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BYL719
N/A, Phase 1, Phase 1/Phase 2, Phase 2
Isoform-specific PI3K inhibitor
Hemat
BYL719 is an α-isoform-specific inhibitor of class I PI3K (PI3Kα inhibitor). Areas of Research: Breast cancer, head and neck cancer, colorectal cancer, gastric cancer, and non-small cell lung cancer (NSCLC).

Compound Descriptionα-isoform-specific inhibitor of class I Pi3K (Pi3Kα inhibitor)

Areas of ResearchBreast cancer, head and neck cancer, colorectal cancer, gastric cancer, and esophageal cancer

Proposed Mechanism of ActionPI3K is an important component of the PI3K/Akt/mTOR pathway, an intracellular signaling cascade that has been strongly implicated in tumor growth and progression.1,2 Class IA PI3Ks are heterodimeric proteins consisting of a regulatory subunit, p85, and a catalytic subunit, p110. In human cells there are 3 isoforms of class IA p110 (α, β, δ) encoded by the genes PIK3CA, PIK3CB, and PIK3CD; the p110α and p110β isoforms are ubiquitously expressed, whereas p110δ is expressed primarily in leukocytes.3 PIK3CA-activating mutations have been identified in a significant proportion of breast,4,5 and colorectal,6,7 and gastric cancers.6,7 Selective inhibition of the α-isoform has demonstrated anti-tumor activity in preclinical PIK3CA-mutated tumor models.8

Key Preclinical DataBYL719, an isoform-specific PI3K inhibitor, inhibits p110α and the most common oncogenic p110α mutants (IC50=5 nM). It has no activity against Vps34 and mTOR, and is selective against a wide range of protein kinases.8 In breast cancer cell lines harboring PIK3CA mutations, BYL719 inhibited the Pi3K/AKT/mTOR pathway and had anti-proliferative effects.8 In addition, cancer cell lines with PIK3CA mutations were more sensitive to BYL719 than those without the mutation across a broad range of different cancers.10 In vivo, BYL719 demonstrated dose-dependent anti-tumor activity in PIK3CA-mutant or -amplified tumor xenograft models, such as breast, head and neck, and ovarian cancers.8,11 BYL719 was also shown to possess anti-angiogenic properties in a rodent breast cancer model.12

Clinical StatusBYL719 was the first PI3Kα inhibitor to enter Phase I clinical trials. A Phase I dose-escalation study (NCT01219699) is investigating the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics, and preliminary efficacy of BYL719 in patients with relapsed/refractory PIK3CA-mutant solid malignancies.13 The single-agent MTD was declared at 400 mg/day in 35 patients.13

MOA data is based on in vitro/in vivo data. Clinical benefit is unknown.
BYL719 is an investigational compound. Efficacy and safety have not been established.
There is no guarantee BYL719 will become commercially available.
References
  1. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009;8:627–644.
  2. Saal LH, Johansson P, Holm K, et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci USA 2007;104:7564–7569.
  3. Kok K, Nock GE, Verrall EA, et al. Regulation of p110delta PI 3-kinase gene expression. PLoS One 2009;4:e5145.
  4. Levine DA, Bogomolniy F, Yee CJ, et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 005;11:2875–2878.
  5. Wu G, Xing M, Mambo E, et al. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res 2005;7:R609–R616.
  6. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
  7. Li VS, Wong CW, Chan TL, et al. Mutations of PIK3CA in gastric adenocarcinoma. BMC Cancer 2005;5:29.
  8. Fritsch CM, Schnell C, Chatenay-Rivauday C, et al. NVP-BYL719, a novel PI3Kalpha selective inhibitor with all the characteristics required for clinical development as an anti-cancer agent [abstract]. AACR Annual Meeting 2012;3748.
  9. Jia S, Roberts TM, Zhao JJ. Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol 2009;21:199–208.
  10. Huang A, Fritsch C, Wilson C, et al. Single agent activity of PIK3CA inhibitor BYL719 in a broad cancer cell line panel. [abstract]. AACR Annual Meeting 2012;3749.
  11. Novartis data on file, 2014.
  12. Schnell CR, Barbe S, Caravatti G, et al. NVP-BYL719, a selective inhibitor of the class Ia PI3K isoform alpha impairs angiogenesis and microvascular permeability [abstract]. AACR Annual Meeting 2012;3743.
  13. Juric D, Rodon J, Gonzalez-Angulo AM, et al, BYL719, a next generation PI3K alpha specific inhibitor: preliminary safety, PK, and efficacy results from the first-in-human study [oral presentation]. AACR annual meeting 2012;CT-01.
  14. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01449058. Updated December 4, 2013. Accessed January 17, 2014.
  15. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01708161. Updated October 25, 2013. Accessed January 17, 2014.
  16. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01872260. Updated December 20, 2013. Accessed January 17, 2014.
  17. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01822613. Updated August 26, 2013. Accessed January 17, 2014.
  18. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01923168. Updated January 21, 2014. Accessed January 27, 2014.
  19. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01602315. Updated January 15, 2014. Accessed January 17, 2014.
  20. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01719380. Updated October 24, 2013. Accessed January 17, 2014.
  21. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01613950. Updated May 9, 2013. Accessed January 17, 2014.
  22. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01735968. Updated October 28, 2013. Accessed January 17, 2014.
  23. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT02051751. Updated January 30, 2014. Accessed February 19, 2014.

The information contained herein was last updated on April 12, 2013.

All Compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

The search results, details, and descriptions of clinical trials viewed in this app are supplied by ClinicalTrials.gov and EUtrialregistry.com. This information is maintained by a third party over whom Novartis Pharmaceuticals Corporation has no control. As such, Novartis Pharmaceuticals Corporation does not guarantee the accuracy, completeness, adequacy, or any other aspect of the information contained on this site.