Agios Presents Updated Phase 1 Data from Dose Expansion Cohort of Ivosidenib (AG-120) in Patients with IDH1 Mutant Positive Glioma
- Durable Stable Disease and Reduction of Tumor Growth Rates Observed for Patients with Low Grade Glioma; Median Treatment Duration of 16 Months with 51% of Patients Still on Treatment –
- Ivosidenib Well-tolerated in Patients with Low Grade Glioma-
- Additional Preclinical Data Demonstrate that Ivosidenib and AG-881 Suppress 2-HG Levels in Brain Tumor Mouse Models -
“Glioma is a difficult-to-treat disease with many patients diagnosed at a young age and exposed to surgery, radiation and chemotherapy and their associated side effects,” said Ingo Mellinghoff, M.D.,
Ivosidenib is being evaluated in an ongoing Phase 1 dose escalation and expansion trial in advanced IDH1 mutant positive solid tumors, including glioma. Enrollment was completed in
As of the
- Twenty-four patients had
World Health Organization(WHO) classified Grade 2 tumors, eight had Grade 3 tumors, one had a Grade 4 tumor and two were unknown.
- Patients received daily doses of ivosidenib ranging from 300 mg to 900 mg. Twenty-eight patients received a daily dose of 500 mg, which was selected as the expansion dose.
- The median age of these patients is 38 (ranging from 21-71).
- The median treatment duration was 16 months (ranging from 1.4 – 27.1 months).
- The median number of prior therapies was 2 (ranging from one to five). The median duration of last systemic therapy was 9.6 months.
○ Sixty-three percent of patients had previously received temozolomide and 57% percent had previously received radiotherapy.
A safety analysis conducted for all 35 treated non-enhancing glioma patients as of the data cut-off demonstrated that ivosidenib was well-tolerated with a favorable safety profile in glioma patients.
- No dose limiting toxicities were observed.
- The majority of adverse events reported by investigators were mild to moderate, with the most common being headache, diarrhea, nausea and vomiting.
- There were 5 patients with serious adverse events (SAE) and all were deemed unrelated to study treatment.
Efficacy data from all 35 non-enhancing glioma patients as of the data cut-off showed:
- Two patients had a minor response by investigator assessment according to the Response Assessment in Neuro-Oncology for low grade glioma (RANO-LGG).
- Twenty-nine (83%) patients had stable disease.
- The median progression free survival (PFS) for all non-enhancing patients was 13 months, the median PFS for Grade 2 patients (n=24) has not been reached.
- For patients in the expansion arm (n=24), the average six-month tumor growth was 24% prior to treatment and 11% following treatment with ivosidenib.
In addition, preclinical data for ivosidenib and AG-881, a brain-penetrant pan-IDH inhibitor, in an orthotopic mouse xenograft model of human mIDH1-R132H glioma are also being presented as posters.
- Preliminary data suggest that both molecules suppress the oncometabolite D-2-hydroxyglutarate (2-HG) in an orthotopic brain tumor model.
○ At the doses explored, treatment with ivosidenib resulted in 85% maximal 2-HG inhibition and treatment with AG-881 resulted in >98% inhibition of 2-HG levels.
○ Neither molecule impeded the therapeutic effect of concomitant or sequenced radiation therapy.
“We are encouraged by both the ivosidenib clinical data demonstrating prolonged stable disease in patients with progressive, low grade glioma and the preclinical data with ivosidenib and AG-881 demonstrating reductions in the oncometabolite 2-HG,” said
Next Steps in Glioma
- To determine the amount of drug penetration in the brain
- To confirm the magnitude of IDH target engagement as measured by 2HG levels in brain tumor tissue
- To assess the impact of IDH inhibition on differentiation and epigenetic profiles in tumor tissue and
- To assess the safety of both molecules.
Glioma presents in varying degrees of tumor aggressiveness, ranging from slower growing (low grade glioma) to rapidly progressing (high grade glioma-Glioblastoma Multiforme). Common symptoms include seizures, memory disturbance, sensory impairment and neurologic deficits. The long-term prognosis is poor with a five-year survival rate of 33 percent. Median survival is 12-15 months for glioblastoma and 2-5 years for anaplastic glioma. IDH1 mutations are highly prevalent, accounting for approximately 68-74 percent of low grade glioma and secondary glioblastoma.
Agios is focused on discovering and developing novel investigational medicines to treat cancer and rare genetic diseases through scientific leadership in the field of cellular metabolism. In addition to an active research and discovery pipeline across both therapeutic areas, Agios has an approved oncology precision medicine and multiple first-in-class investigational therapies in clinical and/or preclinical development. All Agios programs focus on genetically identified patient populations, leveraging our knowledge of metabolism, biology and genomics. For more information, please visit the company's website at www.agios.com.
About Agios/Celgene Collaboration
IDHIFA® (enasidenib) and AG-881 are part of Agios' global strategic collaboration with
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding: the potential benefits of ivosidenib and AG-881; Agios’ plans for the further clinical development of ivosidenib and AG-881; and Agios’ strategic plans and prospects. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “would,” “could,” “potential,” “possible,” “hope” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios' current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios is developing will successfully commence or complete necessary preclinical and clinical development phases; that positive safety and efficacy findings observed in early stage clinical trials will be replicated in later stage trials; or that development of any of Agios' product candidates will successfully continue. There can be no guarantee that any positive developments in Agios' business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other important factors, including: Agios' results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S.
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Source: Agios Pharmaceuticals, Inc.