Afatinib

Afatinib

             Lung cancer is one of the most prevalent forms of cancer today, accounting for 14% of all new cancers and ranking second in most common forms of cancer. It is also fairly fatal, carrying a 5-year survival rate of only 15%.^[1] There are two forms of lung cancer: small cell lung cancer (SCLC), which accounts for about 15% of lung cancers, and non-small cell lung cancer (NSCLC), which accounts for about 85% of lung cancers.^[2] These forms of cancer are differentiated based on type of lung cells affected and therefore require different treatments. A class of drugs called epidermal growth-factor receptor tyrosine kinase inhibitors (EGFR-TKI) is a relatively new treatment option of those affected with NSCLC, with a drug called afatinib (Gilotrif®) being most recently approved for this indication.

            Afatinib is a second-generation, highly selective irreversible inhibitor of EGFR, ErbB2/HER2, and ErbB4/HER4, which are cell-membrane receptors that initiate intracellular signaling cascades through phosphorylation.^[3] Thinking of how cancer manifests itself, by inhibiting intracellular phosphorylation, the hope is to slow/stop the constant proliferation of these cells.  The discovery of afatinib actually stems from a need to improve upon the first-generation of EGFR-TKIs. Erlotinib, a first-generation EGFR-TKI, is still widely used today in the treatment of NSCLC. However, a large number of patients that showed an initial response to treatment developed resistance to the therapy and relapsed after several months. It was found that the resistance to these first-generation EGFR-TKIs comes from receptor mutation, which was T790M, a mutation in exon 20 of the receptor.^[3] This mutation either transforms the receptor to prevent erlotinib from binding, or increases the enzymatic activity leading to increased dosing to achieve therapeutic efficacy.^[4] First-generation EGFR-TK inhibitors like erlotinib are reversible inhibitors, so the idea of making an irreversible EGFR-TK inhibitor was a logical next step.

            Afatinib is created by Boehringer Ingelheim, a private pharmaceutical company that was founded back in 1885 by Albert Boehringer in Ingelheim am Rhein, Germany. Boehringer started out creating tartaric acid for use in the food industry back in 1885, and in 1917, Boehringer hired Heinrich Otto Weiland, future Nobel prize winner, to come and redesign the company and set up a research department. Boehringer further expanded when they purchased Dr. Karl Thomae, a company that produced opium that Boehringer desired to increase his opium share at the German Opium Convention. In 1955, the company acquired Pfizer’s veterinary program and establishes it’s own Animal Health Division. The company continued to grow, and in 1971 opened its US branch, Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut. Then, in 1986, Boehringer Ingelheim began its production of biopharmaceuticals, and thus began the road to the discovery of afatinib.^[6]

            Afatinib, or BIBW2992 as it was labeled while being studied, was derived from the anilino-quinazoline chemical series, which had already been designed to covalently bond to cysteine residues of EGFR.^[4] Specifically, afatinib covalently binds directly to the ATP-binding site in the kinase domains of EGFR, which is Cys 773, and HER2, which is Cys 805.^[4] Erlotinib is also a quinazoline derivative, but does not possess the ability to covalently bind with the same residues, allowing it to dissociate and stay a reversible inhibitor. By covalently binding with these receptors, afatinib shows longer suppression of receptor activity when compared to first-generation EGFR-TKIs. The covalent bond also makes afatinib a more potent drug when compared to erlotinib. Both of these compounds are synthetic and require multi-step synthesis pathways to achieve the final product.

