New Acalabrutinib Formulation Enables Co-Administration with Proton Pump Inhibitors and Dosing in Patients Unable to Swallow Capsules (ELEVATE-PLUS)

Abstract Introduction: Acalabrutinib (Calquence ®), a selective Bruton tyrosine kinase (BTK) inhibitor, is approved for the treatment of mantle cell lymphoma (relapsed/refractory) and chronic lymphocytic leukemia. Patients with hematologic malignancies may require acid-reducing agents (including proton pump inhibitors [PPIs]) for the treatment of gastroesophageal reflux or peptic ulcer disease. The solubility of acalabrutinib is reduced with increasing pH; concomitant administration of acalabrutinib capsules with PPIs reduces acalabrutinib exposure and is currently not recommended. Additionally, many cancer patients are unable to swallow capsules and require alternative methods to deliver acalabrutinib, such as a suspension administered orally or via a nasogastric (NG) tube. To enable the use of acalabrutinib in patients who require co-treatment with PPIs and/or are unable to swallow capsules, a new maleate salt of acalabrutinib, formulated as an immediate-release film-coated tablet (acalabrutinib maleate tablet [AMT]), has been developed which shows fast and complete in vitro release at all physiologic pH. We evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of AMT administered orally or via NG tube in the presence or absence of a PPI. In addition, the effect of food on AMT was evaluated to confirm the absence of a clinically relevant impact, consistent with acalabrutinib capsules. Methods: Three Phase 1, open-label, single-dose, cross-over studies were conducted in healthy subjects to establish PK similarity (bioequivalence) between 100-mg AMT and 100-mg acalabrutinib capsules (N=66); evaluate PPI effect by comparing PK of 100-mg AMT administered in the presence vs absence of rabeprazole (PPI; N=14); evaluate food effect by comparing PK of 100-mg AMT administered with a high-fat diet vs fasted (N=16); and assess PK following administration of 100-mg acalabrutinib maleate suspension (in 15 mL water) delivered via NG tube, in the presence vs absence of rabeprazole (N=20). PD was assessed by measuring BTK target occupancy (BTK-TO) in peripheral blood mononuclear cells across all treatment arms and studies. Results: Exposure geometric mean ratios and 90% confidence intervals (CIs) are shown in Table 1 with the PK profiles shown in Figure 1. Systemic exposures (C max and AUC) of acalabrutinib and its major pharmacologically active metabolite, ACP-5862, between AMT and acalabrutinib capsules were bioequivalent (<5% difference in geometric mean exposures, with the 90% CI contained entirely within the pre-defined range of 80.00% and 125.00%). No clinically relevant difference in acalabrutinib/ACP-5862 exposures was observed following administration of AMT with and without PPI; C max was lower (≤~30% difference) and AUC higher (≤~16% difference) with similar BTK-TO (≥95%) across treatment arms. Additionally, no clinically relevant impact of food on acalabrutinib/ACP-5862 exposures was observed; C max was lower (≤~54% difference), with no impact on AUC (≤~3% difference) or BTK-TO (≥95% across treatment arms). Acalabrutinib/ACP-5862 exposures were comparable (≤10% difference) between 100-mg acalabrutinib maleate NG suspension and 100-mg acalabrutinib capsules. In addition, exposures were comparable (≤16% difference) following co-administration of acalabrutinib maleate NG suspension with and without PPI. Overall, the BTK-TO was comparable (≥95%) across all treatment arms. The new AMT formulation showed a well-tolerated safety profile with the majority of observed adverse events (AEs) mild in intensity and no serious AEs reported. No new safety concerns were observed for the AMT. Conclusions: Acalabrutinib maleate, administered as a tablet or suspension, is safe and well tolerated. Based on the PK (and associated variability), BTK-TO, and established exposure-efficacy/safety relationship, AMT clinical effect is expected to be comparable to acalabrutinib capsules at the approved 100-mg BID dosing, regardless of use of PPIs and ingestion of food. Additionally, AMT improves swallowing ability given the film coating and a 50% reduced volume compared with the capsule, and can be easily suspended in a small amount of water to allow dosing in patients unable to swallow tablets. Figure 1 Figure 1. Disclosures Sharma: AstraZeneca: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Pepin: AstraZeneca: Current Employment. Burri: AstraZeneca: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Zheng: AstraZeneca: Current Employment; Kite Pharma, a Group of Gilead: Ended employment in the past 24 months; Gilead Science Inc., AstraZeneca: Current equity holder in publicly-traded company; Gilead Science Inc.: Divested equity in a private or publicly-traded company in the past 24 months. Kuptsova-Clarkson: AstraZeneca: Current Employment, Current equity holder in publicly-traded company; AbbVie: Current holder of individual stocks in a privately-held company. de Jong: Acerta Pharma B.V. (A Member of the AstraZeneca Group): Current Employment. Yu: AstraZeneca: Current Employment; EMD Serono Research Institute: Ended employment in the past 24 months; AstraZeneca, Johnson and Johnson, AbbVie, Abbott: Current equity holder in publicly-traded company; Merck KGaA: Divested equity in a private or publicly-traded company in the past 24 months. MacArthur: AstraZeneca: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Majewski: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Ware: AstraZeneca: Current equity holder in publicly-traded company; Denali (DNLI) Therapeutics: Current equity holder in publicly-traded company. Mann: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Ramies: AstraZeneca: Consultancy. Munugalavadla: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Sheridan: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Tomkinson: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: New Formulation

