COVID Vaccines, what’s new: an update on the latest clinical trials that are underway.
May 24, 2021
Current Landscape of Cell Therapy Clinical Trials
March 23, 2023
COVID-19 pandemic that emerged in 2019 has adversely affected human life globally. In addition to the health and socio-economic aspects, we have observed its effect on the therapeutic pipeline. There is a decline in new cancer clinical trials due to COVID-19, as noted in previous years (1,2 & 3). We analyzed clinical trial data obtained from clinicaltrials.gov and Kognitic platform to understand the current clinical trial landscape (2021, 2022) and compare it with pre-pandemic (2019) data (4, 5). Our results show a 56% reduction in the FDA approval of novel cancer therapeutics (23 in 2020 compared to 10 in 2022) and a 29% reduction in the total number of clinical trials (8508 in 2020 compared to 6361 in 2022).
In this report, Kognitic brings insights into oncology clinical trials from the years 2021 and 2022. The clinical data is segmented based on phase, indications, drug modality, and targets. More insights on clinical trial intelligence for pharma-commercial strategy can be found at Kognitic Inc.
Phase II clinical trials predominated in 2021 and 2022
We analyzed trials in 2021 and 2022 by their designated Phase of the study. The total number of trials in 2021 was 8000, of which 2097 (26%) trials had no specific Phase information. The total number of trials in 2022 has reduced by 25% to 6361, of which 1809 (28%) had no Phase information. We eliminated the trials without Phase-information from our analysis. Of the remaining 5903 (2021) and 4552 (2022) trials, the highest numbers of trials were in Phase II, accounting for 45% of the trials in 2021 and 52% in 2022. We observed a notable decline in the number of clinical trials in Early Phase trials, Phase II, Phase III, and Phase IV trials from 2021 to 2022. There was no change in the number of Phase I trials in 2021 and 2022 (Figure 1).
Gastrointestinal Cancer is the new leading indication in clinical trials post-pandemics
Oncology clinical trials were distributed in 21 indications. The highest number of trials were in gastrointestinal cancer, with ~50% (2021) and ~40% (2022) of the total trials (Figure 2). The top 5 indications for 2021 and 2022 were gastrointestinal cancer, lung cancer, Non-Hodgkin lymphoma, breast cancer, and gynecologic cancer. Compared to 2019, the number of gastrointestinal trials has significantly increased in 2021 and 2022. The top five indications for oncology clinical trials were solid tumors, leukemia, lung cancer, lymphoma, breast cancer, and gastrointestinal cancers (6). A rise in the early onset of gastrointestinal cancer incidence has increased the disease burden (7). Therefore, leading pharmaceutical companies have been investing in the gastrointestinal clinical pipeline. According to Bloomberg news, over 200 companies are investing in gastrointestinal cancer preclinical and clinical pipelines (8). Thus we expect to have more therapeutics for gastric cancer in the near future.
PD-1 trials continue to lead the clinical trials post-pandemics
The cancer treatment landscape has been evolving from traditional chemotherapy to targeted therapy and precision medicine. To monitor the targeted therapy trend in clinical trials of 2021 and 2022, we analyzed new trials for various targets.
We tabulated the top 20 targets for the year 2022, comparing its number to the year 2021 (Figure 3). Based on our analysis, PD-1 is the most common therapeutic target for oncology clinical trials for 2021 and 2022, similar to the pre-pandemic period (2019) (6). Although there is a rapid increase in new targets and targeted therapies, traditional chemotherapeutic targets are also equally used in newer clinical trials as the standard of care or as combination therapy with targeted therapies. Chemotherapeutic targets microtubulin (TUB) and thymidylate synthase (TYMS) have the second and third-highest clinical trial counts. In general, we see a decrease in the number of trials for most targets in 2022 compared to 2021, except for Adenosine deaminase (ADA), where we observe an increase in trial count in 2022 compared to 2021. Adenosinergic signaling plays a crucial role in the immunosuppression of the tumor microenvironment. Targeting the adenosinergic signaling with antagonists has an antitumor effect, synergistic when combined with other cellular immunotherapy, such as CAR-T and CAR-NK cell therapy (9). Therefore there has been an emergence of combination trials of ADA (a chemotherapy target) and other immunotherapies, leading to a rise in the number of trials targeting ADA.
To understand the novel therapeutics based on their targets in the clinical pipeline in 2022, we further analyzed the targets by the number of drugs in the clinical pipeline (Figure 4). Unlike trial count (Figure 3), where Programmed Cell Death Protein-1 (PD-1) was the most predominant target, Prostate-specific membrane antigen (PSMA) is the predominant target with 25 different therapeutics in the clinical pipeline. The majority of the clinical trials targeting PSMA are radiopharmaceutical agents (71%), followed by cell therapy (20%) and bispecific antibodies (6%). There have been two recent PSMA radiotherapeutics approvals: Pylarify (2021, Lantheus Holdings) and Pluvicto (2022, Novartis).