            Boehringer Ingelheim has both conducted and is conducting a series of research studies on afatinib. This series of trials is called the “Lux-Lung Clinical Trials.” This set of 8 studies takes afatinib into many unique populations ranging from different types of cancer to different genetic mutations. All of these trials began after the drug had been FDA approved, and some of these trials are still ongoing today. One of the points of these studies is to see what this drug can be used in with beneficial clinical outcomes in order to expand the indication range, leading to more sales. Gilotrif, as of January 2018, has received an extended indication list, which will end up increasing sales.^[7]

As of today, there are six active patents that deal with afatinib, five of which are owned by Boehringer Ingelheim. The only patent they do not own, patent US6251912, is owned by Wyeth Holdings LLC, and deals with one of the chemical structures within the molecule. The patent was filed before afatinib was ever in the pipeline, which would indicate that Boehringer Ingelheim would have had to have made a deal with Wyeth Holdings in order to produce afatinib. The other five patents deal with more specific chemical structures (USRE43431 and US9539258), drug-specific release mechanisms (US8545884), methods on how to synthesize the compounds necessary to create afatinib (US8426586), and even drying processes (US10004743).^[8]

            Because there isn’t a way to measure how many of the EGFR-TKIs have bound to receptors, the efficacy is based on whether or not the tumor has shrunk, and if so, by how much.^[3] When compared to first-generation EGFR-TKIs in this manner, afatinib appears to just be comparable, but the niche use of afatinib is in patients that possess this mutation for EGFR-TKI resistance.^[3] As of today, afatinib is approved for first-line therapy in patients that have metastatic NSCLC with exon 19 deletions or exon 21 substitution mutations.^[5] These mutations are the mutations that erlotinib is more specific towards, but due to the large amount of resistance that occurs with this therapy, afatinib has become first-line therapy.

            Adverse reactions of afatinib are not anything pleasant, but neither is NSCLC. In one specific study, 90% of patients either experienced GI or cutaneous adverse event.^[3] While these events are manageable with proper care, they do pose a risk for patient adherence and need to be explained to the patient.

            Gilotrif, afatinib’s brand name by Boehringer Ingelheim, is expected to earn upwards of almost $700 million by the year 2022 ($688.1 million). This estimation was done by GlobalData in 2013 when the drug was approved by the FDA (July 12^th, 2013). While there are some other EGFR-TKIs in the pipeline from other companies that might hinder Gilotrif’s earnings, the drug made $53.28 million on it’s launch in 2013.^[9] Again, with the extended indications that Gilotrif has received, these numbers could increase depending on how much of an influence these other drugs become in the EGFR-TKI market.

            The part of this discovery that fascinates me the most is the choice to try an irreversible inhibitor. While it is a logical step in discovery, the result of the change yielded more than expected. Afatinib does have longer suppression than erlotinib, but when comparing PFS of the two, there isn’t a clear winner (11.1 months with afatinib and 9.7-13.1 with erlotinib. It was the discovery of therapeutic efficacy against first-generation EGFR-TKIs that was really compelling and showed the true nature of drug discovery.

References

1.       American Cancer Society: Key Statistics for Lung Cancer. https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/key-statistics.html (accessed Sep 23, 2018).

2.       American Cancer Society: What Is Non-Small Cell Lung Cancer? https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html (accessed Sep 23, 2018).

3.       Nelson, V.; Ziehr, J.; Johnson, M. Onco Targets Ther. 2013. 6. 135-143.

4.       Li, D.; Ambrogio, L.; Wong, K-K. Oncogene. 2008. 27 (34), 4702-4711.

5.       Wirth, S. M. J Adv Pract Oncol. 2015. 6 (5), 448-455.

6.       Boehringer Ingelheim: History. https://www.boehringer-ingelheim.com/history/history-milestone/1885-1948 (accessed Nov 4, 2018).

7.       Boehringer's Gilotrif widens its reach in crowded EGFR lung cancer field. FiercePharma. https://www.fiercepharma.com/marketing/boehringer-s-gilotrif-widens-its-reach-crowded-egfr-lung-cancer-field (accessed Nov 4, 2018)

8.       DrugBank: Afatinib. https://www.drugbank.ca/drugs/DB08916 (accessed Nov 4, 2018).

9.       Gilotrif (Non-Small Cell Lung Cancer) – Forecast and Market Analysis to 2022. GlobalData: PharmaPoint. 2013.