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Effect of Food on MDM2 Inhibitor KRT-232 Pharmacokinetics and Macrophage Inhibitory Cytokine-1 (MIC-1) Response in Healthy Volunteers

Blood ◽

10.1182/blood-2020-135985 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Shekman Wong ◽

Cecile Marie Krejsa ◽

Dana Lee ◽

Anna Harris ◽

Emilie Simard ◽

...

Keyword(s):

Healthy Volunteers ◽

Small Molecule ◽

Geometric Mean ◽

Wild Type ◽

High Fat ◽

Publicly Traded ◽

Meal Test ◽

Median Tmax ◽

The Past ◽

Mdm2 Inhibitor

Background: KRT-232 is a potent, selective, orally available, small-molecule drug that binds to mouse double minute 2 homolog (MDM2) and inhibits its interactions with tumor suppressor protein p53. KRT-232 is under development for treatment of myeloproliferative neoplasms, acute myeloid leukemia, and Merkel cell carcinoma. Increased serum MIC-1 (pg/mL) is a pharmacodynamic (PD) marker of p53-mediated activity in patients treated with KRT-232 (Allard,HemaSphere, 2020;4:S1, Abstract EP519). The aim of this study was to assess the safety and effect of a high-fat meal on KRT-232 pharmacokinetics (PK) and MIC-1 PD of a new tablet formulation in healthy volunteers. This is the first characterization of a MDM2-inhibitor-induced MIC-1 response in healthy volunteers. Methods: KRT-232-105 was a single-center, open-label, 60-mg single-dose, 3-treatment, 4-period, and 3-sequence study with a partial replicate crossover design. Volunteers (N=30) were randomized to three treatment groups: A: new tablet, fasted (reference, dosed twice in Periods 2-4); B: new tablet, 30 min after a high-fat, high-calorie meal (test 1, dosed once in periods 2-4); C: current tablet, fasted (test 2, period 1 only). Plasma KRT-232, its acyl glucuronide metabolite (M1) and serum MIC-1 concentrations were measured over 0-96 h. Urine from group C was collected over 0-48 h. Doses were one week apart. All volunteers had aH pyloribreath test and were genotyped for UGT1A1*28 polymorphisms. Results: Volunteers were 43% female, 7% African American and 77% Hispanic/Latino. Mean age was 38.1 y (range, 18-54), and mean body mass index was 26.9 kg/m2 (range, 21.4-30.9). No deaths, serious adverse events (SAEs), or discontinuations were reported. Twenty-one treatment-emergent AEs (TEAEs) were observed in 13 (43%) volunteers; constipation was the most frequent AE, followed by headache. All TEAEs were grade 1 (n=17) or grade 2 (n=4: 1 headache event [possibly study drug-related] and 3 events of headache, influenza-like illness, and pharyngitis). Mean (SD) concentration-time plots of KRT-232 and M1 were similar across the 3 groups (Figure 1a and b). A second peak was observed, consistent with enterohepatic recirculation. With a meal (test 1), KRT-232 geometric least-squares mean (GLSM) maximum concentration (Cmax) was similar (431 and 442 ng/mL (GLSM ratio [90% CI], 103% [87.4-121]) and KRT-232 GLSM area under the curve (AUC0-t) decreased from 2858 to 2325 ng∙h/mL (GLSM ratio [90% CI], 81.4 [76.2-86.9]). Median time of Cmax (Tmax) was 2 h fasted and 3 h fed. Geometric mean half life (t1/2) was unchanged (17.0 vs 17.1 h). Under fasting conditions, the current tablet (C, test 2) vs new