Bispecific antibodies and cell therapies are emerging modalities in oncology clinical trials
In terms of the distribution of drugs by modalities (Figure 5), small molecules and monoclonal antibodies continue to predominate similar to what we observed in 2019 and 2020 (6). Of the 698 therapies in clinical trials, 37% were small molecules, and 18% were monoclonal antibodies. Although small molecules and monoclonal antibodies have a large share of clinical trials, we see a decline in these areas in 2022 (37% and 18%, respectively) compared to (43% and 26%, respectively) 2019. Notably, there has been an emergence in clinical trials in bispecific antibodies (13% in 2022 compared to 1.5% in 2019) and cell therapy (11.5% in 2022 compared to 5% in 2019). The cell therapy trials include trials for CAR-T (5.3%), CAR-NK (1.1%), and other cell therapy (5.1%) together.
Bispecific antibodies: Bispecific antibodies are engineered dual-specificity containing antibodies that can engage more than one specific target epitope at a time, making them more efficient than traditional monoclonal antibodies. Current FDA-approved bispecific antibodies are Rybrevant (Janssen), Blincyto (Amgen), Kimmtrak (Immunocore), and Tecvayli (Janssen). Bispecific antibodies that bind to cancer cell targets and recognize and engage immune cells (T cells) called Bispecific T cell Engagers (BiTE) are also on the rise (10,11). We examined various combination targets of all bi-specific antibodies. These drugs primarily fall into T-Cell engagers and checkpoint inhibitors. The highest number of these drugs has CD3 as one of its combination targets. Some of the most common indications for bispecific antibodies are Non-small cell lung cancer (NSCLC), Colorectal cancer, and Ovarian cancer targeting PD-1, 4-1bb, and Gastric cancer and hematological malignancies (Multiple Myeloma, Non-Hodgkin Lymphoma, and Acute Myeloid Leukemia) targeting CD3 combinations. recently Janssen has filed for Biological Licensing Agreement (BLA) for talquteamab, a novel bispecific antibody targeting GPRC5D x CD3 to treat multiple myeloma that is predicted to launch in Q2 of 2024. Targets for bispecific antibodies are listed in table 1.
Table 1: Targets for bispecific antibodies
Cell therapy: Since the FDA approval of Kymriah (Novartis, first CAR T cell) in 2017, there has been growth and new development in cancer cell therapy. The various other CAR T-cell therapies that FDA has approved are Yescarta and Tecartus from Gilead (target CD19), Breyanzi from Bristol-Myers-Squibb (targets CD19), Abecma from Bristol-Myers-Squibb (targets BCMA), and Carvykti from Jassen (targets BCMA) (12, 13, and 14). Our analytics shows a significant growth in clinical trials focused on adoptive cellular therapies such as engineered CAR-T, natural killer cells, and T-cell engagers (Figure 5). These clinical trials are mostly exploring targets such as BCMA and CD19. With advancements in technology and demand for alternative treatment methods, there is a rise in the development of advanced engineered cellular therapies such as Tumor-infiltrating leukocytes and Natural Killer cells that can activate and kill selective tumor cells.
Approved drugs
We observe a decline in novel drug approval by FDA in the year 2022. A total of 37 novel drugs were approved by the FDA, of which 10 were cancer drugs (Table 2). Regarding the total number of drug approval, 2022 saw a 26% reduction from 50 in 2021 to 37 in 2022. However, the number of cancer drugs approved is comparable in 2021 (nine) and 2022 (ten). The approved drugs, like clinical trials, have the highest percentage of drugs in small molecules and monoclonal antibody modalities.
