Investors Thrilled with Recent Results, FDA Chimes in. In 2017, nine years after Introgen’s failure, U.S. FDA approved Novartis’s Kymriah and Gilead’s Yescarta, two novel gene therapies for the treatment of blood cancer. Although the genetic modifications with both drugs are incorporated into T-lymphocytes rather than cancer cells per se, with genetic engineering being completed ex vivo (outside of the human body), there is no doubt that the level of genetic expertise achieved with this technology could translate to other areas of the cancer gene therapy field.

In December 2017, U.S. FDA granted Spark Therapeutics, Inc. (Nasdaq: ONCE, Market Cap $ 1.7 billion) the green light to commercialize gene therapy “Luxturna” for the treatment of “Leber congenital amaurosis”, an eye disease caused by mutation of the RPE65 gene. Luxturna consists of a genetically engineered virus, designed to deliver the normal corresponding copy of the RPE65 gene, which restores the patient’s vision. Given these three FDA approvals of gene therapies, experts believe it will not be long before the success of Spark, Novartis and Gilead translates into better understanding of how to apply a gene therapy approach to cancer patients. 

After approval of first gene therapies last year, FDA Commissioner Scott Gottlieb, M.D., said on a press release “Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases. In just several decades, gene therapy has gone from being a promising concept to a practical solution to deadly and largely untreatable forms of cancer.”

(Interview with Dr. Scott Gottlieb, https://www.youtube.com/watch?v=_L26SFUd1UY)

Hurdles Seem Difficult to Overcome. For several years now, the risk that a gene therapy approach will fail to deliver the “desired gene” to the correct target DNA sequence in a patient remains a practical and theoretical limitation for this field of medicine. Off target integration of a gene therapy vector continues to be a concern for drug developers, regulators and investors. Despite of the advent of gene editing technologies such as CRISP-CAS9, treatment safety still constitutes a significant potential barrier for gene therapy.

In the cancer research field, previous attempts to develop an effective gene therapy to replace a mutated tumor suppressor gene have failed. In 2008, U.S. FDA rejected a drug application from Introgen Therapeutics, Inc., a gene therapy company based in Houston. Introgen have raised $700 mm from investors to completed development of gene therapy, Advexin, which was hailed by the Street as a potential blockbuster medicine at the time. Introgen’s gene therapy was designed to replace a mutated p53, a tumor suppressor gene, for its corresponding normal copy in cancer cells. The medical hypothesis was that the newly inserted normal p53 gene was going to re-establish anti-tumor functions, resulting in killing of cancer cells. A few months after the FDA refused to approve the drug, Introgen declared itself bankrupt. The debacle of Introgen cast doubt among investors, who have remained skeptical about the commercial potential of cancer gene therapy since then.  

Will Gene Therapy Become a Preferred Treatment for Cancer in the Near Future — Resurgence, the rebirth of Genprex. Going forward, the investment community will likely be monitoring the progress of companies in the gene therapy area. The potential success of these novel approaches in human clinical trials could generate significant investors’ appetite for stocks of companies in this segment of the industry. In April this year, cancer gene therapy company Genprex (Nasdaq: GNPX, Market Cap $23 mm) completed a Nasdaq IPO. The company has rescued some of the intellectual property left by Introgen. Genprex is currently developing a gene therapy product, Oncoprex, designed to replace the mutated version of a tumor suppressor gene known as TUSC2 in cancer cells. TUSC2 plays a critical role in signal transduction by regulating tyrosine kinases, preventing tumor formation. Unlike its normal counterpart, mutated TUSC2 fails to exert its functions, causing deregulated signal transduction, leading to malignant transformation and tumor growth.

By treating with Oncoprex, Genprex expects that the newly inserted TUSC2 gene will restore normal functions, killing cancer cells and blocking tumor progression. Furthermore, the company has demonstrated that Oncoprex stimulates an anti-cancer immune response in treated patients. Based on this dual mechanism of action of the drug, Genprex calls its technology an “immunogene therapy approach”. The following video illustrates Oncoprex’s anti-cancer mechanism of action (https://www.youtube.com/watch?v=87DF8gkG4tw). Genprex plans to develop Oncoprex in combination with Roche’s erlotinib (Tarceva®) and checkpoint inhibitors for the treatment of non-small cell lung cancer. In Phase I/II clinical trials performed in collaboration with the University of Texas MD Anderson Cancer Center, Genprex has obtained tantalizing results (PLoS ONE 2012, 7(4)e:34833), which bodes well for the potential of this treatment, and the future of the field of cancer gene therapy.

Sources:

1. Tumor Supressor Gene Regulation in Cancer Cells
   (https://www.youtube.com/watch?v=2NVBsPfOtT8)
2. Introgen Therapeutics, Inc. files for bankruptcy, sees exit in 2009
   (https://www.biospace.com/article/releases/introgen-therapeutics-inc-files-for-bankruptcy-sees-exit-in-2009-/)
3. Bankrupt Introgen seeks reincarnation IPO in biotech bubble
   (https://www.thestreet.com/story/13096791/1/bankrupt-introgen-seeks-reincarnation-ipo-in-biotech-bubble.html)
4. FDA approval brings first gene therapy to the United States
   (https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm574058.htm)
5. FDA Commissioner Scott Gottlieb calls first gene therapy approval a significant milestone
   (https://www.youtube.com/watch?v=_L26SFUd1UY)
6. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma
   (https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm581216.htm)
7. FDA approves Luxturna gene therapy for rare form of inherited vision loss
   (https://www.cnbc.com/2017/12/19/fda-approves-spark-therapeutics-luxturna-gene-therapy.html)
8. FDA approves CAR T-cell treatment Kymriah for adult B-cell lymphoma
   (https://www.ajmc.com/newsroom/fda-approves-cart-cell-treatment-kymriah-for-adult-bcell-lymphoma)
9. Mechanism of action of Oncoprex
   (https://www.youtube.com/watch?v=87DF8gkG4tw)
10. Phase I clinical trial of systemically administered TUSC2(FUS1)-Nanoparticles Mediating Functional Gene Transfer in Humans (Roth J.A., et al. PLoS ONE 7(4)e34833)

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