tablet (A, reference), KRT-232 GLSM Cmax decreased from 431 to 337 ng/mL (GLSM ratio [90% CI], 78.4% [72.0-85.3]) and KRT-232 GLSM AUC0-t had a possible small decrease (2858 and 2455 ng∙h/mL, GLSM ratio [90% CI], 85.9 [80.5-91.7]). Median Tmax (~2 h) and geometric mean t1/2 (17 h) were unchanged. The fraction of the KRT-232 dose in urine as KRT-232 and M1 was negligible at 0.0201% and 0.0220% of dose, respectively. KRT-232 is a carboxylic acid with pH-dependent solubility that increases with increasing pH.H pyloriinfection, which can increase stomach pH, did not have any discernable impact on KRT-232 PK. KRT-232 and M1 exposure in heterozygous UGT1A1*28 poor metabolizers (6/7 TA repeats, N=16) was generally comparable to exposure in wild-type (WT) UGT1A1*28 (6/6 TA repeats, N=12) subjects. MIC-1 concentrations in serum were variable and followed the PK time course with a median Tmax lag of ~8-12 h. Group A: Mean Cmax 2115 pg/mL, C0 (Baseline) 170 pg/mL, AUC0-T 89267 pg*h/mL and mean t1/2 27 h. MIC-1 Cmax and AUC were generally comparable over 96 h across groups (Figure 1c).Figure 1dshows the statistically significant correlation between KRT-232 AUC0-t and MIC-1 AUC0-t. Conclusions: Based on generally comparable PK, KRT-232 can be administered with or without food, and no dose adjustment is warranted with a new tablet formulation. KRT-232 PK was not affected byH pylori, inferring that higher gastric pH did not alter absorption of KRT-232. KRT-232 exposure in UGT1A1*28 heterozygous poor metabolizers was generally comparable to WT UGT1A1*28 wild type healthy volunteers. The 60-mg KRT-232 dose elicited a reproducible and robust MIC-1 response that correlated with KRT-232 exposure, indicating MDM2-p53 target engagement. Disclosures Wong: Kartos Therapeutics:Current Employment;AbbVie Biotherapeutics:Ended employment in the past 24 months.Krejsa:Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company;Seattle Genetics:Current equity holder in publicly-traded company;Acerta Pharma:Current equity holder in private company.Lee:Kartos Therapeutics:Current Employment.Harris:Gilead Sciences:Current equity holder in publicly-traded company;Kartos Therapeutics:Current Employment, Current equity holder in private company;BeiGene:Ended employment in the past 24 months;Clovis:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Simard:Certara:Current Employment;AltaScience:Ended employment in the past 24 months.Wang:Certara:Current Employment.Rubets:Certara:Current Employment.Allard:Certara:Consultancy, Ended employment in the past 24 months;CytomX Therapeutics:Ended employment in the past 24 months;Telios Pharma:Current Employment, Current equity holder in private company.Podoll:IV/PO, LLC:Consultancy.O'Reilly:Celerion:Current Employment.Slatter:Amgen:Divested equity in a private or publicly-traded company in the past 24 months;Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor.

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ANTI-ULCER AGENTS: A PHARMACOLOGICAL UPDATE OF THE PAST TEN YEARS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2019.v12i18.34175 ◽

2019 ◽

pp. 37-41

Author(s):

SUDIP KUMAR MANDAL ◽

SUBHOJIT DAWN ◽

ANINDYA BOSE

Keyword(s):

