Advancing New Chemical Modalities into Clinical Studies

Abstract

Drug discovery and development has experienced an incredible paradigm shift in the past two decades. What once was considered a predominant R&D landscape of small molecules within a prescribed properties and mechanism space now includes an innovative wave of new chemical modalities. Scientists in the pharmaceutical industry can now strategize across a variety of modalities to find the best option to modulate a given target and provide treatment for a specific disease. We have witnessed a remarkable change not only in molecular design but also in creative approaches to drug delivery that have enabled advancement of novel modalities to clinical studies. In this Microperspective, we evaluate the critical differences between traditional small molecules and beyond rule of 5 compounds, peptides, oligonucleotides, and biologics for advancing into development, particularly their pharmacokinetic profiles and drug delivery strategies.

With the advent of the genomic era in the early 2000s and the interest in tackling difficult targets previously considered “undruggable”, a broad research focus was devoted to exploring novel chemical modalities^1,2 that could be more suitable for those challenging targets. In the past 20 years, we have observed a transition toward novel approaches to modulate complex biological targets, resulting in transformative treatments for patients and their families. Traditionally, drug discovery and development has been centered on orally bioavailable small molecules (SMs). “Druggable targets” were considered in a narrow space of a well-defined binding pocket for a SM and its addressable biochemistry. “Undruggable targets” were characterized by large, shallow pockets that required different chemical modalities like cyclopeptides or macrocycles. With rapid technological advances in the field of structural biology,^3,4 like crystal structure determination, cryogenic electron microscopy, protein nuclear magnetic resonance, genomics, and proteomics,⁵ there has been huge progress in understanding protein modulation for different diseases and a realization that intractable targets need novel chemical approaches.

The emphasis on new modalities includes non-traditional SMs (e.g., protein-targeted chimerics) and new generation peptides (e.g., cyclopeptides and macrocycles), also referred to as “beyond rule of 5” (bRo5) chemical space, large peptides, nucleic acid-based therapeutics (oligonucleotides), and biologics (e.g., monoclonal antibodies and antibody–drug conjugates). A key consideration to select one or another modality is based on the location of the target within the body as well as if it is intracellular or extracellular. Biologics, such as therapeutic antibodies, are designed to bind to specific epitopes with high affinity and selectivity to extracellular targets, while simpler and smaller chemical modalities can be designed to access and modulate intracellular targets. In addition to modulating a specific target in an in vitro setting or demonstrating a pharmacodynamic (PD) effect in a preclinical animal model, there are significant challenges to overcome in development. In this paper, we highlight the most recent breakthroughs on novel chemical modalities, culminating with 2021–22 U.S. FDA-approved drugs (Figure 1). We aim to provide a concise and integrated overview in this Microperspective of the critical differences between SMs, bRo5 compounds, peptides, oligonucleotides, and biological approaches regarding preclinical druggability, pharmacokinetic (PK) profile, and drug delivery approaches for advancing into clinical studies (summarized in Tables 1−3). While there has been a wealth of scientific and technological advances in this field in the past few years, the authors recognized that it is not possible to cover all modalities in depth; hence, crucial references are included for the reader to peruse.

Figure 1.

Pie chart showing the percentage by modality of FDA-approved drugs in 2021–22.

Table 1. Basic Property Comparison across Different Chemical Modalities.

chemical modality	MW (Da)	physicochemical properties	site of action	intracellular delivery	potency	selectivity
small molecule (SM)	∼200–500	well-studied and defined; driven by chemical structure	both intracellular and extracellular	generally good	potent	generally, less selective
bRo5 SM	∼500–1200	emerging trends to design orally bioavailable compounds	both intracellular and extracellular	cell-penetrating strategies	potent	selective
bRo5 cyclopeptides/macrocycles	∼500–1200	emerging trends to design orally bioavailable compounds	both intracellular and extracellular	cell-penetrating peptide strategies	potent	selective
large peptides	>5000	well-studied and with emerging interest for further delivery opportunities	extracellular	cell-penetrating peptide strategies	high potency	highly selective
oligonucleotide ASO	4000–10 000	well-described; similar for each chemotype	intracellular	endocytosis strategy	high potency	highly selective
oligonucleotide siRNA	12 000–15 000	well-defined; accounted for delivery strategy	intracellular	limited; need to be encapsulated or conjugated	high potency	highly selective
biologics (antibodies)	∼150 000	complex; heterogeneous products	extracellular	uncommon	high potency	highly selective

