while minimizing risks, and investing in NDD drug development carries significantly more risk than investing in well-studied disease drug development. Without targeted interventions to increase investment incentives and reduce risks, this avoidance cycle will exacerbate the current NDD drug development disparity.
Presence of silos: Many stakeholders operate in silos, often requiring more time to generate data. Little transparency exists on who does what. Sharing data and approaches allows for greater validation, improved analyses, and can potentially spark innovation.²

Funding

The funding ecosystem for neurodegenerative disease research and biotechnology is a complex and multi-faceted landscape. Funding comes from a wide range of sources with varying interests, and allocation of resources varies widely across diseases. Potential policy solutions to tackle funding bottlenecks include:

Addressing the limited funding for neurodegenerative diseases: Neurodegenerative diseases research has historically received substantially lower funding than other diseases, both from government and private actors. Over the past decade, funding for NDD drug development has increased with the NIH budget gradually increasing to higher levels. Continuing to increase budgets for NDD research should be a priority.
Addressing the inefficiency in allocating funding for neurodegenerative diseases: While enough funding may be dedicated to NDD drug research, funding may not be optimally allocated. Potential solutions include accelerating the funding request process, making the administrative work less onerous, so that researchers can spend the vast majority of their time doing science and discussing it, rather than administrative work to request financing. Additionally, implementing policies that promote collaboration among researchers to prevent duplicative work, leveraging the power of artificial intelligence and large-scale data analytics to pinpoint areas of potential research, and implementing a more transparent and accountable system for funding allocation could provide more efficient drug discovery. Finally, there is promise in allocating greater funding to high-risk, high-reward projects that may push the field further than the status quo.
Identifying non-monetary incentives: Currently non-monetary incentives are mostly tied to publications in the highest ranked journals. Some thought must be given to non-monetary means that may promote greater NDD drug development, through increased transparency and information sharing. Awards, authorship, and prizes could be considered to incentivize and recognize the work of the many researchers.

Policy

In recent years, the federal government has utilized policy levers to increase funding support for NDD drug development, provide technical guidance to drug developers, and reduce the regulatory burden for clinical trials, demonstrating a keen interest in facilitating the progression of new NDD drugs through the drug development pathway. Despite the approvals of new drugs such as Aducanumab, Relyvrio, and Lecanemab in 2021 and 2023, there is still a lack of disease-modifying therapies for most NDDs. Several key takeaways can be gleaned from this situation:

Effective drug development and eventual drug approval is largely tied to understanding of disease pathophysiology: This statement is not unique to NDD drug development. The better our understanding of the pathophysiology of a disease, the more likely we are to identify better drug targets and develop effective therapies. A major reason why there have been more drug approvals for NDDs like MS and PD as opposed to other NDDs such as AD or ALS is due to our enhanced understanding of their pathophysiology. Significant investment in basic science research for lesser-known NDDs is essential to bridging this gap.
Policies can level the playing field: Since passage of the 21st Century Cures Act in 2016, there has been greater equity in the number of drugs approved for each NDD (note: equity defined as total number as opposed to being weighted for disease prevalence). This suggests that by using targeted policies and programs, we can eliminate stopgaps in the clinical drug development pipeline.
But are we creating effective drugs? We still lack curative therapies for NDDs. The aforementioned approvals of Aducanumab and Lecanemab have drawn the ire of the public and the lack of evidence has led payers like the Centers for Medicare and Medicaid Services to restrict coverage and access to these new therapies. We need to go back to the drawing board to continue expand and diversify our research.

Bringing It All Together: Basic Science as Pillar for Drug Development

Dr. Patrizia Cavazzoni of the FDA states it best in a 2021 House hearing: “making progress on expanding our basic, scientific understanding of NDDs is absolutely critical to making progress on developing treatments.” She goes on to highlight that if we are to see the same advancements in NDD drug development as we have for oncology and HIV, we must first see similar advances in disease characterization.

She’s not the only one who believes this. Dr. Richard Hodes, the Director of the National Institute of Aging, and Dr. Walter Koroshetz, the Director of the National Institute of Neurological Disorders and Stroke, have both stated the largest barrier to developing effective NDD treatments is our incomplete understanding of NDD pathophysiology.³ Leadership from the Biotechnology Innovation Organization, the largest advocacy organization for the biotech industry, agrees - upstream interventions are needed to identify better drug targets and novel approaches.⁴

Basic science research is a major upstream bottleneck. This challenge further disincentives funding for NDD research, especially in the private sector where investment is often driven by potential profit and shorter timelines. Marginal returns on investment are a key driver for why the private sector and larger pharmaceutical companies historically focus on the later, more de-risked stages of drug development where there is a higher rate of success.

In summary, basic science research is challenging and risky, which often discourages non-governmental funds. Nevertheless, it is imperative for developing effective disease-modifying therapies. Thus, identifying ways to promote more effective basic science research is essential.