Natural Products ◽

Proton Pump Inhibitors ◽

Proton Pump ◽

Biological Activities ◽

Mangifera Indica ◽

Aloe Vera ◽

Zingiber Officinale ◽

Ocimum Sanctum ◽

Cell Hyperplasia ◽

The Past

New anti-ulcer substances are still vitally necessary for the people of countries such as India and South Africa to avoid high cost of the most prescribed marketed anti-ulcer drugs (proton-pump inhibitors). New candidate against gastric ulcer is also necessary to avoid the potential problem (enterochromaffin-like cell hyperplasia may be induced) associated with the long-term use of synthetic proton-pump inhibitors. However, the search for the novel entity against ulceration is challenging because of the complexity of the ulcer process and its role in host defense to infections. Nature is the source of remedies for the humankind. Among the different biological activities of the natural products that have been published till date, anti-ulcer is one of the most reported effects. Some single natural products such as curcumin, 1-hydroxy-3,7,8-trimethoxyxanthone, cinnamic acid, thymol, epoxycarvone, and menthol; single synthetic products such as, 4,6-diaryl-3, 4-dihydropyrimidin-2(1H)-thiones, 1,4-dihydropyrimidine derivatives, and dihydropyrimidinone and piperidine hybrids; plant products such as Aloe vera, Mangifera indica, Zingiber officinale, Azadirachta indica, Psidium guava, Carica papaya, Panax ginseng, Terminalia chebula, Ocimum sanctum, Daucus carota, and Mimosa pudica, Alpinia galangal; nutraceuticals such as garlic, cauliflower, banana, honey, cucumber, and cod liver oil with anti-ulcer effects have been discussed in this review. A complete review of literature was conducted using different databases on ScienceDirect, Scopus, PubMed, and Google Scholar. This review is a genuine attempt to explore the past 10 years’ pharmacological update of some anti-ulcer agents.

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A Quantitative Systems Pharmacology (QSP) Model to Compare the Non-Clinical Biodistribution and Efficacy between Recombinant Factor IX (rIX) Therapies

Blood ◽

10.1182/blood-2021-145878 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4240-4240

Author(s):

Sabine Pestel ◽

Douglas Chung ◽

Alireza Rezvani-Sharif ◽

Ineke Muir ◽

Sivarmurthy Krupa ◽

...

Keyword(s):