Table 3. Pharmacokinetic and Safety Profile Comparison across Different Chemical Modalities.

chemical modality	excretion	Cl (clearance)	DDI risk	immunogenicity	toxicity risk (off-target selectivity)	PD duration
small molecule (SM)	primarily excreted in bile and urine	often linear Cl	high	no	high	generally short
bRo5 SM	primarily excreted in bile and urine	often rapid plasma Cl	variable	no	medium	variable
bRo5 cyclopeptides/macrocycles	primarily excreted in bile and urine	often rapid plasma Cl	variable	no	medium	variable
large peptides	primarily excreted in urine	rapid plasma Cl	low	no	low	longer than SM
oligonucleotide ASO	primarily excreted in urine	rapid plasma Cl due to distribution to tissues; slow Cl from tissues	very low	yes	low	long
oligonucleotide siRNA	primarily excreted in urine	more rapid Cl than ASO	very low	yes	low	long
biologics (antibodies)	very limited	slow Cl	uncommon	yes (high risk of impacting PK and PD)	uncommon	long

In the period extending from January 2021 to mid-September 2022, there have been 70 drugs approved by the FDA (data have been extracted from the FDA’s Center for Drug Evaluation and Research (CDER) website; see Supporting Information for comprehensive table).⁶ As shown in Figure 1, most approvals are still SMs (36 drugs, 52%) for this period. One of the advantages of this modality is the flexibility to use different routes of administration. As such, beyond the predominant and traditional oral route, we can find topical (Vtama for plaque psoriasis), intramuscular (IM; Cabenuva for HIV), and intravenous (IV; Cosela for mitigation of chemotherapy-induced myelosuppression in small-cell lung cancer) administration (Figure 2). Biologics are the second category, with 21 drugs approved (30%), mainly for parenteral administration (IV or SC injection), with one approval for intravitreal injection (IVT, into the vitreous humor of the eye; Vabysmo to treat age-related macular degeneration). The peptide modality has 8 drugs (11%) approved for IV or SC administration. There were 3 oligonucleotide-based drugs (4%) approved: Amvuttra (siRNA, SC injection, to treat polyneuropathy of hereditary transthyretin-mediated amyloidosis, approved in 2022), Leqvio (siRNA, SC injection, to treat heterozygous familial hypercholesterolemia, approved in 2021), and Amondys 45 (an antisense oligonucleotide (ASO) of phosphorodiamidate morpholino oligomer approved in 2021 to treat Duchenne muscular dystrophy via IV administration, Figure 3). Within the bRo5 space, there were 2 compounds (3%) approved: Vonjo, a JAK2 small macrocycle inhibitor for oral treatment of intermediate or high-risk myelofibrosis in adults with low platelets, and Lupkynis, a calcineurin cyclopeptide inhibitor to orally treat lupus nephritis.

Figure 2.

Graphic summarizing the number of FDA-approved drugs by modality and route of administration for the past 2 years.

Figure 3.

Representative approved drugs of different modalities in 2021–22.

Small Molecules, PROTACs, and Beyond

Synthetic SMs have been paving the way toward useful therapeutics for over a century. The impact of this modality has been appreciated from the early 1900s commercialization of synthetic pharmaceutical drugs like acetyl salicylic acid (aspirin) to nowadays approvals of more sophisticated molecules like Lumakras (sotorasib, a covalent KRAS inhibitor, Figure 3)⁷ approved in 2021. The sustained success of SMs comes from their versatility to modulate targets while crossing biological barriers due to their physicochemical properties (molecular weight (MW) < 500, Table 1). The ability to be orally bioavailable enables convenient patient-centric delivery as a tablet (a significant advantage versus biologics or other modalities, Table 2). This characteristic also facilitates targeting both intracellular or extracellular targets across a variety of different target tissues. In particular, SMs remain the preferred choice for central nervous system (CNS) targeted therapeutics. The deep molecular design knowledge around this modality and easily achievable passive permeability allow for specific guidelines to enable brain penetration or limit the brain exposure.⁸ Another important feature is the low risk of immunogenicity (a critical differentiator from biologics) which facilitates clinical development (Table 3).

