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TESETAXEL

Tesetaxel is an investigational, orally administered chemotherapy agent that belongs to a class of drugs known as taxanes, which are widely used in the treatment of cancer. Tesetaxel is an investigational product, and its safety and efficacy have not been established by any agency. Tesetaxel has several pharmacologic properties that make it unique among taxanes, including: oral administration with a low pill burden; a long (~8-day) terminal plasma half-life ("t1/2") in humans, enabling the maintenance of adequate drug levels with relatively infrequent dosing; no history of hypersensitivity (allergic) reactions; and significant activity against chemotherapy-resistant tumors. More than 500 patients have been treated with tesetaxel in clinical studies. In patients with metastatic breast cancer (“MBC”), tesetaxel was shown to have significant, single-agent antitumor activity in two multicenter, Phase 2 studies. In December 2017, Odonate initiated CONTESSA, a multinational, multicenter, randomized, Phase 3 study of tesetaxel in patients with locally advanced or metastatic breast cancer (“LA/MBC”) (clinicaltrials.gov). Our goal for tesetaxel is to develop an effective chemotherapy choice for patients that provides quality-of-life advantages over current alternatives.

 

Tesetaxel, which we believe will qualify as a New Chemical Entity (“NCE”) if and when a New Drug Application (“NDA”) is submitted, retains the same taxane core as the approved taxanes, but includes the addition of two novel, nitrogen-containing functional groups. Tesetaxel is chemically designed to: (i) not be substantially effluxed by the P-glycoprotein (“P-gp”) pump, with the intent of retaining activity against chemotherapy-resistant tumor cells; (ii) have high oral bioavailability; (iii) have high solubility; and (iv) have a long (~8 day) t1/2 in humans. The table below includes the chemical and pharmacologic properties of paclitaxel, docetaxel and tesetaxel.

Tesetaxel has a simple, patient-friendly dosing regimen, as shown in the table below.

Tesetaxel has a long (~8 day) t1/2 in humans (see figure below), which may allow adequate drug levels to be maintained with relatively infrequent dosing.

We believe that tesetaxel’s unique properties may translate into significant benefits for patients. These may include:


• Oral administration with a low pill burden;


• A long (~8-day) t1/2 in humans, enabling the maintenance of adequate drug levels  with relatively infrequent dosing;


• No history of hypersensitivity reactions; and


• Significant activity against chemotherapy-resistant tumors.

 

NONCLINICAL STUDIES

Tesetaxel has exhibited potent antitumor activity in both in vitro (in a test tube) and in vivo (in a live organism) nonclinical studies (Shionoya et al, Cancer Science 2003;94(5):459-466). Tesetaxel retains potent antitumor activity against chemotherapy-resistant tumor cells, including tumor cells over-expressing the P-gp efflux pump. A defense mechanism of tumor cells, this efflux pump functions to expel toxins, including many chemotherapy agents.

In Vitro Antitumor Activity

Tesetaxel has exhibited potent antitumor activity in in vitro nonclinical studies, with an overall GI₅₀ (the concentration of drug required to inhibit growth by 50%) of less than 1 nM. GI₅₀ is a commonly used nonclinical measurement of antitumor potency; lower GI₅₀ numbers connote higher potency (1 nM is 1/1,000th of 1 µM). In human tumor cell lines, tesetaxel largely retained antitumor cytotoxic (cell-killing) potency against taxane-resistant (P-gp positive) and other chemotherapy-resistant tumors, while paclitaxel and docetaxel lost considerable antitumor potency (Shionoya et al, Cancer Science 2003;94(5):459-466). Consistent with this finding, the uptake and accumulation of tesetaxel in both P-gp negative and P-gp positive tumor cells were greater than that of either paclitaxel or docetaxel. The relative loss of cytotoxic potency between P-gp negative and P-gp positive tumor cells for paclitaxel, docetaxel and tesetaxel is shown in the following table (low numbers connote high potency, and high numbers connote low potency).