Blood Loss ◽

Significant Role ◽

Bleeding Time ◽

Total Blood Loss ◽

Publicly Traded ◽

Total Blood ◽

The Past ◽

Binding Partners ◽

Pharmacologically Active

Abstract Background and Aims: Replacement FIX therapy (rIX) is an effective treatment for hemophilia B even with undetectable levels in the blood 1. However, the mechanistic reason for hemostasis with low plasma levels is not well understood. There is growing evidence that FIX interactions with one or multiple binding partners (BP), may play a significant role in the exposure and hemostatic efficacy of rIX 2,3. The aim of this study is to explore this hypothesis by comparing the plasma PK, tissue biodistribution, and in vivo endpoints of different rIX variants using a mouse QSP model. Method: in vitro and in vivo FIX-KO mice studies and mathematical models were used to build a QSP model consisting of 8 tissue compartments , with each tissue divided into vascular, endothelial and interstitial spaces 4,5. The model simulates endogenous mouse IgG (mIgG), mouse serum albumin (MSA), and rIX dynamics including key clearance and distribution mechanisms. Competition for the endothelial FcRn receptor between Fc, albumin, mIgG, and MSA is explicitly modeled 6,7,8. The model was calibrated using mouse studies of radiolabeled rIX-Fc (Alprolix®), rIX-WT (BeneFIX®), and rIX-FP (Idelvion®). Tail-clip experiments following administration of rIX-Fc, rIX-WT, and rIX-FP were used to correlate the predicted exposures with the observed effects on bleeding time and total blood loss. Results: Preliminary simulations proved that having at least one BP best explains the rapid distribution of rIX-Fc and rIX-WT into the tissues, and the long plasma T 1/2 of rIX-Fc and rIX-FP. Visual predictive checks of the full PBPK model showed good agreement with the PK in the tissues. The best fit was achieved using a specific arrangement of four distinct binding partners: Shared BP (SBP) between all compounds (e.g. N-terminal binder) located within the vasculature with estimated K D of 470/600/4100 nM, for rIX-WT/rIX-FP/rIX-Fc, respectively. BP binding specific to rIX-WT (e.g. C-terminal binder) located in the interstitium of the tissue (varying densities) with estimated K D of 23 nM BP binding only for rIX-FP (e.g. albumin binder) located in both; the vasculature and interstitium of the tissue with estimated K D 20/0.05 μM (vascular/interstitial) BP binding only for rIX-Fc (e.g. Fc binder) located in the interstitium of tissue (varying densities) with estimated K D 3 μM The high degree of extravasation of rIX-Fc (and rIX-WT to a lesser degree) results in rapid distribution and sequestration in the tissues. The limited extravasation of rIX-FP and its high affinity to the SBP, results in increased recovery and a greater pool of bound rIX available in the tissue vasculature. Additionally, strong inverse correlation between the bound rIX in the vasculature and bleeding time/total blood loss suggests that the vascular pool plays a more significant role in FIX pharmacology, as compared to the pool in the extravascular space. Conclusion: The mouse QSP model demonstrated that the plasma and tissue biodistribution of rIX-Fc, rIX-FP, and rIX-WT cannot be explained without a BP, and that it is plausible to assume that different binding partners, both intra- and extravascular, for different rFIX variants exist. The correlation between the levels of bound rIX and the coagulation endpoints suggests that the vascular bound rIX may be the pharmacologically active pool or reservoir for haemostasis. The extravasation and sequestration of rIX-WT and rIX-Fc into the tissues may explain the decreased vascular exposure, and hence, the reduced efficacy (increased bleeding time/total blood loss) at later time points. Although the exact identity of the BP's remains to be further elucidated, the model estimates of their affinity, density and location provide guidance for further experimental investigations. Expansion of the QSP model with additional data and coagulation kinetics will further our understanding of the role of BPs in rIX pharmacology. References 1Srivastava A et al (2013) Haemophilia 19(1), e1-47 2Feng D et al (2013) JTH, Vol. 11 (12), 2176-2178 3Cheung WF et al (1996) PNAS USA, 93(20), 11068-11073 4Li L et al (2014) AAPS Journal 16(5), 1097-1109 5Shah DK & Betts AM (2012) J Pharmacokinet Pharmacodyn 39(1), 67-86 6Chia J et al (2018) J Biol Chem 293(17), 6363-6373 7Andersen JT et al (2010) J Biol Chem 285(7), 4826-4836 8Andersen JT et al (2013) J Biol Chem 288(33), 24277-24285 Disclosures Pestel: CSL Behring Innovation GmbH: Current Employment, Current equity holder in publicly-traded company. Rezvani-Sharif: CSL Behring Ltd: Current Employment, Current equity holder in publicly-traded company. Muir: CSL Behring Ltd: Current Employment, Current holder of stock options in a privately-held company. Krupa: CSL Behring LLC: Current Employment, Current equity holder in publicly-traded company. Brechmann: CSL Behring Innovation GmbH, Ended employment in the past 24 months: Bayer Ag (Bayer Pharmaceuticals),: Current Employment, Ended employment in the past 24 months, Patents & Royalties: Bayer. Verhagen: CSL Behring Ltd: Current Employment, Current equity holder in publicly-traded company. Dower: CSL Behring Ltd: Current Employment, Current equity holder in publicly-traded company. Herzog: CSL Behring GmbH: Current Employment, Current equity holder in publicly-traded company.

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Engineering CD70-Directed CAR-NK Cells for the Treatment of Hematological and Solid Malignancies

Blood ◽

10.1182/blood-2021-148649 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1691-1691

Author(s):

Eugene Choi ◽

Jae-Woong Chang ◽

Joshua Krueger ◽

Walker S Lahr ◽

Emily Pomeroy ◽

...

Keyword(s):

