Vincerx Pharma Provides American Society of Hematology Annual Meeting 2022 Poster Highlights on Enitociclib in Multiple Tumor Types
In a multiple myeloma (MM) preclinical study, antitumor efficacy was observed with enitociclib as a monotherapy and in combination with several anti-MM agents
Significant MYC downregulation was observed in patients with double-hit diffuse large B-cell lymphoma (DH-DLBCL) and other B-cell malignancies with a 30-mg dose level while maintaining a favorable safety profile
Clinical trial to evaluate enitociclib in combination with venetoclax and prednisone (
Enitociclib is a potent and selective CDK9 inhibitor currently in clinical development. The small molecule inhibitor targets P-TEFb/CDK9 and has shown robust pathway modulation as well as efficacy and safety in several preclinical tumor models and in early phase clinical studies.
“We are excited with the progress we have made in our enitociclib program,” said
Dr.
Dr.
Dr.
Key ASH 2022 Presentation Highlights:
Poster presentation titled, “Preclinical Study of Enitociclib, a Selective CDK9 Inhibitor, in Combination with Bortezomib, Lenalidomide, Pomalidomide, or Venetoclax in the Treatment of Multiple Myeloma”, presented by
- Enitociclib was identified as a top hit in small molecule inhibitor screening and exposure to enitociclib for 96 hours against a representative panel of MM cell lines (NCI-H929, MM.1S, OPM-2, and U266B1) demonstrated significant cytotoxic activity, with IC50 values ranging from 36 to 78 nM.
- Induction of apoptosis was observed with cleavage of pro-caspase-3 and PARP by western blotting in a time- and dose-dependent manner with enitociclib as a single-agent, in addition to the depletion of phosphorylated RNAPII (Ser 2/5), MYC, MCL1, and PCNA proteins.
- Enitociclib synergizes with several anti-MM agents (bortezomib, lenalidomide, pomalidomide, and venetoclax [synergy scores >10]) at pharmacologically relevant concentrations across several MM cell lines.
- Enitociclib enhances the efficacy of lenalidomide and venetoclax as demonstrated by robust apoptosis induction through caspase-3 activation and PARP cleavage at 2 hours.
- In a JJN-3 MM xenograft mouse model, intravenous administration of enitociclib transiently inhibits the transcription of MYC and MCL1 and promotes apoptosis by induction of pro-caspase-3 and PARP cleavage with the onset of drug-induced effects seen as early as 1 hour after enitociclib treatment. Tumor volumes were reduced by 96% to 99% as compared with control mice on day 20 after the commencement of treatment. Increased efficacy of enitociclib in combination with lenalidomide was observed.
- Overall, these studies present evidence that enitociclib has significant antitumor activity against MM cell lines and provides specific pharmacologic targetability of several key oncogenic pathways involving proteins such as MYC, MCL1, and PCNA, leading to growth inhibition and apoptosis.
Poster presentation titled, “Enitociclib (VIP152/formerly BAY1251152) Is a Selective and Active CDK9 Inhibitor: Preliminary Safety and Early Signs of Efficacy in Patients with Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)”, presented by
- Updated clinical data on 20 patients, 16 NHL from study VNC-152-101 (NCT02635672) and 4 CLL patients from study VNC-152-102 (NCT04978779) were presented. Safety and preliminary efficacy data for 5 newly enrolled patients with MYC+ tumors (one each: DH-DLBCL, Richter syndrome [RS], transformed follicular lymphoma [tFL],
Burkitt lymphoma, and mantle cell lymphoma [MCL]), in addition to the previously reported 11 patients, making a total of 16 NHL patients in VNC-152-101. - Patients with NHL were heavily pretreated with >3 prior therapies with a median number of 4 enitociclib doses administered. As part of prior therapy, patients with CLL had received an approved BTKi, 3 patients had received venetoclax, and 2 patients had received CAR-T.
- Monotherapy treatment with enitociclib (doses of 10 to 30 mg) has a favorable safety profile in a pooled safety analysis for NHL/CLL (n=20) that is consistent with previously reported safety data:
- Mainly Grade 1 and 2 gastrointestinal adverse events (AEs).
- Neutropenia was observed in 8 patients with supportive care (G-CSF) administered to 3 patients.
- There were no discontinuations due to an AE; 3 deaths due to disease progression.
