Talon Therapeutics, Inc.

Marqibo®

Marqibo® (vincristine sulfate liposome injection, OPTISOME™)

A Novel, Targeted, Nanoparticle-Encapsulated, Anti-Cancer Compound for Hematologic Cancers.

Marqibo® is a new, targeted, nanoparticle-encapsulated, cancer therapeutic specifically designed to improve patient outcomes by combining the potential for enhanced efficacy with the potential for reduced toxicity. Marqibo consists of vincristine sulfate, a potent vinca alkaloid anti-mitotic, encapsulated in the aqueous core of proprietary, sphingomyelin-based liposomes called Optisomes™. This distinct formulation has been developed to facilitate high-concentration, targeted drug delivery and predictable, first-order, continuous drug release kinetics. In animal models, this unique technology resulted in enhanced cancer tissue drug penetration and accumulation compared to that achievable with un-encapsulated, standard vincristine. In human clinical trials, Marqibo facilitated marked vincristine dose-intensification compared to historical standard vincristine dosing. The dose-intensification results from both a larger milligram dose per unit of body surface area (2.25 mg/m² versus 1.4 mg/m²) and elimination of the need for the dose capping that is routinely applied to standard vincristine. The net results from Marqibo are individual (2-3-fold increase) and cumulative (up to 10-fold increase) vincristine dose increases that may facilitate activity against relapsed and refractory cancer. Liposomal drug delivery may limit toxicity despite dose-intensification. The novel technical characteristics of Marqibo are protected by a series of US and ex-US patents.

A New Drug Application for Marqibo® was submitted to the FDA to provide a standard of care in adults with Philadelphia chromosome (Ph) negative acute lymphoblastic leukemia (ALL) in second or greater relapse or that has progressed following two or more prior lines of anti-leukemia therapy and was accepted for filing under Subpart H accelerated approval. In March 2012, Talon received a positive vote of 7-4 from the Oncologic Drugs Advisory Committee (ODAC). A PDUFA date of August 12, 2012 has been set. Marqibo will also be studied in front-line older adults with ALL in a Phase 3 trial which received Special Protocol Assessment agreement from the FDA. In addition, the National Cancer Institute is conducting a Phase 1 trial in children and adolescents with solid tumors and hematologic malignancies, including ALL. Finally, Marqibo will be studied in a European Phase 3 trial, conducted by the German High-Grade Lymphoma Study Group in elderly patients with newly diagnosed aggressive Non-Hodgkin's Lymphoma, or NHL. Marqibo side effects were predictable and manageable in these study populations and there were no new unexpected toxicities observed.

Ongoing Trials

Phase III:
HALLMARQ - Study to Evaluate Marqibo in the Treatment of Subjects ≥ 60 Years Old With Newly Diagnosed ALL

Study in Adults aged 61-80 with newly diagnosed aggressive NHL (being conducted by the German High-Grade Lymphoma NHL Study Group (DSHNHL))

Phase II:

Substituting Marqibo for vincristine in Hyper-CVAD to create Hyper-CMAD (being conducted by MD Anderson Cancer Center)

Safety and Efficacy of Marqibo® in Metastatic Malignant Uveal Melanoma

Phase I:

Study in children and adolescents with relapsed or refractory cancers(being conducted by the Pediatric Branch of the National Cancer Institute (NCI))

Menadione Topical Lotion

A Topical Compound for the Prevention and Treatment of Skin Toxicity Associated with Epidermal Growth Factor Receptor Inhibitor Anti-Cancer Treatment.

Menadione Topical Lotion (MTL) is a first-in-class, topical formulation of menadione (vitamin K3) being developed for the prevention and treatment of the common, painful, unsightly, and cancer treatment-limiting skin toxicity (“rash”) reported to be caused by both small molecule (e.g., Tarceva®) and antibody (e.g., Erbitux® and Vectibix®) epidermal growth factor receptor (EGFR) inhibitors. The menadione in MTL has phosphatase inhibitory activity, distinct from other vitamin K species, that can normalize and up-regulate EGFR cellular signaling. Following topical application, the menadione in Talon’s proprietary MTL formulation affects skin EGFR at the dermal-epidermal interface without any appreciable systemic absorption. MTL targets the underlying cause of the rash with negligible potential for interference with EGFR inhibitor therapy at the tumor level. Talon has issued or pending patents (U.S. and E.U.) covering mechanism, use, and formulation.

EGFR inhibitors are prescribed for the treatment of lung, colon, breast, pancreas, and head & neck cancers. Up to 90% of EGFR inhibitor exposed patients develop early onset skin rash involving the face, neck, and upper torso, with up to 30% of affected patients stopping EGFR inhibitor therapy because of rash alone. The rash may indirectly and adversely affects cancer outcomes by leading to sub-optimal drug dosing and a lack of compliance. Empiric combination oral antibiotic and over the counter topical agent regimens have not been shown to address the rash etiology and are believed to be generally ineffective. There are no approved products that address this growing cancer treatment-related toxicity.