Nk Cells ◽

Stock Options ◽

Cell Activation ◽

Nk Cell ◽

Expression Cassette ◽

Publicly Traded ◽

Cell Therapies ◽

The Past ◽

Car T ◽

Privately Held

Abstract Advances in cellular immunotherapy have led to multiple FDA approvals for autologous CAR-T cell therapies in acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphomas (NHL), and multiple myeloma (MM). While effective, autologous CAR-T therapies are limited by safety concerns, lack of scalability for patient derived starting material, and long vein-to-vein timelines. Allogeneic CAR-NK cell therapies have the potential to overcome these limitations by providing an off-the-shelf product capable of delivering clinical benefit without the safety and manufacturing challenges associated with CAR-T therapy. CAR-NK cell therapies are particularly attractive in AML as the inherent graft-versus-leukemia activity of NK cells can be effectively augmented by a CAR directed to an AML expressed antigen. CD70 expression is associated with several indications, including AML, NHL, and renal cell carcinoma (RCC), and it is an attractive target for CAR therapy in AML since it is highly expressed on leukemic stem cells and blasts and is absent in normal bone marrow hematopoietic stem cells. 1 While aberrant expression of CD70 is associated with several solid and hematological indications, its expression in normal tissue is restricted to immune cells including T, B, DC, and NK cells. 2 Here we demonstrate that CD70 is not expressed in resting peripheral blood NK cells but is strongly upregulated in response to NK cell activation by engineered feeder cells. Introduction of CARs targeting CD70 into activated NK cells leads to substantial reduction of NK cell expansion due to fratricide. While CD70 is expressed in activated NK cells, knockout (KO) of CD70 by CRISPR/Cas9 editing does not inhibit NK cell expansion nor impair endogenous cytotoxicity against K562 target cells. Using the non-viral TcBuster™ Transposon System (Bio-Techne), we were able to deliver transposons containing a CD70 CAR and an IL15 expression cassette while simultaneously knocking out CD70 by CRISPR/Cas9 in primary human peripheral blood NK cells. This single-step process resulted in >70% CAR integration/expression and >80% knockout of CD70. The resulting CD70 knockout CAR-NK cells were resistant to fratricide and expanded comparably to mock-engineered NK cells following feeder cell activation. The IL15 expression cassette enabled enhanced persistence of CAR-NK cells in vitro without exogenous cytokine support. In functional assays, CD70 KO NK cells engineered with the CD70 CAR and IL15 expression cassette mediated cytotoxicity against multiple CD70-positive tumor cell lines, expressed the degranulation marker CD107a (LAMP1), and expressed the cytokines IFNγ and TNFα. Overall, the results demonstrate the potential for targeting CD70 with CAR-NK cell therapy for the treatment of AML, RCC, and other CD70-positive malignancies while overcoming the risk posed by fratricide by engineering with a non-viral transposon delivery system in combination with CRISPR/Cas9 editing. 1 Perna et al. 2017, Cancer Cell. 32:506-519. 2 McEarchern et al. 2008, Clin Cancer Res. 14(23):7763-7772. Disclosures Choi: Unum Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Walsh: Obsidian Therapeutics: Ended employment in the past 24 months. Khamhoung: Rubius Therapeutics, Inc.: Ended employment in the past 24 months. Johnson: Celsius Therapeutics: Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Franco: KSQ Therapeutics: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months. Swiech: Agenus: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months; Unum Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Richardson: Novartis Pharma: Current equity holder in publicly-traded company; Obsidian Therapeutics: Current holder of stock options in a privately-held company, Ended employment in the past 24 months.

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VIP152 Is a Novel CDK9 Inhibitor with Efficacy in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2021-153812 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 270-270

Author(s):

Steven Sher ◽

Larry Beaver ◽

Katie Williams ◽

Shelley Orwick ◽

Brandi R. Walker ◽

...

Keyword(s):