In Vivo Antitumor Activity

Tesetaxel exhibited significant growth-inhibitory effects (inhibition rate [“IR”] >94%) in a P-gp positive, human breast cancer (DU4475) mouse model that exhibited resistance to both paclitaxel and docetaxel (IR values of 26%-46%) (Shionoya et al, Cancer Science 2003;94(5):459-466). The relative in vivo antitumor activity for a control, paclitaxel, docetaxel and tesetaxel is shown in the following graph.

 

CNS Penetration

In contrast to the approved taxanes, paclitaxel and docetaxel, which do not significantly penetrate the brain (brain to plasma exposure of only 1% and 8%, respectively), tesetaxel brain concentrations exceeded concentrations required for tumor killing for a sustained period of time in preclinical testing.

Central nervous system ("CNS") metastases in cancers such as breast and lung cancer are common and associated with poor outcomes, as shown in the table below.

CLINICAL STUDIES

More than 500 patients have been treated with tesetaxel across 22 clinical studies. Tesetaxel has been administered as monotherapy in 17 studies and in combination with other agents in 5 studies. Studies have been completed in LA/MBC, gastric cancer, colorectal cancer, non-small cell lung cancer and other cancers as first-line, second-line or salvage therapy.

Tesetaxel, administered both alone and in combination with capecitabine, has been generally well tolerated. In the 8 studies (927A-PRT001, 927A-PRT004, 927E-PRT003, 927E-PRT005, 927E-PRT007, 927A-PRT006, TOST107 and TOST107XT) for which final study data are available, a total of 187 patients were treated with tesetaxel at 27 mg/m² once every three weeks as monotherapy (N=156) or in combination with capecitabine at 1,750-2,500 mg/m² (N=31). In this population, the most common Grade ≥3 (severe or serious) treatment-related adverse events (AE) was neutropenia (low level of neutrophils, a type of white blood cell) (33%), febrile neutropenia (fever coinciding with neutropenia) occurred in 5% of patients. The most common non-hematologic Grade ≥3 treatment-related AEs were: dehydration (5%); diarrhea (5%); fatigue (5%); and anorexia (4%). Other non-hematologic Grade ≥3 treatment-related AEs include: nausea (3%); peripheral neuropathy (weakness, numbness and/or pain from damage to the nerves) (3%); and vomiting (2%). Treatment-related alopecia (hair loss) (any grade) occurred in 14% of patients overall, and Grade 2 treatment-related alopecia occurred in 3% of patients. There were no hypersensitivity reactions.

Tesetaxel’s adverse event profile across all completed studies is shown in the following table.

The results from a Phase 2 clinical study of tesetaxel monotherapy in MBC (TOB203) are summarized below.

 

Study TOB203: A Phase 2 Study of Tesetaxel as First-line Chemotherapy for MBC

In Study TOB203, 38 patients with human epidermal growth factor receptor 2 ("HER2") negative, hormone receptor ("HR") positive MBC received tesetaxel orally as a single agent once every three weeks at a starting dose of 27 mg/m². Objective response rate (“ORR”) based on Response Evaluation Criteria in Solid Tumors ("RECIST") 1.1 was the primary endpoint (Seidman et al., 2018 ASCO Annual Meeting).

 

Median age was 58 years (range: 36-80 years). Eighty-seven percent (87%) had visceral disease, 74% previously received at least one endocrine therapy, 68% previously received neoadjuvant or adjuvant chemotherapy and 53% previously received a taxane-containing regimen. The figures that follow show the study design and patient characteristics (Seidman et al., 2018 ASCO Annual Meeting).

ECOG=Eastern Cooperative Oncology Group

In all 38 patients, the confirmed response rate was 45%. The confirmed response rate was consistent across subgroups. Forty-four percent (44%) of patients who did not previously receive a taxane-containing regimen achieved a confirmed response, compared to 45% of patients who previously received a taxane-containing regimen. Median duration of response ("DoR") was 10.9 months, and median progression-free survival ("PFS") was 5.4 months (Seidman et al., 2018 ASCO Annual Meeting).

Tumor change from baseline in target lesions by individual patient is shown in the following figure.

TOB203: Best Response

Patient response is shown in the following figure.

