Most prominent FDA approvals in 2023
Below is my version of most notable approvals in 2023. Some will become blockbusters, some are controversial, but all are worth mentioning
Obesity drugs
Obesity news is out there far beyond the biopharma space, and there is nothing I can do but to mention it and to add some colors to the story. These are the drugs with megablockbuster future, meaning their sales are likely to surpass $10B per year. Science called them a breakthrough of the 2023.
Obesity affects the majority of people in developed countries and it is a risk factor for diseases such as stroke, heart attack, cancer, type 2 diabetes, among many others. For a long time, creating safe treatments for obesity proved challenging. The situation only changed in 2014 when a drug for type 2 diabetes, liraglutide (Novo Nordisk), was approved by the FDA for obesity treatment as well. However, the real revolution began in 2021 when the FDA approved an improved version of liraglutide for obesity treatment, semaglutide. It demonstrated an impressive average 15% reduction in body weight among study participants over 16 months. The demand for the drug increased so much that Novo Nordisk faced a shortage, leading the company to open new production facilities. Its market capitalization even surpassed Denmark’s GDP, which is the company’s homeland.
In 2023, the results of a study involving 17,000 overweight patients with cardiovascular complications were released. It demonstrated a 20% reduction in major adverse cardiac events (MACE — heart attacks, strokes, cardiovascular-related deaths) in patients taking semaglutide compared to the placebo. This reduction is on par with other cardiovascular drugs. While one might assume this effect is solely linked to weight loss, other studies suggest that this class of drugs also lowers blood pressure, triglyceride levels, and “bad” cholesterol (LDL-C), indicating potential mechanism of action independent of weight loss.
Semaglutide is a synthetic agonist of GLP-1 receptors, which mediates food absorption, metabolism, and hunger sensation. Eli Lilly developed tirzepatide, a medication acting on both GLP-1 and GIP receptors (GIP being another peptide with similar functions). This dual action resulted in an even greater weight reduction, averaging 20%. Tirzepatide, initially approved for type 2 diabetes, received approval for obesity in 2023.
There is a possibility that medications of this class may also impact other organs, such as the kidneys, liver, etc. (fig. 1), potentially extending even to the treatment of alcohol dependence.
Triple inhibitors (affecting another similar receptor, GCGR) and oral analogs, which are more convenient than existing subcutaneous ones, are currently under development.
However, there’s a downside: some patients cannot tolerate the medication, experiencing adverse effects such as nausea, diarrhea, and other gastrointestinal issues. There are concerns about long-term safety: cases of thyroid cancer in animals have been observed, potential development of pancreatitis, and worries about suicidal tendencies. Doctors and regulatory agencies continuously gather information and conduct additional assessments of the risk-benefit ratio. These medications are currently quite expensive — costing over $1000 for a monthly course — and are prescribed only to patients with a body mass index (BMI) over 30. While they should be prescribed by a doctor, it is known that many individuals seeking weight loss self-administer these injections. Another drawback of medications in this class is the need for lifelong use. After discontinuation, patients, on average, regained two-thirds of the lost weight within a year, and cardiovascular indicators returned to pre-treatment levels.
Nevertheless, despite all the challenges, the projected market size for this class of drugs is nearly $80 billion by 2030. It is unclear how healthcare systems and insurance will cope with covering these expenses, but it’s essential to consider that these costs are likely to be justified. For instance, it was estimated that in the United States alone, excess expenses for treating obesity-related diseases amounted to $170 billion in 2019.
Alzheimer’s: Success or Empty Hope?
Alzheimer’s disease is a debilitating condition primarily affecting the elderly, leading to rapid deterioration of mental abilities, memory, and premature death. The causes of the disease are still unclear, and the mechanism of pathogenesis is insufficiently understood to create disease modifying drugs. Since the early 1990s, it has been observed that the brains of many patients accumulate plaques consisting of peptides — the so-called amyloid plaques. The development of drugs aimed at reducing these plaques began. However, several drugs in this category failed in clinical trials — even if they managed to reduce plaque content in the brain, it did not lead to an improvement in patients’ cognitive abilities. In 2021, the FDA granted accelerated approval to Biogen’s antibody Aduhelm (aducanumab) despite its failure to show significant improvement in patients’ conditions in both registration trials. An independent commission voted against approval. The Centers for Medicare and Medicaid Services (CMS), responsible for insurance coverage of medications, refused to reimburse aducanumab treatment, and as a result, it is not currently used.
