Innovative Medicines in 2021 and Beyond

Major scientific innovations and transformative therapies have been realized in the year 2021. 50 new drugs were FDA approved that help improve the health of patients with unmet medical needs and protect them against life-threatening conditions. It is noteworthy that 27 out of the 50 FDA-approved new drugs were first-in-class, with mechanisms that are differentiated from existing therapies. This piece highlights some of the notable innovative medicines that were approved in 2021 across major disease areas including cancer, inflammatory, endocrine, infectious, and neurological disorders [1]. Also, a perspective is presented on the emerging scientific breakthroughs and biomedical innovations that are likely to shape the future of therapeutics over the next few years.

Cancer

The war on cancer, a disease resulting from uncontrolled growth and division of abnormal cells, started in 1971 with the National Cancer Act, a United States Federal law that was enacted to effectively enhance the national effort against cancer. The year 2021 marked the 50th anniversary of the National Cancer Act, and it was only fitting that many novel therapies were approved for different types of cancer during this year.

An estimated 2.3 million people worldwide will be diagnosed with lung cancer this year [2]. Non-small cell lung cancer (NSCLC) is one of the two major types of lung cancer that affects smokers and nonsmokers, accounting for 85% of all lung cancer diagnoses. NSCLC with tumors containing a specific type of genetic mutation in a gene called KRAS, once deemed ‘undruggable’, has been among the most challenging cancers to treat. Tumors with KRAS mutation account for approximately 25% of mutations in non-small cell lung cancers. Over the last four decades, scientists have made futile attempts to develop drugs against KRAS. Finally, Sotorasib was approved in 2021 as the first targeted therapy for lung cancer mutation KRAS G12C, which represents about 13% of mutations in non-small cell lung cancers. Another transformative therapy (Amivantamab) was also approved for locally advanced or metastatic non-small cell lung cancer [3].

An estimated 9,000 new cases will be diagnosed with chronic myeloid leukemia in the United States this year [4]. The innovative discovery of Asciminib [5] offers hope and a new treatment option for patients with Philadelphia chromosome-positive chronic myeloid leukemia who become resistant to existing therapies.

The approval of idecabtagene vicleucel adds to the growing body of innovative cancer immunotherapies that are meant to stimulate the immune system to recognize and fight cancer. An autologous T cell immunotherapy, idecabtagene vicleucel treats adult patients with relapsed or refractory multiple myeloma [6]. An estimated 34,000 new cases will be diagnosed with multiple myeloma in the United States this year [7].

Heart, Blood, Kidney and Endocrine Diseases

Cardiovascular disease remains one of the major public health challenges of our time. 20 years ago, it was hard to imagine that one could lower cholesterol levels with gene knockdown, let alone keep these levels low with only two doses a year.

In 2021, the FDA approved inclisaran as the first and only small interfering RNA (siRNA) therapy to lower low-density lipoprotein cholesterol (also known as bad cholesterol or LDL-C) with two doses a year, after an initial dose and one at three months [8]. In clinical trials, it provided effective and sustained LDL-C reduction of up to 52% vs. placebo for certain people with atherosclerotic cardiovascular disease on maximally tolerated statin therapy. There are roughly 16 million Americans with atherosclerotic disease who are currently on statin therapies, yet their LDL-C levels are above recommended targets [9]. Inclisaran presents a transformative approach to lowering LDL-C and could revolutionize the treatment landscape for millions of Americans with cardiovascular disease.

2021 also marked the 100th anniversary since the discovery of insulin. While there have been significant advances in the treatment and management of diabetes across the globe, many challenges remain ahead for defeating this disease. Finerenone is a first-in-class, non-steroidal drug that was approved by the FDA to reduce the risk of serious complications in adults with chronic kidney disease associated with type 2 diabetes [10]. The discovery of finerenone represents a major advancement in the development of non-steroidal small molecule drugs to treat diabetic chronic kidney disease.

Another notable innovative therapy is vosoritide [11], which represents the first treatment to increase height in people with achondroplasia, the most common type of dwarfism or disproportionate short stature. Achondroplasia occurs in approximately 1:20,000 to 1:30,000 live births per year [12]. No pharmacologic therapies have been approved for achondroplasia, except for growth hormone which is approved for achondroplasia only in Japan. Treatment with vosoritide could have significant impact on pediatric patients with achondroplasia who are 5 years of age and older.