Board Of Directors ◽

Stock Options ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

Publicly Traded ◽

Advisory Committees ◽

The Past ◽

Binding Partners ◽

Target Activity ◽

Privately Held

Abstract Background: Chronic Lymphocytic Leukemia (CLL) is a genetically heterogeneous disease characterized by clonal expansion of B-lymphocytes that induce secondary immune suppression. CLL is now treated with inhibitors of Bruton tyrosine kinase (BTK) and BCL2. Virtually all patients respond to therapy, however resistance to these therapies has been described justifying the need for novel CLL therapies. Broad inhibition of cyclin dependent kinases (CDK) and associated alternative target enzymes with agents such as flavopiridol or dinaciclib have demonstrated significant clinical activity in CLL but are hindered by a relatively narrow therapeutic window. VIP152 is a highly specific inhibitor of CDK9 - considered the most important CDK kinase member for CLL clinical activity. VIP152 has favorable pharmacokinetic properties and has demonstrated durable, preliminary single-agent clinical activity in double-hit diffuse large B-cell lymphoma. Herein, we report the efficacy of VIP152 preclinically in CLL. Methods: On-target activity of VIP152 was measured using a KinomeScan from DiscoveryRx at 100nM and 1000nM. Kinase profiling for VIP152 was performed on 6 kinases in a 10-dose assay at ReactionBio. Cell-based viability and proliferation assays (MTS, Annexin-V (AV), and propidium iodine (PI)) were performed in primary CLL cells and the CLL cell lines, HG3 and MEC1. Transcriptional activity after VIP152 exposure was measured via qPCR and limiting-cell RNA sequencing (lcRNAseq). Proteomic and immunoblot studies were performed to measure perturbations in CDK9 binding partners and on-target activity of VIP152. A genome-wide CRISPR/CAS9 knockout screen was performed to identify any synthetically lethal targets and pathways. Results: The KinomeScan identified CDK9 as the kinase with maximal inhibition upon VIP152 treatment and no other CDKs were identified at 100nM. Kinase profiling revealed the IC 50 of VIP152 was lowest for CDK9/Cyclin T1 and CDK9/Cyclin T2 with close similarity to dinaciclib and greater than 1 log superiority over KB-0742. Co-immunoprecipitation and proteomics experiments have identified a CDK9 specific mechanism of action relating to perturbations of CDK9 binding partners. Specifically, we showed that CDK9 nuclear immunoprecipitation resulted in decreased co-immunoprecipitation of 7SK RNA components (HEXIM1 & MEPCE) as well as decreased RNA Polymerase II (RNAP2). The decrease in RNAP2 CoIP was further seen via proteomics. A 2-hour exposure of VIP152 against HG3 and MEC1 demonstrated growth inhibition, with an IC 50 of 0.9814µM and 1.092µM respectively. Continuous exposure of the compound for 24 hours resulted in a statistically significant drop in relative viability of 30% across a 10-fold dose range (0.1µM to 1.0µM) as measured by AV/PI. Primary CLL cells (n=10) responded with similar dosing strategies with a 54% reduction in viability at 1µM; moreover, stromal cell co-culture experiments demonstrated VIP152's ability to induce cell death and overcome stromal protection with short exposure. Induction of apoptosis was observed with pro-caspase-3 and PARP cleavage on immunoblot. qPCR and immunoblot studies demonstrated a time dependence of phosphorylated serine 2 (pS2) RNAP2 decreases alongside diminishment of MYC and MCL1 mRNA and protein. pS2 was shown to decrease as early as 2 hours after VIP152 treatment with similar decreases in MCL1 and MYC at both the protein and mRNA levels. We identified several pathways which are disrupted following treatment via lcRNAseq, including TNFR1 and TNFR2 signaling as well as upregulation of autophagy signals. Finally, CRISPR screen identified several potentially synergistically lethal targets, including transcriptional co-activators, DNA binding proteins, and cell proliferation pathways. Validation of these is ongoing as is an in vivo study of VIP152 in a CLL mouse model. Conclusions: Our data demonstrate VIP152 to be a highly selective and potent CDK9 inhibitor that disrupts the CDK9 nuclear complex and mediates significant preclinical activity against CLL cell lines and primary CLL cells. VIP152 also demonstrates predictable and new pharmacodynamic markers to assess target engagement. Collectively, these data support the recently initiated CLL clinical trial (NCT04978779). Disclosures Johnson: Vincerx: Current Employment; Janssen: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Frigault: Vincerx Pharma Inc: Current Employment; AstraZeneca: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months, Patents & Royalties. Greer: Gilead: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Vincerx Pharma Inc: Current Employment. Hamdy: Vincerx Pharma Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma Inc: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months, Patents & Royalties. Izumi: Acerta Pharma Inc: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months, Patents & Royalties; Vincerx Pharma Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Hwang: Vincerx Pharma Inc: Current Employment, Current equity holder in publicly-traded company. Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees.

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Majic: A Phase 3 Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Blood ◽

10.1182/blood-2021-148155 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1553-1553

Author(s):

Matthew S. Davids ◽

Anthony R. Mato ◽

Juliette Hum ◽

Susana Wargo ◽

Ugochinyere Emeribe ◽

...

Keyword(s):