In January 2023, another drug from the same category received accelerated approval — lecanemab by Biogen/Eisai, and in July it was granted the full approval, as the company provided phase 3 data. This is the first drug against Alzheimer’s disease that has shown statistically significant improvement on the dementia scale compared to a placebo. However, skeptics note that the result is not very significant clinically: deterioration occurred in both the lecanemab and placebo groups. The difference between the groups at the end of the 18-month observation period was 0.45 points (fig. 2), which is not substantial.
It is unclear why researchers initially decided to establish set such a low threshold for clinical significance, as previous studies indicated that this difference should be at least 1–2 points. In real-world conditions, a 0.45-point difference can turn into a completely insignificant advantage, and even if the drug were entirely safe, that would only be half the battle. Unfortunately, the use of all anti-amyloid antibodies is associated with rare cases of brain edema, which sometimes lead to death.
Donanemab by Eli Lilly is following closely behind lecanemab, showing a reduction of 0.7 points on the same scale compared to a placebo. In January, the FDA rejected the company’s application for accelerated approval based on phase 2 data, citing an insufficient number of patients. The company collected the necessary data, submitted the dossier, and the FDA’s decision is expected in early 2024.
Some analysts believe that by 2028, these two drugs will generate $12.9 billion of sales. Time will show how successful they will actually be in real-world application, but in any case this is an important step that helps advance our understanding of the pathogenesis of the disease.
RSV Vaccines
Respiratory Syncytial Virus (RSV) causes a common cold in healthy adults but can be deadly for newborns and the elderly. According to the World Health Organization (WHO), about 160,000 people die from it every year. Attempts to develop an RSV vaccine date back to the 1960s, but that candidate worsened the course of the disease and led to the deaths of two children. After dozens of failures, scientific progress by the 2010s allowed the development of safe and effective vaccines, which were approved in 2023.
Only in 2008 the failure of the 1960s received an explanation: in response to immunization, children produced ineffective antibodies that formed immune complexes in the lungs, worsening the course of the disease. To create an effective vaccine, it was necessary first to determine the structure of the RSV-F viral protein responsible for the virus entry into cells. It was found that the protein exists in two conformations: pre-fusion, before merging with the cell membrane, and post-fusion, after merging (fig. 3). During regular vaccination, antibodies were produced against the post-fusion protein, and were ineffective in preventing the virus from merging with the cell. In 2013, after numerous meticulous experiments, an artificial form of the pre-fusion F protein was created, covalently fixed in such a position through amino acid substitutions to induce an immune response. Clinical trials of the new vaccines began in 2017, and the first results were obtained in 2019. Interestingly, the idea of fixing the protein in the pre-fusion state was used in the design of the Pfizer/BioNTech and Moderna vaccines against SARS-CoV-2.
Success was achieved by two companies: GlaxoSmithKline with the drug Arexvy, approved for people over 60, and Pfizer, which obtained approval for its Abrysvo vaccine for both the elderly people and pregnant women, for preventing RSV in newborns. The effectiveness of both vaccines is quite high: the risk of developing severe respiratory disease decreases by 94% for Arexvy, 86% for Abrysvo in the elderly, and 82% in newborns after maternal immunization. Moderna created its RSV vaccine on the same platform as the COVID vaccine, demonstrating an efficacy of 83.7% and high safety in clinical trials (unlike the other two vaccines, with no cases of encephalomyelitis and Guillain-Barré syndrome). Its approval is expected in 2024.
