St. Jude's contribution to a new class of cancer drugs

ALK Inhibitors discovered in the mid-1990s were licensed to be developed into drugs for NSCLC. Though the original patents expired, the drugs approved in 2011, 2014, and 2017 laid the foundation for a growing new class of drugs.

Non–small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths, both worldwide and in the United States. Most patients who have NSCLC present with advanced or incurable disease, and cytotoxic chemotherapy generally results in low response rates and only modest improvements in overall survival. A sub-portion of NSCLC is Anaplastic Lymphoma Kinase positive (ALK+) NSCLC, which is a type of lung cancer associated with younger age, never smoking or light smoking history, and adenocarcinoma histology. Patients who have advanced disease are highly responsive to ALK inhibitors. Current estimates are approximately 3-5% (6,500 to 11,000) of patients with non-small cell lung cancer carry the ALK rearrangement and may be candidates for treatment with these drugs.

The anaplastic lymphoma kinase (ALK) gene was discovered (SJ-93-0002) in the 1990s by St. Jude scientists searching for genes affected by a chromosomal change common in the cancer cells of pediatric patients with anaplastic large cell lymphoma (ALCL). This discovery led to issued patent rights that were non-exclusively licensed to companies who would build on the discoveries to find and develop therapeutics for treatment of ALK-driven cancers. Three companies developed these FDA approved ALK inhibitor drugs:

• Xalkori® (crizotinib, approved 8/2011) made by Pfizer for use with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).
• Zykadia™ (ceritinib, approved 4/2014) made by Novartis for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval of Zykadia addresses an unmet medical need for patients with this type of lung cancer who have progressed on prior therapy.
• Alunbrig™ (brigatinib, approved 4/2017) made by Takeda (developed by Ariad, which was acquired by Takeda in 2017) as a potent dual inhibitor of ALK and epidermal growth factor receptor (EGFR), useful to overcome resistance in certain patients.

New classes of ALK inhibitors are being developed, with additional second-generation approved drugs that include:

• Alectinib FDA approved Dec. 2015 (accelerated), full approval in 2017 for ALK-positive NSCLC.
• Lorlatinib approved in 2018 by the US FDA for ALK-positive NSCLC.
• Entrectinib approved Aug. 2019 (Nerviano's NMS-E628, licensed by Ignyta and renamed RXDX-101, in the U.S. orphan drug designation and rare pediatric disease designation for the treatment of neuroblastoma and orphan drug designation for treatment of TrkA-, TrkB-, TrkC-, ROS1- and ALK-positive NSCLC).

These second-generation agents have improved performance; however, the problem with most is that many patients may still develop resistance, particularly central nervous system (CNS) relapse, so third-generation drugs are under development to better penetrate the blood-brain barrier and to retain potency to acquired resistant mutations that developed during therapy with first- and second-generation drugs. Results from a global phase II study of third-generation ALK inhibitors show a high overall response rate and high intracranial response rate for patients with advanced ALK-positive NSCLC, as reported by Solomon et al in The Lancet Oncology and reviewed in The ASCO Post (2/2019). ALK-positive NSCLC was identified early on as a very sensitive tumor type for ALK inhibitors, first with crizotinib as a first-generation inhibitor and then with several second-generation inhibitors, and now with high sensitivity to the third-generation inhibitors.

The estimated value of the Non-Small Cell Lung Cancer market** was $6.21B in 2015. Just over half of these sales, $3.25B (52%), were generated in the U.S., with $1.53B (25%) coming from eight European Union Countries, and $981M (16%) and $445M (7%), respectively, for Japan and China. NSCLC sales are expected to rise to $26.8B by 2025. New targeted ALK+ therapies overcome resistance from previous treatments, and/or have superior efficacy in certain subpopulations. The revenue from ALK+ inhibitor portion of the NSCLC drug sub-market should be a similar or slightly higher percentage of the ALK+ patient population (3-5% ($180MM to $310MM, 2015; $800MM to $1.4B, 2025)). Read more about the market size at: https://drug-dev.com/nsclc-market-global-drug-forecast-market-analysis-to-2025/.

For the last few years, our newsletter contained a table about our activities, like managing our over 200 licenses; and patient impact, describing the Millions impacted by products based on our technology. This year I wanted to explain this impact in more depth using an specific example. The three ALK+ drugs we licensed impacted about 45,000 people a year, but it grwos far beyond those numbers now.

The original ALK+ research was funded by St. Jude Children’s Research Hospital along with some grant funding from the National Institutes of Health. The Bayh-Dole act was developed as a mechanism for how government-funded research could benefit the public by being transferred to industry using the patent system. This allows industry an accessible and reliable path forward for investment in academic research, to produce and approve a drug or other product. It also stipulates that royalties paid to non-profit institutions must use these funds for more research, to reward their inventors and to off-set tech transfer expenses. While the intellectual property - granted patents and published applications* - expired, the invention remained alive until drug discovery milestones from Cephalon (now Teva), Ariad, Novartis and Xcovery were achieved and paid.

During the patent protected portion of this invention’s life, it survived intellectual property challenges, and was jointly licensed (w/an ALK monoclonal antibody made by Oxford University) to 5 drug discovery and development companies, 14 diagnostic companies and several reagent companies. In 2011 a law firm was retained to enforce the issued patent rights against infringers. This resulted in license income that totaled under $10MM. After expenses*** of around $4MM, the remainder was split between funding further research at St. Jude; and with inventors, as described in the faculty handbook. With the related patents expired, the income has stopped; however, those drugs developed with the original patents may be produced as generics, as work on even better ALK+ inhibitor drugs proliferates, built on the foundation laid by the original patents.

Also, after years and millions of dollars in industry development, government reinvested in the class to optimally sequence the ALK inhibitors. Specifically, the U.S. National Cancer Institute is developing a “Master Protocol” for treatment of patients with advanced NSCLC who have ALK+ tumors, in which the different mutations will direct the given therapy and sequence. Such a study concept could lead to the most optimal treatment strategies by taking molecular biology and new drug development into account.

Now, to close our story nicely, we circle back to where all this development began… The drugs created for NSCLC can and were also used off label for other ALK+ driven cancers; in fact, we started using Xalkori off-label here for the pediatric patients with ALK-positive anaplastic large cell lymphoma (ALCL) – the patient population the gene was discovered in, shortly after its approval. That all began to change on January 14, 2021, because the Food and Drug Administration approved Xalkori for those pediatric patients. Then, on July 14, 2022, the Food and Drug Administration approved Xarlkori for adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory anaplastic lymphoma kinase (ALK)-positive myofibroblastic tumors (IMT). This mean that after a nearly thirty-year journey, the same medicine will be available to those children dealing with ALK+ lymphomas outside of St. Jude.

*U.S. Patent Nos. 5,529,925; 5,770,421;6,174,674; 6,451,997 and 6,696,548; with Australian Patent No. 679,833; and European Patent No. 731,806 (registered in Germany, France, Great Britain, and Italy)
** In the 8 major markets
** This includes the expense the companies paid for patenting in several countries