Case Studies on Basic Science Research

There is evidence that investing in basic science research works. Previous literature looking at new drug approvals in the 2010s has shown how investment by the NIH in basic science has directly contributed to drug development.^5,6

This is very apparent and well-documented for HIV/AIDS and cancer. In the case of HIV/AIDS, the first breakthrough was discovery of the retroviral etiology and identification of the virus that causes this disease. Increased federal investment in basic science led to advances in molecular virology including identification of structural and regulatory genes encoding HIV viral proteins, furthering our understanding of the pathogenesis and providing targets for potential antiretroviral drugs.⁷The translation of this basic science research into drug development, eventually led to creation of new drug classes like protease inhibitors and has allowed us to reach a point where patients can have a undetectable HIV viral load by taking antiretroviral therapy.⁸ Similarly, in oncology, advances in basic science have directly led to new therapies. For instance, improved understanding of DNA repair pathways has led to treatments like olaparib, a treatment for ovarian cancer that works by inactivating DNA repair pathways and promoting cell death.⁹And basic science research can “work” even when it’s not targeted. Basic science research into bacteria, for instance, ultimately laid the groundwork for CRISPR and gene-editing technologies that hold promise to revolutionize cancer treatment.¹⁰

The success of basic science research has also been seen in brain-related disorders like schizophrenia. In the 1950s, the discovery of a new class of medications named chlorpromazine and its unexpected effects on schizophrenia unleashed a flurry of research into the pharmacology of this specific class of drugs and how it intersects with the pathophysiology of schizophrenia. This wave of basic science research led to further understanding of the pathophysiologic mechanisms of schizophrenia, ultimately resulting in the unveiling of the D-2 receptor as an important step in the underlying mechanism of schizophrenia and a target for future therapeutics. This discovery has led to generations of new antipsychotics including aripiprazole. In fact, no drug without a modicum of antagonism of DA at the D-2 receptor has yet been approved by the FDA as an antipsychotic. In addition, the so-called “dopamine hypothesis” has laid the groundwork for more extensive research into the pathophysiology of schizophrenia, producing newer theories such as the “glutamate hypothesis” (emphasizing the importance of N-methyl-D-aspartate (NMDA) receptors). This new discovery has introduced a new potential target for the development of antipsychotic drugs, and suggests a promising new horizon for the development of newer, more effective antipsychotic medications.¹¹

The timeline of clinical drug development in Schizophrenia is depicted in the graphic¹², following the discovery of chlorpromazine's antipsychotic activity in 1952. The pharmacological mechanisms of individual compounds are listed in the boxes. Several mechanisms have been targeted with multiple compounds, as indicated by the value in parentheses. The dates provided are approximations based on publication or drug approval dates. The list also includes allosteric modulators.

Limitations

As discussed above, one potential reason for the lack of funding for NDD drug research is the lack of return on investment for investors, which is a valid concern given the relatively higher returns of medications for other common diseases. This higher risk disproportionately affects private investors, as their investments will be highly dependent on the probability of promised return, while the public sector has different incentives and timelines. There is a growing consensus that basic research should be conducted primarily by the government and government-sponsored research, and several pharmaceutical companies have completely abandoned basic science in favor of translational and clinical research. Consequently, it is imperative to determine whether it is necessary to revisit incentives to encourage additional participants in fundamental research or identify areas for enhancing the effectiveness of government-sponsored research.

Recognizing the pivotal role of human capital in basic research, we tried to conduct a comparative analysis of the number of clinicians and PhDs in NDDs versus Oncology. Assess the number of physicians practicing neurology and hematology/oncology (the subspecialties focused on cancer treatment), we observed that the latter has roughly 2000 more clinicians than neurology. However, it is essential to note that while hematology/oncology is a fellowship after internal medicine residency, neurology is a residency program that provides a broad range of fellowships, with only a few focused on treating neurodegenerative disorders. In addition, there are no specific ACGME-accredited fellowships for neurodegenerative diseases in the United States, which means that the patients are being managed by different physicians, including general neurologists, primary care providers, and geriatricians. Thus, while comparing the exact number of physicians devoted to NDDs versus oncology is challenging, the fragmentation of care for NDDs, in contrast to oncology, reflects the lack of specialized interest in the field, which may hinder research progress. We then focused on PhDs graduates as a proxy for future basic science researchers. According to the National Science Foundation, there were more neurobiology and neuroscience Ph.D. graduates than oncology and cancer biology Ph.D. graduates in 2021 (1014 versus 713). However, it is probable that many of the other 6000+ Ph.D. graduates in biological and biomedical sciences, such as cell biology, genetics, and immunology, may be conducting research in the oncology basic science field as well.¹³

Figure 2 presents bar graphs comparing the number of individuals who received research doctorates in the United States in 2021, with a specific focus on the biological and biomedical sciences. The figure provides a detailed breakdown of the number of doctorate recipients in the fields of "Neurobiology and neuroscience" and "Physiology, oncology, and cancer biology". While the number of neurobiology and neuroscience doctorates exceeds that of oncology and cancer biology, it is important to note that other PhD graduates in various biological and biomedical science disciplines (such as cell biology, genetics, and immunology) may also be conducting research in NDD or oncology basic science. This factor complicates the analysis of the number of researchers in these fields.

Next Steps

In the following weeks, we will delve deeper into the issue of basic science research in NDDs. Our objective is to conduct interviews with experts from different stakeholder groups such as government institutions (NIH, DOD), academic researchers, private investors (VC firms), and policy experts (politicians, think tanks).

We aim to explore a wide range of topics, including the sufficiency of funding for basic research, the inefficiency of funding allocation, the misaligned or lacking incentives for stakeholders to engage in basic research, and potential non-financial resources or tools for basic research (e.g., technology, talent, etc.).

Additionally, we will begin providing potential recommendations to further explore, such as following the successful models of previous government initiatives (NIH Blueprint for Neuroscience Research, NIH Research Director's Transformative Projects), increasing push incentives (as seen in the antimicrobial resistance drug development space), and adopting approaches from other countries and non-healthcare sectors.