Table 2. Pharmacokinetic and Safety Profile Comparison across Different Chemical Modalities.

chemical modality	route of administration	dosing frequency	%F (bioavailability)	Tmax (SC or IM)	Vd (volume of distribution)	metabolism
small molecule (SM)	primarily oral	often once a day	generally good	variable	generally high; broad distribution to organs and tissues including CNS	primarily by CYP and phase II enzymes
bRo5 SM	emerging examples of orally bioavailable	daily to weekly	few examples of orally bioavailable	variable	mostly peripheral distribution	variable depending on functional groups
bRo5 cyclopeptides/macrocycles	emerging examples of orally bioavailable	daily to weekly	few examples of orally bioavailable	variable	mostly peripheral distribution	mainly proteolytic enzymes
large peptides	not orally bioavailable; mainly IV, SC	weekly to monthly	good for SC	variable	peripheral distribution	proteolytic enzymes
oligonucleotide ASO	not orally bioavailable; IV, SC, IT, and IVT	weekly to monthly	good for SC	0.25–5 h after SC	high; broad distribution to kidneys and liver	by nucleases
oligonucleotide siRNA	not orally bioavailable; IV, SC, IT, and IVT	weekly to once every 3–6 months	not reported	not reported	broad distribution to kidneys and liver	by nucleases
biologics (antibodies)	not orally bioavailable; mainly IV, SC, and IM	weekly to monthly	good for SC and IM	1–8 days after SC or IM	low; often limited to plasma and extracellular fluids	catabolized by proteolytic enzymes

The rapid advancement of novel approaches in synthetic organic chemistry⁹ has played a critical role in the development of efficient structure activity relationship (SAR) analysis and modular synthesis, identifying key precursors and quickly incorporating variation of the structure to improve selectivity or the PK profile. While it is possible to tune their physicochemical properties to enable suitable permeability and solubility, in general, they are stable enough to be compatible with most drug formulation approaches and routes of administration.

The well-studied and well-defined properties for SMs have long allowed for guidelines to fine-tune parameters for oral delivery¹⁰ and, even further, use predictive computational tools¹¹ to prioritize synthesis.

More recently there has been a trend to expand the mechanistic mode of action of SMs. Modalities like allosteric modulators and covalent inhibitors have attracted significant attention. Allosteric modulators¹² offer significant advantages in comparison with orthosteric agonists or inhibitors, with increased selectivity and modulation of the pharmacology profile that often translate into enhanced safety margins. A noticeable instance of this trend is the 2021 approval of the allosteric inhibitor Scemblix (ascinimib, Figure 3)¹³ for oncology. This compound binds at the ABL1 myristate pocket, resulting on an endogenous activation mechanism yielding an inactive state for the full-length BCR-ABL1.

While most SMs are designed not to covalently bind to their targets, it is possible to introduce specific functional groups (or warheads) to form a covalent bond. Remarkable examples of this approach are (1) Imbruvica (ibrutinib), a covalent inhibitor of the Bruton’s tyrosine kinase (BTK)¹⁴ approved in 2013 for B-cell cancer, and (2) Lumakras (sotorasib, Figure 3), another oncology covalent inhibitor of KRAS that selectively binds to a cysteine residue only present in the mutated G12C form. This approach has revolutionized the field of the once considered undruggable KRAS target.

Within the SM space, there has been an intense interest in a newer modality, PROTACs and other bifunctional degraders.¹⁵ These types of compounds tend to be larger than traditional “rule of 5” bioavailable SMs; however, they are considered within the “bRo5” space (MW between 500 and 1200, Table 1). The term PROTACs refers to proteolysis targeting chimeras, as heterobifunctional drug conjugates that comprise two linked SM moieties, one binding to a target protein of interest and the other to an E3 ligase. This approach leverages the E3 ligase mechanism by transferring ubiquitin to the protein substrate and marking it for proteasomal degradation. Based on MW and properties, enabling oral bioavailability and cell permeability for these bifunctional molecules can be challenging, while maintaining productive interactions with both the E3 ligase and the target protein. Currently, numerous medicinal chemistry campaigns¹⁶ are focused on identifying reliable guidelines for the oral design of this modality. Arvinas has been pioneering this approach, with recent compounds (ARV-110 and ARV-471) entering clinical studies for oncology and leading an explosion in this field.¹⁷

Other variations within the degrader modality are mainly (1) molecular glues,¹⁸ (2) deubiquitinase-targeting chimeras (DUBTACs),¹⁹ and (3) lysosomal-targeting chimeras (LYTACs).²⁰ Molecular glues are based on a proximity-induced target protein degradation approach that involves stabilizing the interaction of a protein of interest to an E3 ubiquitin ligase. Molecular glues are monofunctional and smaller than PROTACs, and thus more in line with SM properties. DUBTACs are heterobifunctional SM recruiters of a deubiquitinase for targeted protein stabilization. Nomura and co-workers showed proof of concept with the discovery of a covalent recruiter for the deubiquitinase OTUB1.¹⁹ LYTACs use the lysosome pathway for protein degradation, targeting membrane and extracellular proteins and overcoming some limitations of PROTACs and molecular glues. LYTACs have high MW and suffer from poor oral drug delivery opportunities.