For newborns, vaccination is not available because they have not yet developed a sufficient immune response, but for many years they have had the option of passive immunization with the antibody Synagis (palivizumab, AstraZeneca). In 2022, in the EU, and in 2023, in the USA, its improved version Beyfortus (nirsevimab) was approved, developed by AstraZeneca in collaboration with Sanofi. Unlike Synagis, which needs to be administered monthly, one injection of the new drug is sufficient to provide 70–75% protection against infection, so it is recommended for all children in the US up to 8 months.
Multiple Successes in Gene and Cell Therapy
The year 2023 continued the trend of 2022 and marked a series of approvals in the field of gene and cell therapy — a new type of medicine with hopes of curing many rare and not-so-rare diseases.
First Approval of Gene Editing
The most significant was the approval of the sickle cell anemia therapy by CRISPR/Vertex, the first drug obtained using CRISPR/Cas9 genome editing. The drug was first approved in the UK on November 16 and then in the US on December 8. Remarkably, only 11 years passed from the discovery of CRISPR/Cas9 to the registration of a drug based on this technology.
Sickle-cell disease is a hereditary disorder caused by mutations in hemoglobin gene. When untreated, it leads to anemia, thromboses, and painful crises. Current chronic treatment may alleviate the symptoms, but the disease is still a significant burden. New therapy after just a single shot was able to reduce crises to zero in 28 of 29 patients.
In the US, simultaneously with CRISPR/Vertex, gene therapy for sickle cell anemia by bluebird bio (one of the pioneers in gene therapy) was also approved. Interestingly, CRISPR/Vertex set the price for the drug at $2.2 million per injection, while bluebird set it at $3.1 million. The independent non-profit organization ICER (The Institute for Clinical and Economic Review), which conducts pharmacoeconomic analysis in the US, calculated that the justified price for both drugs ranged from $1.35 to $2.05 million. How the drugs will share the market is still unclear, as each has its advantages and disadvantages. For example, bluebird has a longer patient monitoring period and experience commercializing a product for beta-thalassemia. Still, with approval, the company faced an unpleasant surprise: the product received a black box warning about the risk of developing secondary oncohematological diseases. Indeed, during clinical trials, two patients developed acute myeloid leukemia, although these cases were later deemed unrelated to the therapy. CRISPR also has a theoretical risk of off-target genome editing, although this has not been observed in practice. According to surveys, 60–80% of doctors see no practical difference between the two therapies.
In any case, these approvals are an important milestone for patients with sickle cell anemia, who now have the opportunity to forgo constant blood transfusions and painful episodes with just one injection, and for the field of gene therapy as a whole. Sickle cell anemia is a much more common disease than the previous diseases for which gene therapies were approved, so this approval expands the possibilities of the new approach.
In March 2024, the FDA is expected to decide on CRISPR/Vertex therapy for a similar indication, beta-thalassemia. Bluebird’s drug already received approval for it in 2022.
Both sickle cell anemia and beta-thalassemia are caused by a defect in the gene encoding the beta chain of hemoglobin. Both bluebird and CRISPR/Vertex modify the patient’s isolated cells and then reintroduce them. However, in the case of bluebird, normal copies of the gene encoding the beta chain of hemoglobin are introduced into the cells. In the case of CRISPR/Vertex, the gene responsible for silencing the fetal hemoglobin gene is “broken.” In both cases, the patient requires fairly intense chemotherapy to “clear the space” for modified cells, limiting the use only to severe cases of the disease.
Gene Therapy Gel
An interesting case of gene therapy application is the topical product by Krystal Biotech for treating epidermolysis bullosa. This is the first approved gene therapy that is a gel, rather than an injection. Secondly, unlike other gene therapy products that predominantly use adeno-associated viruses to deliver genetic constructs into human cells, Krystal’s product uses the herpes virus (fig. 4). This is a clever solution considering the pathogenesis of epidermolysis bullosa: in this disease, the collagen-7 gene is defective in skin cells, and the herpes virus has specifically evolved to infect skin cells. Lack of collagen-7 leads to detachment and damage to the skin with the slightest friction (hence epidermolysis bullosa is also called “butterfly disease”), which poses a constant risk of infection, increases the likelihood of developing skin cancer, and premature death.