Talon is developing MTL for patients treated with an EGFR inhibitor in order to prevent and treat rash, allow EGFR inhibitor dose optimization, and improve cancer patient outcomes. The recently completed Phase 1 program consisted of two trials and demonstrated that MTL is generally safe and well tolerated. The Phase 1 program identified the apparent maximum tolerated lotion strength and provided preliminary evidence of lotion ability to mitigate rash severity. A Phase 2 trial conducted by the Mayo Clinic has been initiated.

Brakiva™

Brakiva™ Brakiva™ (topotecan liposomes injection, OPTISOME™)

A Novel, Targeted, Nanoparticle-Encapsulated, Anti-Cancer Compound for Small Cell Lung and Ovarian Cancers.

Brakiva™ is a new, targeted, nanoparticle-encapsulated, cancer therapeutic specifically designed to improve patient outcomes by combining the potential for enhanced efficacy with an absence of increased toxicity. Brakiva consists of topotecan HCl, a potent semi-synthetic derivative of camptothecin, encapsulated in the aqueous and acidic core of proprietary sphingomyelin-based liposomes called Optisome™. This distinct formulation has been developed to facilitate high-concentration, targeted drug delivery and sustained drug release kinetics. The acidic Optisome core is critical to the maintenance and delivery of the non-hydrolyzed and fully active form of topotecan to the target cancer tissue. In animal models, this unique technology resulted in prolonged plasma circulation and 10-fold enhanced cancer tissue drug penetration and accumulation compared to that achievable with un-encapsulated, standard topotecan. A 10- to 20-fold increased milligram for milligram anti-tumor activity of Brakiva compared to standard topotecan was demonstrated in non-clinical models. The intra-tumoral topotecan dose intensification facilitated by the Optisome technology is expected to improve cancer cell killing beyond the capability of standard topotecan. The prospect of providing enhanced anti-cancer activity without enhanced toxicity is of particular importance in the treatment of patients with relapsed and refractory solid tumors such as small cell lung cancer and ovarian cancer. The novel technical characteristics and use of Brakiva are protected by a series of US and ex-US patents.

Brakiva™ is being developed to replace standard topotecan therapies in persons with newly diagnosed or relapsed solid tumors such as small cell lung cancer (SCLC) and ovarian cancer. A two-arm, Phase 1, dose-escalation trial of Brakiva administered every 21 days or on days 1 and 8 of a 21-day cycle is ongoing in mostly heavily pre-treated adults with advanced solid tumors. Based on preliminary encouraging tolerability and activity, pre-Phase 2 planning is focused on evaluating Brakiva administered every 21 days in women with relapsed ovarian cancer.

Alocrest™

Alocrest™ (vinorelbine liposomes injection, OPTISOME™)

A Novel, Targeted, Nanoparticle-Encapsulated, Anti-Cancer Compound for Lung and Breast Cancers.

Alocrest™ is a new, targeted, nanoparticle-encapsulated, cancer therapeutic specifically designed to improve patient outcomes by combining the potential for enhanced efficacy with an absence of increased toxicity compared with conventional vinorelbine. Alocrest consists of vinorelbine, a potent vinca alkaloid anti-mitotic, encapsulated in the aqueous core of proprietary sphingomyelin-based liposomes called Optisome™. This distinct formulation has been developed to facilitate high-concentration, targeted drug delivery and sustained drug release kinetics. In animal models, this unique technology resulted in prolonged plasma circulation (100-fold increased area under the concentration time curve) and 9.5-fold enhanced cancer tissue drug penetration and accumulation compared to that achievable with un-encapsulated, standard vinorelbine. The intra-tumoral vinorelbine dose intensification facilitated by the Optisome technology is expected to improve cancer cell killing beyond the capability of standard vinorelbine. The prospect of providing enhanced anti-cancer activity without enhanced toxicity is of particular importance in the treatment of elderly cancer patients and those with marginal performance status (PS). The novel technical characteristics and use of Alocrest are protected by a series of US and ex-US patents.

Alocrest™ is being developed to improve the standard of care in adults with newly diagnosed or relapsed solid tumors such as non-small cell lung cancer (NSCLC) and breast cancer. A Phase 1 dose-escalation trial of Alocrest administered every 21 days demonstrated promising anti-cancer activity (47% disease control rate) across a range of doses, as well as acceptable and predictable toxicity in heavily pre-treated persons with advanced solid tumors. In contrast to historical reports for vinorelbine, there were no cases of peripheral vein irritation associated with intravenous Alocrest. Pre-Phase 2 planning is focused on evaluating Alocrest administered every 21 days against standard vinorelbine given weekly in elderly and PS 2 NSCLC patients.