New Generation Peptides

The therapeutic large peptide modality has been well established²¹ since the introduction of insulin over a century ago. Currently there are >80 peptide drugs commercialized for a variety of diseases from diabetes to oncology, HIV infection, multiple sclerosis, chronic pain, and osteoporosis. This peptide modality demonstrates high potency and selectivity for the target (Table 1). However, therapeutic development is regularly impeded by low membrane permeability, low plasma stability, and limited oral bioavailability (Table 2). Hepatic metabolism of peptides is usually not significant, with low drug–drug interaction (DDI) risk and off-target safety concerns (Table 3). The lack of suitable intestinal absorption mandates a parenteral administration (via IV or SC injection). For the same reason, peptides are generally not capable of crossing the blood–brain barrier, reducing the options for CNS indications.

The unique structural features of some natural cyclopeptides,²² like cyclosporin, combined with its remarkable permeability for this class has inspired many researchers to identify precise chemical modification strategies to enhance membrane permeability and gut stability. One key approach to stabilize peptides is to design cyclic or constrained (stapled, stitched, or cyclotide) peptides,²³ focusing on smaller size peptides (cyclopeptides, also known as bRo5²⁴ molecules in comparison with SMs, Table 1) to improve their cell-penetrating attributes and PK profile. In particular, these strategies balance lipophilicity and solubility²⁵ characteristics, with conformational flexibility (“chamaleonicity”)²⁶ to adapt different configurations depending on the polarity of the environment. Specifically, efforts around masking polar amide backbones with intramolecular hydrogen bonds, N-methylation, or β-branched side chains to reduce the polar surface area have been implemented in molecular design to increase permeability.²⁷ Furthermore, cyclic or constrained peptides offer an enhanced resistance to proteolytic enzymes, the main metabolic route for this modality (Table 2).

Recent innovation in formulation approaches, such as permeation enhancers (PEs), can increase intestinal peptide absorption. The two main PEs used in clinical trials for macromolecule oral delivery are Salcaprozate sodium (SNAC) and sodium caprate (C10). There are formulation strategies to prolong the half-life and customize the PK profile depending on the target and patient population.²⁸ As examples, conjugation of peptides with fatty acids (lipidation) or polyethylene glycol (PEGylation) can extend the half-life without impacting the potency. Nanoparticles and micelles can also increase oral bioavailability of peptides. In-depth descriptions of recent technologies to optimize oral delivery of peptides can be found in recent reviews.²⁹

The field continues to evolve effective strategies for oral peptides. This endeavor has recently culminated with the approval of Rybelsus (oral semaglutide), a glucagon-like peptide 1 agonist that has become the first orally bioavailable peptide to treat type 2 diabetes.³⁰ Rybelsus incorporates a fatty acid moiety through a synthetic linker, resulting in increased protein binding and extended half-life. To enable a tablet for once-a-day oral administration, the peptide was co-formulated with SNAC as an absorption enhancer.

Oligonucleotide Approaches

Nucleic acid therapeutics and in particular oligonucleotides have experienced enormous growth in the past several years.³¹ The development of RNA-based vaccines to combat the SARS-CoV-2 pandemic has exponentially accelerated the interest in RNA therapeutics. In general, RNA therapeutics can be classified as messenger RNA (mRNA)-based (700–70 000 kDa) and small RNA based (12–20 kDa). For the purpose of this paper, we will focus on small RNA therapeutics: antisense oligonucleotides (ASOs) and small interfering ribonucleic acid (siRNA), as they are the most commonly approved and most abundantly represented in recent clinical studies. Oligonucleotides have larger MW (Table 1) than traditional SM therapeutics. They usually have a MW of 4–10 kDa for ASOs and 12–15 kDa for siRNAs. They are characterized by being highly charged and having poor oral bioavailability (Table 2) and are mainly administered via an IV or SC route. As a consequence of being negatively charged molecules, oligonucleotides are unable to passively diffuse across lipid membranes, resulting in very limited cellular uptake. Current research is focusing on the release of RNA using non-viral delivery systems to circumvent the limitations of viral delivery vectors (mainly pre-existing immunity, viral-induced immunogenicity, payload size constraints, and expensive vector production). The cellular uptake of oligonucleotides often occurs via endocytosis. After endocytosis, a second issue is to obtain adequate release from endosomes into the cytosol. Approaches to facilitate the “endosomal escape” include (1) chemical modifications of naked oligonucleotides, (2) addition of a synthetic lipid-based nanoparticle formulation to induce endosomal release, and (3) exploration of endogenous delivery pathways by loading oligonucleotides into biological vesicles.