Table 2: FDA approved drugs in 2021 and 2022 (13,14)
| Year of approval | Drug Name | Active Ingredient | Indication | Modality | Company | Target |
| 2022 | Krazati | adagrasib | Non-small cell lung cancer | Small Molecule | Mirati | KRAS G12C |
| 2022 | Rezlidhia | olutasidenib | Myeloid leukemia | Small Molecule | Rigel and Forma | IDH1 |
| 2022 | Elahere | mirvetuximab soravtansine-gynx | Ovarian cancer | ADC | Immunogen | FRa |
| 2022 | Tecvayli | teclistamab-cqyv | Multiple myeloma | Bi-specific | Janssen | BCMA/CD3 |
| 2022 | Imjudo | tremelimumab | Hepatocellular carcinoma | mAb | Astrazeneca | CTLA-4 |
| 2022 | Lytgobi | futibatinib | Cholangiocarcinoma | Small Molecule | Taiho | FGFR2 |
| 2022 | Rolvedon | eflapegrastim | Non-myeloid malignancies | Protein (Glycoprotein) | Spectrum | GSF |
| 2022 | Pluvicto | lutetium (177Lu) vipivotide tetraxetan | Prostate cancer | Radiopharmaceutical | Novartis | PSMA |
| 2022 | Opdualag | nivolumab and relatlimab-rmbw | Melanoma | mAb | BMS | LAG-3 and PD-1 |
| 2022 | Kimmtrak | tebentafusp-tebn | Uveal melanoma | Bi-specific | Immunocore | gp-100/ CD3 |
| 2021 | Tivdak | tisotumab vedotin-tftv | Cervical cancer | ADC | Genmab/Seagen | TF |
| 2021 | Exkivity | mobocertinib | Non-small cell lung cancer | Small molecule | Takeda | EGFR / HER2 |
| 2021 | Lumakras | sotorasib | Non-small cell lung cancer | Small molecule | Amgen | KRAS G12C |
| 2021 | Pylarify | piflufolastat F 18 | Prostate cancer | Radiopharmaceutical | Lantheus holdings | PSMA |
| 2021 | Rybrevant | amivantamab-vmjw | Non-small cell lung cancer | Bi-specific | Janssen | EGFR / MET |
| 2021 | Jemperli | dostarlimab-gxly | Endometrial cancer | mAb | GSK | PD-1 |
| 2021 | Cosela | trilacicilib | Small cell lung cancer | Small Molecule | Boehringer Ingelheim / G1 Therapeutics | CDK4 / CDK6 |
| 2021 | Tepmetko | tepotinib | Non-small cell lung cancer | Small Molecule | Merck KGaA | TKI |
Conclusion
Our analysis shows a changing landscape in oncology clinical pipeline with a trend towards decreasing number of clinical trials as well as approvals of cancer therapeutics post pandemics (2021 and 2022) compared to what was in pre-pandemic period (2019). The global adverse effect of the COVID-19 pandemic, current macroeconomics, and increased scrutiny by regulatory agencies like the FDA may have accounted for the reduction in oncology clinical trials and subsequent approvals. Despite the reduction in trials and approvals, we see an emerging trend moving from traditional therapeutics to targeted precision medicine using novel methods such as bispecific antibodies and engineered cell therapies. Notably, there were novel approvals, including three bispecific antibodies to treat various cancers, novel radioligand therapies, and targeted therapeutics to treat difficult-to-treat cancers like KRASG12C non-small cell lung cancer. We also observed increased combination trials using traditional chemotherapy, emerging immunotherapy, and other targeted approaches. Thus we can stay optimistic that despite reduced trial counts, there is advancement in the oncology clinical therapeutic pipeline with better therapies to come in the future.
References:
- Wilkinson E. Dramatic drop in new cancer drug trials during the COVID-19 pandemic. Lancet Oncol. 2021 Mar;22(3):305. doi: 10.1016/S1470-2045(21)00067-X. Epub 2021 Feb 4.
- Ali JK, Riches JC. The Impact of the COVID-19 Pandemic on Oncology Care and Clinical Trials. Cancers (Basel). 2021 Nov 25;13(23):5924. doi: 10.3390/cancers13235924.
- Lamont EB, Diamond SS, Katriel RG, et al. Trends in Oncology Clinical Trials Launched Before and During the COVID-19 Pandemic. JAMA Netw Open. 2021;4(1):e2036353. doi:10.1001/jamanetworkopen.2020.36353
- https://clinicaltrials.gov
- https://www.kognitic.com
- Kognitic Oncology Outlook 2019 vs 2020. https://www.kognitic.com/reports
- Ugai, T., Sasamoto, N., Lee, HY. et al. Is early-onset cancer an emerging global epidemic? Current evidence and future implications. Nat Rev Clin Oncol 19, 656–673 (2022). https://doi.org/10.1038/s41571-022-00672-8
- https://www.bloomberg.com/press-releases/2022-12-21/gastric-cancer-pipeline-space-brims-with-novel-emerging-therapies-with-over-200-key-companies-working-in-the-domain
- Wei Q, Zhang L, Zhao N, Cheng Z, Xin H, Ding J. Immunosuppressive adenosine-targeted biomaterials for emerging cancer immunotherapy. Front Immunol. 2022 Oct 25;13:1012927. doi: 10.3389/fimmu.2022.1012927. PMID: 36389700; PMCID: PMC9641176.
- Zhou S, Liu M, Ren F, Meng X, Yu J. The landscape of bispecific T cell engager in cancer treatment. Biomark Res. 2021 May 26;9(1):38. doi: 10.1186/s40364-021-00294-9. PMID: 34039409; PMCID: PMC8157659.
- Wei J, Yang Y, Wang G, Liu M. Current landscape and future directions of bispecific antibodies in cancer immunotherapy. Front Immunol. 2022 Oct 28;13:1035276. doi: 10.3389/fimmu.2022.1035276. PMID: 36389699; PMCID: PMC9650279.
- https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
- Novel Drug Approvals for 2022 https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2022
- Novel Drug Approvals for 2021 https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2021
For more information, email info@kognitic.com