In the context of blood disorders, pegcetoplan is a new therapy for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria, a rare, acquired disease that leads to premature death and impaired production of blood cells. The disease is estimated to affect between 1 and 5 per million people [13].

Pegcetoplan represents the first complement C3 inhibitor to treat this rare form of anemia and may result in better control of disease compared to existing therapies.

Autoimmune, Inflammatory and Lung Diseases

It is estimated that there are roughly 1.5 million Americans who have a form of lupus [14]. Systemic lupus erythematosus (SLE) is the most common form of lupus, a disease in which the immune system attacks the body’s own tissues, causing inflammation and tissue damage. The disease could affect any organ, leading to debilitating symptoms, long-term organ damage and poor health-related quality of life. In 2021, the only new medicine in over a decade (Anifrolumab) was approved for patients with moderate to severe SLE [15], highlighting a major advancement in the treatment of this form of autoimmune disease.

Other notable innovative advances include a new therapy to treat moderate-to-severe atopic dermatitis (eczema) in adults that have not responded to other therapies [16]. Tralokinumab offers a targeted approach for adults living with this debilitating disease and represents the first biologic to neutralize IL-13 selectively.

2021 was an important year for therapies to treat disorders involving inflammation of the digestive tract. The year was marked by approval of adalimumab and ozanimod for adults and pediatric patients with moderately to severely active ulcerative colitis, a disease in which the lining of the colon becomes inflamed and develops tiny open sores (ulcers).

Neurological Disorders

Notable innovative treatments approved in 2021 for rare neurological disorders included a treatment for myasthenia gravis, a chronic neuromuscular disease, and another treatment for an inherited muscle disorder. Casimersen [17] is indicated to treat patients with Duchenne muscular dystrophy, a genetic disorder that occurs primarily in young boys and leads to progressive muscle degeneration and weakness. In clinical trials, treatment with Casimersen led to an increase in dystrophin production in skeletal muscle.

Generalized myasthenia gravis (gMG) is a rare and chronic neuromuscular disease characterized by debilitating and potentially life-threatening muscle weakness. Patients typically struggle with basic personal tasks such as speaking, chewing and swallowing food, brushing teeth and hair. Efgartigimod alfa was approved for the treatment of gMG in adult patients who are positive for autoantibodies against the acetylcholine receptor [18]. Efgartigimod alfa represents the first approved therapy designed to reduce pathogenic immunoglobulin G (IgG) antibodies, an underlying driver of gMG.

Infectious Diseases

Existing treatment regimens have led to improved control of human immunodeficiency virus (HIV) infection, paving the way for exploring new therapeutic alternatives such as long-acting therapies which could improve the quality of life for patients living with HIV. The year 2021 marked some important advances in the treatment and prevention of HIV-1 infection, the most common type of HIV. Cabotegravir and rilpivirine represent the first injectable and complete regimen to treat HIV-1 infection in adults on a once monthly basis [19]. This treatment option simplifies therapy for HIV patients as it reduces the number of drugs that they typically take on a frequent basis and, therefore, could be a beneficial alternative for the control of HIV-1 infection in the modern era.

The first antiviral drug to treat adults and adolescents with post-transplant cytomegalovirus (CMV) infection was developed. Maribavir [20]. represents an important advancement in the treatment options for transplant patients with CMV infection, as it shows superiority and a lower incidence of treatment-related toxicities compared to conventional therapies.

Scientific innovations in the infectious disease area also led to the first drug in a new antifungal class in more than 20 years. Ibrexafungerp was approved to treat vulvovaginal candidiasis, a type of yeast infection [21]. In rare infectious diseases, fexinidazole [22] represents the first all-oral treatment for sleeping sickness (Human African trypanosomiasis), an endemic in sub-Saharan Africa caused by parasites transmitted by infected tsetse flies. Fexinidazole could change the treatment paradigm for sleeping sickness as current therapies include oral components taken together with non-oral drugs.