Patient response by prior taxane exposure is shown in the following figure.

Tesetaxel was generally well tolerated. Neutropenia was the most common Grade ≥3 AE and occurred in 25% of the 24 patients who were not dose-escalated beyond the 27 mg/m² starting dose (the dose selected for CONTESSA, our ongoing Phase 3 study); in these patients, febrile neutropenia occurred in one patient (4%) and Grade ≥3 neuropathy occurred in one patient (4%). There were no hypersensitivity reactions or drug-related deaths, and the rate of Grade 2 alopecia (significant hair loss) was 18%. A summary of Grade ≥3 AEs regardless of relationship is shown in the following table.

 

CONTESSA

We are conducting a 600-patient, multinational, multicenter, randomized, Phase 3 study, known as CONTESSA, that is comparing tesetaxel dosed orally at 27 mg/m² on the first day of a 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m²/day on the first 14 days of a 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m²/day on the first 14 days of a 21-day cycle) in patients with HER2 negative, HR positive LA/MBC previously treated with a taxane in the neoadjuvant (prior to surgery) or adjuvant (immediately following surgery) setting. Where indicated, patients must have received endocrine therapy with or without a cyclin-dependent kinase ("CDK") 4/6 inhibitor. Patients with central nervous system metastases are eligible. CONTESSA’s primary endpoint is PFS assessed by an Independent Radiologic Review Committee (“IRC”). CONTESSA’s secondary endpoints are overall survival (“OS”), ORR assessed by IRC and disease control rate ("DCR") assessed by IRC. To learn more, please visit contessastudy.com.

BID=twice per day

In designing CONTESSA, we received non-binding advice from both the U.S. Food and Drug Administration (“FDA”) and the European Medicines Agency (“EMA”). We believe CONTESSA may serve as a single pivotal study sufficient for product registration, provided that the study demonstrates a statistically significant and clinically meaningful improvement in the primary endpoint, PFS, for tesetaxel plus a reduced dose of capecitabine as compared to the approved dose of capecitabine alone as well as an overall favorable benefit-risk profile for the tesetaxel plus a reduced dose of capecitabine regimen. Generally, a single pivotal study can be sufficient for FDA approval only when the study provides highly reliable and statistically strong evidence of an important clinical benefit and in which confirmation of the result in a second clinical trial would be practically or ethically impossible. There can be no assurance that the outcome of CONTESSA will be sufficient for the approval of tesetaxel by the FDA, EMA or other regulatory agencies or that tesetaxel will be approved at all.

 

Rationale for CONTESSA Study Design

CONTESSA is designed to evaluate whether tesetaxel plus a reduced dose of capecitabine results in improved PFS with manageable toxicity and favorable quality-of-life compared to the approved dose of capecitabine alone. Tesetaxel plus a reduced dose of capecitabine incorporates two agents with synergistic mechanisms of action and is an all-oral regimen that offers a significant pill-burden reduction compared to the approved dose of capecitabine alone.

Our rationale for the CONTESSA study design includes the following points:

  • Capecitabine is a preferred agent as a first- or second-line chemotherapy treatment for patients with HER2 negative, HR positive LA/MBC. Therefore, capecitabine, at the approved dose, is an appropriate control regimen for a registration-enabling Phase 3 study.

  • There is a high unmet medical need for combination chemotherapy regimens with improved benefit-risk profiles.

  • Combining the approved dose of capecitabine with currently available taxanes results in robust efficacy but with significant toxicity.

  • Nonclinical and clinical studies support investigating whether reducing the dose of capecitabine in combination with a taxane will reduce toxicity without a reduction in efficacy.

  • Single-agent tesetaxel has demonstrated antitumor activity in two Phase 2 studies in MBC.

Capecitabine as an Appropriate Control Regimen

Capecitabine is a preferred agent as a first- or second-line chemotherapy treatment for patients with HER2 negative, HR positive LA/MBC, particularly those previously treated with a taxane in the neoadjuvant, adjuvant or advanced setting. Therefore, capecitabine, at the approved dose, is an appropriate control regimen for a registration-enabling Phase 3 study. The FDA- and EMA-approved capecitabine regimen is 2,500 mg/m² on the first 14 days of a 21-day cycle.

