Tibsovo Gets A Win In AML Following Servier Takeover
Executive Summary
Positive Phase III topline results follow the US FDA’s acceptance of the drug in cholangiocarcinoma and encouraging data in low-grade glioma at ASCO 2021.
Les Laboratoires Servier SAS has added to a string of incremental wins for the drug Tibsovo (ivosidenib) since the company bought the rights from Agios Pharmaceuticals, Inc. near the end of 2020, with new positive topline Phase III results in acute myeloid leukemia (AML), though it will be entering a field with steep competition.
Paris-based Servier said 2 August that topline results of AGILE showed that Tibsovo combined with Bristol Myers Squibb Company’s Vidaza (azacitidine) improved event-free survival (EFS), the trial’s primary endpoint, as well as producing improvements on key secondary endpoints like complete remission (CR) rate, objective response rate (ORR) and overall survival (OS). The placebo-controlled trial enrolled newly diagnosed AML patients with IDH1 mutations who were ineligible for intensive chemotherapy.
The company stopped enrolling patients in the study in June due to compelling signs of efficacy.
Tibsovo has US Food and Drug Administration approval as a monotherapy in IDH1-mutant relapsed/refractory AML, as well as frontline IDH1-mutant AML in patients 75 and older who are ineligible for intensive chemotherapy.
The AGILE results would allow for a broadening of the AML market opportunity for Tibsovo. Servier told Scrip that there are about 20,000 new AML cases in the US each year and 43,000 in Europe. Of those, about 50% of newly diagnosed patients are unable to receive intensive chemotherapy, with most of them receiving Vidaza as a result. IDH1 mutations are present in around 6%-10% of AML cases.
In a 29 July note following Agios’s second quarter earnings, Cantor Fitzgerald analyst Alethia Young said that commercial risks to Tibsovo as well as Idhifa still remain, particularly in the form of competitors like AbbVie Inc. and Roche Holding AG’s BCL2 inhibitor Venclexta (venetoclax), which is also approved for combination with Vidaza as well as Otsuka Pharmaceutical Co. Ltd.’s Dacogen (decitabine) and low-dose cytarabine in AML patients 75 and older unable to take standard chemotherapy.
Servier has its own BCL2 inhibitor candidate, partnered with Novartis AG and Vernalis Therapeutics Inc and in Phase I development for AML, non-Hodgkin’s lymphomas, chronic lymphocytic leukemia and multiple myeloma. Chengdu, China-based HitGen Inc. acquired Vernalis for $25m in October 2020. (Also see "Deal Watch: Roche Partners With Dyno On AAV-Delivered Gene Therapies" - Scrip, 14 Oct, 2020.)
The AML indication is the first of several expansions for Servier’s cancer franchise. On top of the data from the AGILE study potentially expanding Tibsovo’s reach in IDH1-mutant AML, the drug could also see approval in a rare bile duct cancer, while another drug candidate Servier acquired from Agios is in late-stage development for low-grade gliomas.
Servier’s Takeover Of Agios’s Cancer Portfolio
Servier announced its move to acquire Agios’s oncology portfolio on 21 December, in exchange for $1.8bn upfront and a $200m regulatory milestone fee related to the IDH1/2 inhibitor vorasidenib, along with 15% royalties on US sales of vorasidenib and 5% royalties on sales of Tibsovo, which BMS co-owns. The deal also includes sharing co-commercialization responsibilities with Agios for BMS’s Idhifa (enasidenib), an IDH2 inhibitor. (Also see "Agios Sells Cancer Portfolio To Servier To Focus On Genetic Diseases" - Scrip, 21 Dec, 2020.)
Agios decided to sell its cancer business after determining that the number of drug candidates its cellular metabolism R&D platform generated in genetically defined diseases would likely reach a larger number of patients than its cancer drugs and pipeline. Its lead candidate drug for genetically defined diseases, mitapivat, produced positive results in the Phase III ACTIVATE-T trial in pyruvate kinase deficiency (PKD) and also has activity against sickle cell disease and beta-thalassemia. (Also see "Agios’ Mitapivat Shows Improvement In Regularly Transfused PKD Patients" - Scrip, 27 Jan, 2021.)
For Servier, the deal provided a means for the company to expand its operations in the US. The company is keeping former Agios employees in Cambridge, MA, where it established its stateside location after acquiring Shire plc’s oncology portfolio for $2.4bn in 2018. (Also see "Servier's Shire Oncology Buy Gives Base For US Expansion " - Scrip, 17 Apr, 2018.)
Agios reported Tibsovo had sales of $121.1m for all of 2021. During the second quarter, Agios reported royalty revenues from the drug of $2m, a figure that Raymond James analyst Danielle Brill said in a 29 July note had beat her $1.9m estimate.
Potential In Solid Tumor Indications
The next steps for Tibsovo will be exploring use in multiple solid tumors, including those where IDH1 mutations may occur at a much higher rate.
On the lower end of that spectrum is cholangiocarcinoma, a bile duct cancer that the company noted is diagnosed in around 8,000 people in the US each year, with about 20% presenting with IDH1 mutations. However, because it is difficult to diagnose and often misclassified as other cancers, the actual incidence may be higher. Servier said 5 May that the FDA had accepted its filing for the drug’s approval in that disease, where IDH1 mutations occur in about 13% of cases, though are not associated with prognosis.
On the other end are low-grade gliomas, where IDH mutations occur in about 80% of cases and play a role in promoting tumorigenesis, through the oncometabolite D-2-hydroxyglutarate, or 2-HG. Servier said 7 July that it had presented data at the American Society of Clinical Oncology annual meeting in June showing that in patients with IDH1-mutated low-grade gliomas, treatment with Tibsovo and vorasidenib resulted in a mean 92.6% reduction in levels of 2-HG. The company has moved forward with the pivotal Phase III INDIGO trial of vorasidenib in IDH-mutant grade 2 residual or recurrent low-grade glioma.
Another solid tumor candidate from Agios is AG-270, a MAT2A inhibitor in Phase I development for MTAP-deleted pancreatic cancer.