Looking Ahead in 2022 and Beyond: A Technology Revolution in Medicine

As new areas of science and disruptive technology platforms continue to emerge, new scientific innovations will likely impact and shape the next generation of therapies. Below is a highlight of some of the most compelling areas that are likely to fuel the next- generation of innovative therapies.

mRNA therapeutics and manufacturing. Recent breakthroughs in genetic engineering technologies could enable the advancement of a new class of therapeutics based on mRNA, beyond just vaccines. COVID-19 has expedited the application of mRNA in vaccine research but also opened a world of possibilities for new drug modalities. While it’s still early days, mRNA therapeutics represent an important next frontier in drug development that could be leveraged to generate antibodies and proteins with specific functions to address pathologies in cells. Moreover, the development of innovative manufacturing processes for mRNA vaccines and oligonucleotides in general remains an active area of significant value that could transform mRNA- and cell-based therapies to deliver life-changing medicines in future.

Delivery and gene editing. Drug delivery is another important area that is likely to shake up the field of drug discovery, in particular gene editing therapies. While there has been tremendous progress demonstrating the applicability of gene editing approaches in various fields of medicine, ongoing and future work could unlock new approaches to develop and deliver targeted genetic therapies to specific tissues and across the brain.

Illuminating drug discovery and novel biology via condensates and organoids. Biomolecular condensates (aka membraneless droplets or assemblies inside cells) highlight another emerging area of biology that is likely to impact how drugs are discovered and provide new opportunities against challenging targets that could not be drugged effectively with existing drug discovery platforms. In addition, new condensate platforms could unlock diverse target classes and enable the study of various disease-relevant phenotypes as applicable in the context of drug discovery.

Advancements in human organoids are also making an impact on the discovery of novel drugs with novel mechanisms of action that are cell type- and tissue specific. These 3D culture models bring us a step closer to in vivo systems but provide the throughput and the biological system that is a better mimic of physiology than traditional 2D culture models.

Integrated omics and the machine learning revolution in drug discovery. Major advances in proteomics, genomics, and single-cell technologies, coupled with machine learning and analysis algorithms, are also changing the way drugs are discovered and optimized. Providing a systematic comprehensive view on the entire cellular system, beyond just the single target-centric mindset, could have a potential impact on the way drug candidates are selected and advanced to clinical development. When combined with spatial information, the omics technologies could be a powerful approach to revolutionize therapeutics discovery and development.

Moreover, machine learning approaches to predict completely new proteins with novel functions is an area that could shape precision medicine in the coming years, in particular molecules that could potentially correct disease pathologies by targeting specific surfaces on proteins to restore their function or interactions with other partners.

The AlphaFold Protein Structure Database and the continuous addition of disease-relevant proteomes, including those of rare and neglected diseases, could accelerate research and lead to scientific innovations that impact the lives of communities globally. The predictive power of AlphaFold would continue to have an impact on our understanding of protein — protein interfaces and how to develop effective therapeutics in this context.

Navigating the extracellular protein degradation space. Protein degradation has emerged as a key area of science, providing a new wave of drug leads with totally distinct mechanisms for blocking pathogenic proteins. While most of the approaches have been primarily focused inside cells, ongoing scientific progress points in the direction of a new generation of degraders in the extracellular space. These new entities could provide an opportunity to address challenging disease targets that have remained elusive to therapeutic intervention with existing approaches.

Cancer immunology and cell therapies. Fundamental research coupled with key technological advances could expand the scope of targets and machinery in cancer immunology. This could lead to the discovery of novel types of drugs, transfer therapies, vaccines, and immune modulators. Moreover, technological advances in the continuous, scalable production of well-defined macrophage populations derived from human induced pluripotent stem cells could have a transformative impact on immunology and cell therapies as well as shape the pre-clinical landscape for drug safety screening and discovery.

Regenerative medicine. This is an emerging field of medicine that is focused on replacing or regenerating organs or tissues to restore their lost function due to aging or disease. Innovative scientific approaches are being developed for reprogramming cells with the goal of converting one cell type to another or generating new types of cells from induced pluripotent stem cells. Moreover, novel platform technologies are being developed to help identify the reprogramming factors that could be required in regenerating tissues and organs. These scientific and technological advances could offer differentiated treatment options in the future for chronic conditions like hearing loss, retinal degeneration in age-related ophthalmic disease, hair loss, deterioration in bone cartilage, and liver and kidney malfunctioning.