Medical Need for Combination Chemotherapy Regimens with Improved

Benefit-risk Profiles

 

To date, combination chemotherapy regimens generally have not demonstrated superior benefit-risk profiles as compared to single-agent, sequential chemotherapy. Specifically, while currently available combination regimens have been associated with increased PFS and, in the case of docetaxel-capecitabine, increased OS, they also have been associated with significantly increased toxicity. As a result, single-agent, sequential chemotherapy remains the standard of care for many patients.


Nonetheless, there remains a large unmet need for chemotherapy regimens, including combination regimens, with improved benefit-risk profiles. In particular, newer combinations that preserve the response rates and PFS of currently available combination regimens, but are better tolerated and easier to take, are needed.


There is a need for improved combination chemotherapy regimens due to the fact that approximately a third or more of LA/MBC patients do not receive second-line chemotherapy after progressing on first-line chemotherapy, as shown in the following table. For these patients, who are not necessarily identifiable when first-line chemotherapy is initiated, there is no opportunity for a second chemotherapy treatment. Therefore, regimens that can significantly increase PFS with minimal increase in toxicity, including regimens that incorporate two therapeutic agents, would significantly benefit patients.

 

Combining the Approved Dose of Capecitabine with Docetaxel, an Approved Taxane

 

In a multicenter, randomized Phase 3 study in 511 patients receiving first-, second- or third-line chemotherapy that served as the basis for approval for capecitabine combined with docetaxel in the treatment of MBC, capecitabine at the approved dose of 2,500 mg/m² (1,250 mg/m² BID) on the first 14 days of a 21-day cycle combined with docetaxel resulted in superior time to disease progression (“TTP”) (hazard ratio = 0.65, 95% confidence interval: 0.54-0.78, p=0.0001) and OS (hazard ratio = 0.78, 95% confidence interval: 0.63-0.95, p=0.01) as compared to docetaxel alone. However, there was significant drug-related toxicity on the combination regimen, resulting in a large percentage of dose reductions and discontinuations (59% of patients reduced their dose of docetaxel and 51% reduced their dose of capecitabine) (O'Shaughnessy et al, Journal of Clinical Oncology 2002;20(12):2812-2823). The results of this Phase 3 study are as follows.

Reducing the Dose of Capecitabine in Combination with a Taxane

Synergy when Combining a Taxane with Capecitabine in Nonclinical Studies

Nonclinical studies have shown synergy when combining a taxane with capecitabine. Taxanes up-regulate tumor levels of thymidine phosphorylase, the enzyme essential for the activation of capecitabine. These studies suggest the potential to reduce the dose of capecitabine without loss of efficacy. In two in vivo nonclinical studies of breast cancer, the combined administration of capecitabine and docetaxel resulted in antitumor efficacy significantly greater than the sum of the efficacy resulting from either agent administered as monotherapy (see the following figures). Furthermore, the synergy may be tumor-specific, as toxicity as measured by weight loss and effect on peripheral blood cells was minimal. These studies suggest the potential to reduce the dose of capecitabine without loss of efficacy.

Clinical Studies Evaluating Lower Doses of Capecitabine Combined with a Taxane

Consistent with nonclinical findings of synergy between taxanes and capecitabine, clinical studies support investigating the combination of a taxane with a reduced dose of capecitabine such as 1,650 mg/m²/day on the first 14 days of a 21-day cycle, the dose of capecitabine chosen for combination with tesetaxel in CONTESSA. In a review of 18 first-line MBC studies of taxane plus capecitabine combinations shown in the following table, there was no apparent loss of efficacy when comparing capecitabine at 1,650 mg/m²/day to capecitabine at 2,000 mg/m²/day (on the first 14 days of a 21-day cycle). Among these studies, the capecitabine 1,650 mg/m²/day dose was the most studied dose less than 2,000 mg/m²/day (5/8 studies). According to Lortholary, the trend toward improved efficacy with lower doses of capecitabine may result from the significantly lower proportion of patients discontinuing study therapy prematurely because of toxicity, and highlights the importance of administering capecitabine using a schedule that optimizes dose intensity and tolerability (Lortholary et alBreast Cancer Research and Treatment 2012;131:127-135).