- Enitociclib monotherapy treatment showed 1 stable disease (SD), 3 radiologic disease progression, and 1 clinical progression.
- The patient with tFL with SD had a 16% reduction in tumor burden at the end of cycle 2 and at cycle 7 a 22% reduction in tumor burden (this patient is currently still on study); this response kinetics is consistent with the 2 previously reported DH-DLBCL patients who achieved SD at cycle 2 and metabolic CRs at cycle 10.
- Enitociclib does not inhibit T-cell dependent antibody response in a rat model.
- AUC0-24 was 390 ng*hr/mL and 1820 ng*mg/mL following enitociclib doses of 0.33 mg/kg/week and 1.25 mg/kg/week, respectively.
- The exposure observed for the 1.25 mg/kg group was comparable to the exposure observed in patients who received 30 mg enitociclib.
- Results from this preclinical study suggests enitociclib is not expected to hamper vaccine response.
- In patients with NHL and CLL, enitociclib PK properties are comparable at the same dose (Cmax, AUC0-t) and across doses (CL, VSS and t1/2). Enitociclib PK are consistent with previously reported data in patients with NHL.
- Pharmacodynamic data show enitociclib 10/15 mg does not deliver adequate control of oncogenic signals of MYC, MCL1, and PCNA mRNA as compared with other NHL patients (MCL and DH-DLBCL) dosed at 30 mg.
- The 30-mg dose of enitociclib is well-tolerated by patients with CLL/RS, consistent with observations of 30 mg in NHL/solid tumor indications.
- Patients will CLL (n=2) treated with 10/15 mg did not respond to enitociclib, in line with the data showing that the 10/15-mg dose level does not appear to be able to deliver downregulation of MYC, MCL1 and PCNA mRNA.
- In blood, the maximum extent of inhibition for MYC, MCL1, and PCNA mRNAs was 98%, 76%, and 92%, respectively. The maximal inhibition of all mRNAs in the blood occurred within 4 hours of enitociclib treatment in patients with DH-DLBCL and other B-cell malignancies (CLL, tFL, MCL, and
Burkitt lymphoma) with the once weekly 30-mg dose of enitociclib.
Copies of the presentation materials can be accessed on the Investors section of the Company’s website at www.vincerx.com.
ABOUT
CAUTIONARY STATEMENT
This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act of 1934, as amended, that are intended to be covered by the “safe harbor” created by those sections. Forward-looking statements, which are based on certain assumptions and describe future plans, strategies, expectations and events, can generally be identified by the use of forward-looking terms such as “believe,” “expect,” “may,” “will,” “should,” “would,” “could,” “suggest,” “seek,” “intend,” “plan,” “goal,” “potential,” “on-target,” “on track,” “project,” “estimate,” “anticipate” or other comparable terms. All statements other than statements of historical facts included in this press release are forward-looking statements. Forward-looking statements include, but are not limited to: Vincerx’s business model, pipeline, strategy, timeline, product candidates and attributes and preclinical and clinical development and results. Forward-looking statements are neither historical facts nor assurances of future performance or events. Instead, they are based only on current beliefs, expectations and assumptions regarding future business developments, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Forward-looking statements are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control.
Actual results, conditions and events may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause actual results, conditions and events to differ materially from those indicated in the forward-looking statements include, but are not limited to: general economic, financial, legal, political and business conditions and changes in domestic and foreign markets; the potential effects of health epidemics and pandemics, including COVID-19; risks associated with preclinical or clinical development and trials, including conducted prior to Vincerx’s in-licensing; failure to realize the benefits of Vincerx’s license agreement with Bayer; risks related to the rollout of Vincerx’s business and the timing of expected business milestones; changes in the assumptions underlying Vincerx’s expectations regarding its future business or business model; Vincerx’s ability to develop and commercialize product candidates; Vincerx’s capital requirements and availability and uses of capital; the effects of competition on Vincerx’s future business; the impact of Vincerx’s workforce and cost reductions; and the risks and uncertainties set forth in Forms 10-K, 10-Q and 8-K most recently filed with or furnished to the SEC by Vincerx. Forward-looking statements speak only as of the date hereof, and Vincerx disclaims any obligation to update any forward-looking statements.
Contacts
646-889-1200
bmackle@lifesciadvisors.com
Source: Vincerx Pharma, Inc.