Oligonucleotides can also be unstable and are primarily degraded by serum nucleases and excreted through the liver and kidneys. To address this issue, all approved ASOs have a sulfur-derived linkage (phosphorothioate, PS, Figure 4).³² The incorporation of sulfur to the phospho-linker (usually referred to as the “backbone”) adds resistance to hydrolysis by serum nucleases and increases stability during circulation. Another advantage is the ability of the PS linker to bind to serum albumin (increasing plasma protein binding) and other intracellular proteins, avoiding rapid renal excretion. Incorporation of the PS leads to improvements in the overall PK profile, broad distribution, tissue delivery, cellular uptake, intracellular trafficking, target potency and safety. This approach also facilitates effective delivery to other tissues outside the liver without an extra delivery system. Currently available therapeutic oligonucleotides are complex isomeric mixtures of the two stereoisomers (Rp and Sp) of the PS modification (Figure 4). A promising technique is to prepare stereopure isomers to further minimize degradation and increase binding affinity. However, there is still debate in the field between the value of stereopure isomers vs stereorandom ASOs.³³

Figure 4.

Most common chemical modifications used in oligonucleotide drugs. B = nucleobase or nucleotide base substitution, including cytosine, guanine, adenine, and uracil.

After SC administration, ASOs are absorbed quickly and generally reach T_max between 0.25 and 5 h (Table 2). Additionally, specific chemical modifications³⁴ have been applied to further improve potency, binding affinity, and metabolic stability. Most of the chemical changes have been focused on 2′-substitutions in the ribose sugar, in particular substituting the 2′-hydroxy moiety with 2′-O-methoxyethyl (MOE), 2′-O-methyl (2′-OMe), bicycle 2,4′-O-methylene bridge (i.e., locked nucleic acid (LNA)), and fluoro substitution, among others (Figure 4).

Selective gene silencing by RNA interference (RNAi) uses a double-stranded siRNA (formed by a single-stranded (ss) guide and passenger RNAs) which must be delivered into the cytosol. siRNA is identified and processed by endonucleases of the RNA-induced silencing complex (RISC). The RISC then cleaves the passenger RNA, revealing the guide RNA for base-pairing with the corresponding mRNA target. siRNAs have attracted significant interest as promising gene-silencing therapeutic modalities; however, their PK profile and cellular uptake continue to be challenges. Double-stranded RNAs need to be chemically modified to improve serum stability, minimize immunogenicity, and enhance potency. Similar to ASOs, standard chemical alterations include replacing the 2′-hydroxy in the ribose sugar (Figure 4). Additional medicinal chemistry modifications are an active area of research.³⁵ Since the siRNAs only need to be delivered outside the nucleus, in contrast to ASOs, other delivery approaches have been investigated, like lipid nanoparticles and GalNAc conjugates. We refer the readers to recent literature for further insights on those approaches.³⁶

As highlighted in Table 2, oral delivery for oligonucleotide approaches remains a significant challenge due to poor cell permeability and enzymatic stability. As a result, chemical campaigns are needed to address those issues with early exploration of delivery systems and formulation enablement even during preclinical evaluation.

Since fomiversen (marketed as Vitravene) received approval in 1998, the field of oligonucleotides has matured significantly, with 15 more regulatory approvals.³⁷ Currently there are >60 clinical trial registered for oligonucleotides in phase 2 and 3 for indications ranging from multiple types of cancer to Duchenne muscular dystrophy, Dravet and Angelman syndromes, amyotrophic lateral sclerosis (ALS), and Huntington’s disease to genetic eye diseases like retinitis pigmentosa and Leber congenital amaurosis.