In summary, we believe that the data support the investigation of tesetaxel at 27 mg/m² on the first day of a 21-day cycle plus capecitabine at 1,650 mg/m²/day on the first 14 days of a 21-day cycle as a novel, all-oral regimen with a potentially favorable benefit-risk profile for the treatment of patients with HER2 negative, HR positive LA/MBC.

 

CONTESSA 2

CONTESSA 2 is an ongoing multinational, multicenter, Phase 2 study of tesetaxel, an investigational, orally administered taxane, in patients with LA/MBC. CONTESSA 2 is investigating tesetaxel dosed orally at 27 mg/m² on the first day of each 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m²/day dosed orally for 14 days of each 21-day cycle) in approximately 125 patients with HER2 negative, HR positive LA/MBC not previously treated with a taxane. Capecitabine is an oral chemotherapy agent that is considered a standard-of-care treatment in LA/MBC. Where indicated, patients must have received endocrine therapy with or without a CDK 4/6 inhibitor. Patients with central nervous system metastases are eligible. The primary endpoint is ORR as assessed by an IRC. The secondary efficacy endpoints are DoR as assessed by the IRC, PFS as assessed by the IRC, DCR as assessed by the IRC and OS.

CONTESSA 2 Study Design

BID=twice per day

 

CONTESSA TRIO

CONTESSA TRIO is an ongoing multi-cohort, multicenter, Phase 2 study of tesetaxel, an investigational, orally administered taxane, in patients with LA/MBC. In Cohort 1, approximately 90 patients with locally advanced or metastatic triple-negative breast cancer ("TNBC") who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive tesetaxel dosed orally at 27 mg/m² on the first day of each 21-day cycle plus either: (1) nivolumab at 360 mg by intravenous infusion on the first day of each 21-day cycle; (2) pembrolizumab at 200 mg by intravenous infusion on the first day of each 21-day cycle; or (3) atezolizumab at 1,200 mg by intravenous infusion on the first day of each 21-day cycle. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are immuno-oncology (IO) agents approved for the treatment of multiple types of cancer. One of these agents, atezolizumab, in combination with the intravenously delivered taxane, nab-paclitaxel, was recently approved by the U.S. FDA as a first-line treatment for patients with metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and PFS. Secondary endpoints include DoR and OS. In Cohort 2, approximately 40 elderly patients with HER2 negative MBC will receive tesetaxel monotherapy dosed orally at 27 mg/m² on the first day of each 21-day cycle. The primary endpoint for Cohort 2 is ORR. Secondary endpoints include PFS, DoR and OS. Patients with central nervous system metastases are eligible for both cohorts.

CONTESSA TRIO Study Design

 

TESETAXEL PRESENTATIONS AND PUBLICATIONS

CONTESSA

CONTESSA 2

CONTESSA TRIO

TOB203

Tesetaxel: Activity of an Oral Taxane as 1st-Line Treatment in Metastatic Breast Cancer – Presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting

Tesetaxel, an Oral Taxane, as First-Line Therapy for Women with Metastatic Breast Cancer – Presented at the 2011 San Antonio Breast Cancer Symposium (SABCS)

927E-PRT005

Efficacy and Prediction of Response to the New Oral Taxane DJ-927 [Tesetaxel] in Anthracycline Pre-Treated Advanced Breast Cancer – Presented at the 2006 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium

TOST107

Phase 1B Study of an All-Oral Chemotherapy Regimen, Tesetaxel Plus Capecitabine, in Patients with Advanced Solid Tumors – Presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting

Preclinical

Tesetaxel, a novel, oral taxane, crosses intact blood-brain barrier (BBB) at therapeutically relevant concentrations – Presented at the American Association for Cancer Research (AACR) Annual Meeting 2019

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