Krystal’s therapy, unlike other gene therapies, is not a one-time treatment but requires constant weekly administration because the herpes virus used is incapable of reproducing; it merely delivers a functional copy of the collagen-7 gene into the cells. In a study of 31 patients, wounds closed in 65% of patients compared to 26% in the placebo group. The company reported that the therapy would cost $631,000 per year.
Genetic Drug for Duchenne Muscular Dystrophy
Duchenne muscular dystrophy poses a significant challenge for pharmaceutical companies. It is caused by mutations in the dystrophin protein, the largest protein in the human body, which is responsible for muscle function. Defects in dystrophin lead to progressive muscle weakness, and patients rarely survive beyond 40 years. Since 2016, drugs for treating this disease have been emerging, but none has succeeded in achieving a significant delay in the progression of the disease.
In June 2023, Sarepta received accelerated FDA approval for the first gene therapy for Duchenne muscular dystrophy. Such approval is granted under the condition of continuing studies, and with positive results in a controlled study, it can be converted into full approval. If the results are negative, approval may be revoked. In October, the company published the study results where the primary endpoint (difference in scores compared to placebo on the motor function scale) did not reach statistical significance. Formally, the study failed, but all secondary endpoints indicate some superiority of the drug over placebo. The company plans to submit this data to the FDA and obtain full approval. However, even with accelerated approval, the company has the right to sell the drug, and its price is set at $3.2 million. For Sarepta, such a strategy has become routine: the company obtained its first, highly controversial, approval in 2016 for the drug eteplirsen. Its mechanism of action is very interesting — it is an RNA molecule that makes the ribosome skip the defective segment of mRNA corresponding to the mutation in the dystrophin gene. However, the study was conducted on only 12 patients and showed modest results. Nevertheless, largely under pressure from patient organizations, the FDA granted accelerated approval to the drug. Although the company was supposed to conduct a confirmatory study by 2020, it has not done so, and its results would not be available until 2024. Meanwhile, sales of the drug, priced at $300,000 per year, bring the company substantial income. In 2019 and 2021, two more drugs were approved using the same scheme.
Sarepta’s new drug is a microdystrophin gene (microdystrophin being a truncated version of the dystrophin protein) packaged in the AAVrh74 viral capsid, which serves as the delivery vehicle (vector) for the gene to the muscles. After intravenous administration, the vector is distributed in muscle tissue, and the expression of microdystrophin compensates for the deficiency of normal dystrophin.
First Microbiome Drug
In recent years, there has been a lot of speculation about the human microbiome as an important component in both healthy and diseased states. Studies on the influence of the gut microbiome on everything from cancer to autism are all over the place. However, despite the abundance of information, in most cases it is still unclear what is the causal relationship here and how to influence the microbiome to improve the condition of patients. One exception is recurrent Clostridioides difficile infection. This opportunistic bacterium normally lives in the intestines without causing problems. Still, with the intake of antibiotics, especially in hospital settings where a person takes several drugs simultaneously, the bacterium can become activated, multiply, and cause severe diarrhea and inflammation of the intestines, even leading to death. In the US alone, 20,000 people die from this infection every year. In 2013, a small study showed the effectiveness of fecal transplantation for treating recurrent C. diff infection. Fecal transplantation is a well-known method (first described in the 4th century in China). However, it is not very technologically advanced, although in the US and Europe, entire fecal banks have been created where healthy volunteers can donate. The FDA issued several warnings regarding the transmission of antibiotic-resistant bacteria through donor stool. In November 2022, the Ferring Pharmaceuticals received approval for its fecal transplant product.