Research Funding ◽

Lymphocytic Leukemia ◽

Publicly Traded ◽

Open Label ◽

Phase 3 ◽

Free Survival ◽

The Past ◽

History Of ◽

Time Point ◽

Privately Held

Abstract Background: Novel targeted agents, namely Bruton tyrosine kinase inhibitors (BTKis), B-cell leukemia/lymphoma-2 inhibitors (BCL-2is), and anti-CD20 monoclonal antibodies, have advanced chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) treatment beyond traditional chemoimmunotherapy. While 1-year fixed-duration venetoclax-obinutuzumab (VO) is effective, about 25% of patients do not achieve peripheral blood (PB) undetectable minimal residual disease (uMRD). This regimen contains intravenous therapy with obinutuzumab, which presents potential additional toxicities such as infusion reactions and tumor lysis syndrome as well as the potential inconvenience of an intravenous drug. Moreover, patients with higher-risk genomic features such as TP53-aberrant disease or unmutated IGHV have shorter progression-free survival (PFS) than lower-risk cohorts. Whether extending the course of venetoclax beyond 1 year in patients with detectable MRD improves PFS remains unknown. Preclinical data support combining BTKi and BCL-2i, and recent studies with the first-generation BTKi ibrutinib plus venetoclax (IV) have demonstrated deep/durable responses with uMRD rates similar to VO in previously untreated patients with CLL; however, toxicities of this regimen (e.g., cardiac events, neutropenia, etc.) may be challenging, particularly in older patients and those with comorbidities. Acalabrutinib, a highly selective next-generation BTKi, showed an improved safety profile versus ibrutinib in a phase 3 head-to-head trial in relapsed/refractory CLL, and was very effective and well tolerated in a phase 2 study combined with VO. We hypothesize that time-limited doublet therapy with acalabrutinib plus venetoclax (AV) would induce PFS and levels of uMRD similar to those of VO in treatment-naïve (TN) CLL/SLL irrespective of genomic risk features and offer the convenience and favorable tolerability of an all-oral regimen. Moreover, we hypothesize that MRD-guided therapy duration approach will help to define the optimal duration of therapy for both VO and AV. Methods: MAJIC is a phase 3, open-label, randomized, multicenter, global study evaluating AV vs VO in patients aged ≥18 years with TN CLL/SLL. The primary objective of the MAJIC trial is to evaluate investigator-assessed PFS of MRD-guided AV vs MRD-guided VO in a noninferiority design. Key secondary endpoints include uMRD rates at sequential time points, complete and overall response rate, event-free survival, overall survival, quality of life/patient-reported outcomes, and safety. After the screening period, approximately 600 patients will be randomized (1:1, with stratification by age, TP53, and IGHV status) to receive either AV: acalabrutinib (100 mg twice daily with 2 lead-in cycles) then combined with venetoclax introduced at cycle 3 (including dose ramp-up) for 12 cycles, or VO: intravenous obinutuzumab at standard dosing with venetoclax initiated per standard dosing at day 22 cycle 1 (including dose ramp-up) for 6 cycles, followed by 6 cycles of venetoclax monotherapy, for a total of 12 cycles of venetoclax therapy in both arms. Patients with detectable MRD (10 -5 sensitivity by clonoSEQ ® next-generation sequencing) at that time will continue therapy for an additional 12 cycles with either AV (acalabrutinib-containing cohort) or venetoclax monotherapy (for the VO cohort) for a total of 24 months of therapy in both arms, unless they experience progressive disease or unacceptable toxicity. All patients will discontinue study therapy after 24 months, regardless of MRD status at that time point. Response assessments including MRD will occur at the end of 12 months of venetoclax (and 24 months if receiving a second year of therapy) in both arms, and patients with PB uMRD by clonoSEQ at 10 -5 sensitivity at that time point will discontinue therapy. Further correlative studies such as association of baseline genetic markers with clinical outcomes and MRD kinetics will be conducted. Key exclusion criteria are clinically significant cardiovascular disease, history of bleeding diathesis, and history of significant cerebrovascular disease/event. Patient enrollment is to begin at the end of 2021. Summary: This trial in progress is to inform the choice of which of these doublet therapy approaches might be most appropriate for patients with previously untreated CLL/SLL without restriction by genetic background or age. Disclosures Davids: Eli Lilly and Company: Consultancy; BMS: Consultancy, Research Funding; Merck: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; AbbVie: Consultancy; Surface Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Research to Practice: Consultancy; Adaptive Biotechnologies: Consultancy; Takeda: Consultancy; BeiGene: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mato: DTRM BioPharma: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Genmab: Research Funding; Nurix: Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; MSKCC: Current Employment; LOXO: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding. Hum: AstraZeneca: Current Employment. Wargo: AstraZeneca: Current Employment. Emeribe: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company. Shahkarami: Astrazeneca: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Sokolowski: AbbVie: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Biondo: Roche: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Current Employment. Abhyankar: Genentech, Inc: Current Employment; Roche: Current equity holder in publicly-traded company. Hermann: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Sharman: AbbVie: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; BMS: Consultancy; Lilly: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; TG Therapeutics: Consultancy. OffLabel Disclosure: Investigational study

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