Biologics

In the past few years, the FDA has approved multiple antibody-based therapeutics, including monoclonal antibodies (mAbs) and antibody–drug conjugates (ADCs), reaching the milestone of approving the 100th monoclonal antibody in 2021.³⁸ In addition to mAbs and bispecific antibodies, other modalities like nanobodies³⁹ (single-domain antibody fragment) are emerging, with caplacizumab being approved in 2019. Currently, there are >55 antibody-based studies⁴⁰ in late-stage clinical trials. This field is anticipated to provide critical treatments in a vast range of disease areas, such as cancer, cardiovascular diseases, inflammation, autoimmune diseases, infectious diseases, and neurological disorders.

Gene therapy could be considered within the larger biologics modality. Regulatory agencies classified gene therapy under the broad umbrella of biologics, which can include viral vectors or DNA/RNA sequences, as in the example of chimeric antigen receptor (CAR) T cells.⁴¹

Biologics are typically selected for their high affinity, potency, and in particular specificity that commonly results in less off-target toxicity than traditional SMs (Tables 1–3). Physiochemical and biophysical properties like MW, secondary and tertiary structures, hydrophobicity and charge characteristics, post-translational modifications (e.g., glycosylation, methylation, or amide hydrolysis), and metabolic and thermal stability play a critical roles in their PK profile and development process. Antibodies are mainly administered parenterally (SC, IM, and IV routes, Table 2) due to their poor absorption. Absorption and distribution of mAbs can be slow when they are administered subcutaneously, reaching peak concentration 6–9 days after injection. Large biomolecules are not able to distribute broadly and have challenges to effectively reach the tissue and target site due to their size, complexity, and hydrophilicity.

The precise route of administration (Table 2) depends on the targeted dose. Recently there have been significant efforts to enable oral delivery of biological macromolecules focused on nanomedicine-based strategies and other drug delivery technologies.⁴²

Delivery to the CNS⁴³ presents a challenge due to the blood–brain barrier. Therapeutic antibodies have very limited brain distribution when administered intravenously, measuring <1% delivered to the brain. However, intrathecal (IT) injection offers an access point to the cerebrospinal fluid (CSF) and CNS, circumventing the blood–brain barrier. This route of administration needs to be balanced with invasiveness, disease and patient population, safety, and efficacy.

From a safety perspective, biologics tend to be highly species-specific, showing low risk of significant toxicity. In contrast, they are known to have a higher risk for unwanted immunogenicity compared to SMs (Table 3). The immunogenicity is a result of the formation of anti-drug antibodies⁴⁴ (ADAs), which can modify the bioavailability and clearance of the therapeutic antibody, significantly decreasing its efficacy. Furthermore, in severe cases, ADAs can completely obliterate the antibody’s therapeutic effects or even produce adverse effects to the patient. The specific molecular mechanisms of ADA creation remain unclear, although they sometimes can affect up to 70% of patients, depending on both drug properties and patient characteristics. While biologics have the potential to treat a vast range of disorders, their immunogenic reaction can greatly influence the safety, PK, and PD profiles of this modality, making their development more problematic.

Conclusions

The medicinal chemistry community is witnessing an incredible change in the chemical modalities used to tackle human diseases. Specific modalities are tailored for disease indication and pathway considerations like intracellular location and site of action. While it is important to know the challenges and limitations for each modality for specific site of action and route of administration, recent innovations in formulation technologies have overcome multiple obstacles to make available effective therapies for patients beyond traditional SMs. The intrinsic advantages of SMs have inspired new approaches, including the use of degraders, covalent inhibitors, and allosteric modulators. A continuous expansion of SM modalities is anticipated, driving innovation in the pharmaceutical industry and transforming the lives of patients.

Glossary

Abbreviations

ADC

antibody–drug conjugate

ASO

antisense oligonucleotide

bRo5

beyond rule of 5

DDI

drug–drug interaction

SC

subcutaneous

IM

intramuscular

IV

intravenous

IT

intrathecal

IVT

intravitreal

MW

molecular weight

PD

pharmacodynamics

PK

pharmacokinetics

Ro5

rule of 5

siRNA

small interfering RNA

SM

small molecule

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00375.

• List of all the drugs approved, modality, route of administration, date of approval, and FDA-approved use on approval date (XLSX)

The authors declare the following competing financial interest(s): M.N.N. discloses that his research is funded by AbbVie. He is a consultant for Axonis and on the SAB of Sionna Therapeutics.

Special Issue

Published as part of the ACS Medicinal Chemistry Letters virtual special issue “New Drug Modalities in Medicinal Chemistry, Pharmacology, and Translational Science”.