Seres took a more technological approach (fig. 5): their product consists of purified bacteria isolated from the stool of healthy donors, in a capsule for oral administration — unlike fecal transplantation, which is usually done rectally. Despite initial failures in clinical trials, the company did not lose heart, increased the dose of the drug, and conducted a phase 3 study, which turned out to be successful. Among patients who took the drug, only 12% experienced a recurrence of C. diff infection after 8 weeks, while in the placebo group, there were 40% of them . The safety of treatment did not differ from placebo.
Seres’ product was approved in 2023. For commercialization, Seres entered into collaboration with the Swiss food giant Nestlé, which already sells probiotics and dietary fibers.
Unfortunately, other microbiome drugs have not yet demonstrated sufficient effectiveness, although attempts have been made to study them for inflammatory bowel diseases, autism, and obesity. But research on the microbiome is expanding, and perhaps new drugs of this type are not far off.
Geographic Atrophy
For a moment, let’s turn away from cutting-edge therapy and focus on a more “conventional” drug — Apellis’ pegcetacoplan, approved in 2021 for the rare blood disorder paroxysmal nocturnal hemoglobinuria and in 2023 for the eye disease geographic atrophy. It became the first approved drug acting on the pathogenesis of geographic atrophy — an eye disease where cells in the macula, responsible for central vision, die off. It is called “geographic” because the appearance of the retina begins to resemble a geographical map (fig. 6).
How is it possible for the same drug to help with such different diseases? The key lies in the fact that in both cases, the pathogenesis of the disease involves the complement system, whose excessive activation leads to cell death (normally, the complement system plays an important role in the body’s defense against pathogens). Pegcetacoplan binds to one of the key proteins of the complement system, C3, and consists of two identical peptides connected by a polyethylene glycol bridge. In clinical trials, the drug demonstrated the ability to slow down the growth of the damaged area of the retina by 36%. Unfortunately, this cannot restore vision to people yet, but in such a complex field, any success is highly valuable. Analysts predict sales of the drug to reach $2.6 billion by 2028.
The drug’s mechanism of action raises hopes that it will also be effective for other diseases where excessive complement activation is observed, such as amyotrophic lateral sclerosis, glomerulonephritis, and others.
Just a few months later, a second drug against geographic atrophy was approved, the RNA aptamer avacincaptad pegol (Astellas/Iveric), acting on another protein of the complement system, C5. Avacincaptad became the second drug in the RNA aptamer class approved by the FDA. The previous one, pegaptanib (Pfizer/Eyetech), was approved 19 years ago in 2004 for the wet form of age-related macular degeneration (an eye disease characterized by the proliferation of blood vessels in the retina) but failed to gain a significant market share. Aptamers were considered a promising class of drugs in the early 2000s due to the apparent simplicity of development: they are single-stranded DNA or RNA selected by screening to selectively bind to the target and, for example, block the interaction of two proteins. However, they generally lost out to antibodies, of which there are almost 200 on the market. Only time will tell whether the new aptamer can reverse this trend.
C5 is a well-known target; the antibody Soliris (eculizumab) against the complement protein C5 by Alexion (acquired by AstraZeneca in 2020 for $39 billion) was approved back in 2007 for paroxysmal nocturnal hemoglobinuria and became a blockbuster. It later received several approvals for other indications (though it did not show efficacy specifically in geographic atrophy). Later, Alexion released an improved analog of Soliris, Ultomiris (ravulizumab). The company ChemoCentryx (acquired by Amgen in 2022 for $3.7 billion) released avacopan, a low-molecular-weight C5aR receptor inhibitor, against the rare vascular disease — ANCA-associated vasculitis.
The year 2023 was marked by the approval of several more drugs against the complement system (fig. 7): another antibody against C5 was approved — pozelimab (Regeneron) for the rare genetic syndrome CHAPLE, which leads to complement hyperactivation. The company UCB also received approval for the cyclic peptide Zilucoplan, which also binds to C5, for the indication of myasthenia gravis (an autoimmune disease leading to muscle weakness).
In 2023, the FDA also approved another drug against paroxysmal nocturnal hemoglobinuria, also inhibiting the complement — iptacopan from Novartis, acting against factor B, which is responsible for the cleavage of C3.