In sum, there were 50 new FDA-approved drugs in the last year that make a positive impact on patient health and care. There were many areas of medicine that benefited from these drugs including cancer, autoimmune, inflammatory, and lung diseases, heart, blood, kidney, and endocrine diseases, infectious diseases, and neurological and psychiatric disorders. It’s noteworthy that the approved innovative therapies spanned multiple and diverse drug modalities beyond just the traditional small molecule drugs and antibody formats, such as peptides, oligonucleotides, and cell therapies, to name a few. This reflects the scientific breakthroughs and advances in platform technologies that enabled the discovery and development of therapies that otherwise would have been challenging to attain. As new scientific breakthroughs emerge and innovative medicines continue to be discovered, they will no doubt continue to fuel the biotechnology revolution that is happening right now in medicine, leading to the development of life-changing therapies.

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[1] Newly approved innovative therapies span various drug modalities including small molecules, monoclonal antibodies, bispecific antibodies, peptides, siRNA, mRNA, antisense oligonucleotides, T cell immunotherapies, enzyme replacement therapies, and vaccines, among others.

[2] Lung Cancer — Non-Small Cell: Statistics | Cancer.Net 118(26.7%)

[3] Amivantamab is a bispecific EGF receptor-directed and MET receptor-directed antibody indicated for metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

[4] Key Statistics for Chronic Myeloid Leukemia (cancer.org) 69(15.6%)

[5] Asciminib is an allosteric BCR-ABL1 protein kinase inhibitor and, as such, does not bind to the ATP-binding site on the active site of the enzyme, unlike imatinib.

[6] ABECMA is a B-cell maturation antigen (BCMA)-directed genetically modified immunotherapy.

[7] Myeloma Statistics | American Cancer Society — Cancer Facts & Statistics 116(26.2%) (https://cancerstatisticscenter.cancer.org)

[8] Inclisaran is siRNA that is directed to PCSK9 (proprotein convertase subtilisin kexin type 9) mRNA, which plays a key role in lipid regulation. It is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (ASCVD).

[9] Circulation. 2019;139:e1082–e1143.

[10] Finerenone is a first-in-class, orally administered, selective, non-steroidal mineralocorticoid receptor antagonist (MRA).

[11] Vosoritide is a peptide therapeutic that mimics the natural C type natriuretic peptide (CNP) which promotes the formation and growth of bone tissue.

[12] Am J Med Genet A. 2008;146A(18):2385–9.

[13] Paroxysmal nocturnal hemoglobinuria: MedlinePlus Genetics 69(15.6%).

[14] Lupus facts and statistics | Lupus Foundation of America 70(15.8%).

[15] Anifrolumab is a first-in-class antibody against type I interferon receptor, which plays a major role in the pathophysiology of lupus.

[16] Tralokinumab is a fully human monoclonal antibody that neutralizes the interleukin-13 (IL-13) cytokine, which is believed to be one of the main contributors of inflammation in atopic dermatitis.

[17] Casimersen is an antisense oligonucleotide to treat patients who have a confirmed mutation of a gene called Duchenne muscular dystrophy that is amenable to exon 45 skipping.

[18] Efgartigimod alfa is a human IgG1 antibody fragment that blocks the neonatal Fc receptor (FcRn), resulting in the reduction of circulating immunoglobulin G (IgG) antibodies. It represents the first-and-only FDA-approved FcRn blocker.

[19] Cabotegravir and Rilpivirine are small molecule inhibitors that act as HIV-1 integrase strand transfer (INSTI) and HIV-1 non-nucleoside reverse transcriptase (NNRTI) inhibitors, respectively.

[20] Maribavir is a cytomegalovirus (CMV) pUL97 kinase inhibitor.

[21] Ibrexafungerp is a triterpenoid antifungal tablet.

[22] Fexinidazole is a nitroimidazole antimicrobial small molecule drug.