Completed Trials Summary

MARQIBO®

HBS 407
Title: A Phase 2 Study to Evaluate the Safety and Efficacy of Weekly Doses of Marqibo® (vincristine sulfate liposome injection) in Adult Patients with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (ALL) in Second Relapse or Adult Patients with Philadelphia Chromosome-negative ALL Who Failed Two Treatment Lines of Anti-leukemia Chemotherapy.

A Phase 2, multi-national study (rALLY Trial) enrolled 65 adults with Philadelphia chromosome negative acute lymphoblastic leukemia (ALL) who were either in second or greater relapse or who had progressed after two or more prior lines of treatment. Study subjects received single-agent, intravenous Marqibo 2.25 mg/m2 (without any dose cap) weekly over 1 hour as salvage therapy. Bone marrow assessments were conducted every 4 weeks. The primary efficacy endpoint was achievement of a complete response (CR) or CR without full hematologic (CRi) recovery. Additional endpoints included CR/CRi duration, overall survival, and safety.

Summary of results:

The overall response rate was 35% in very heavily pretreated patients with ALL
The CR/CRi rate was 20% and compares favorably to historical experience of 4% CR with single agents
The median CR/CRi duration was 5.3 months and median overall survival was 4.6 months
46% of subjects received Marqibo as fourth line or greater therapy
Side effects were predicable and manageable and no new side effects were observed
10 subjects (15%) were able to proceed to stem cell transplant

HBS408
Title: A Phase 2 Study of Marqibo in Patients with Metastatic Uveal Melanoma

A Phase 2 open-label, multi-center, single arm study in patients with metastatic uveal melanoma is being conducted to evaluate efficacy and safety. Patients with controlled brain metastases are allowed. In the first cohort, up to 35 patients with no more than one prior systemic therapy received 2.25 mg/m2 Marqibo (no dose capping) by 1-hour intravenous infusion every 14 days until tumor progression. Responses are assessed every 6 weeks using the Response Evaluation Criteria in Solid Tumors (RECIST). Toxicity is assessed at least as frequently as before each dose. In the second cohort, up to 20 patients who have not received any prior systemic chemotherapy will receive Marqibo at 2.25 mg/m2 intravenously over 60 minutes every 7 days. Two doses of Marqibo will constitute one cycle of study treatment (14 days). In addition to efficacy and toxicity assessment, cohort 2 will be monitored by cardiac Holter for 24 hours prior to their first Marqibo dose and continue for 24 hours after the start of infusion to establish cardiac safety.

Cohort 1 is closed to enrollment and cohort 2 is being enrolled. This study will not only evaluate the effect of Marqibo in this rapidly progressive and fatal form of melanoma, but also will allow the collection of EKG data to support Marqibo's registration.

VSLI-06
Title: Phase I Study of Liposomal Vincristine (VSLI) and Dexamethasone in Relapsed or Refractory Acute Lymphoblastic Leukemia

A Phase 1 open-label, multi-center, standard dose escalation study enrolled 36 patients with relapsed or refractory acute lymphoblastic leukemia. Study subjects received weekly intravenous Marqibo infused over 60 minutes at 1.5 mg/m2, 1.825 mg/m2, 2.0 mg/m2, 2.25 mg/m2, or 2.4 mg/m2 with pulse dexamethasone (40 mg) given on Days 1 through 4 and on Days 11 through 14 of each 28 day cycle. Determination of the maximum tolerated dose (MTD) and evaluation of anti-leukemic activity were the major study objectives. There were no restrictions on the number of prior therapies, but subjects with grade 2 or higher peripheral neuropathy at study screening were ineligible.

Summary of results:

The MTD of VSLI was determined to be 2.25 mg/m2
The most common toxicities attributed to Marqibo were peripheral neuropathy and constipation
All patients were previously treated with conventional vincristine
A complete response (CR) was achieved by 7 of 36 (19%) patients based on intent to treat analysis
Of the 7 responders, 4 patients proceeded to allogeneic stem cell transplantation after achieving a CR

MENADIONE TOPICAL LOTION

HBS 701
Title: A Phase 1, Multi-center, Randomized, Double-Blind, Sequential, Placebo Controlled Study of the Safety, Tolerability, and Systemic Absorption of Menadione Topical Lotion as an Emergent and Pre-emergent Treatment for Epidermal-Growth-Factor-Receptor (EGFR) Inhibitor-Associated Rash

A phase 1, multi-center, randomized, double-blind, sequential, placebo controlled study was conducted in 18 patients to assess the safety and tolerability of twice-daily Menadione Topical Lotion 0.2%. Two groups of 9 evaluable subjects were enrolled. Subjects with existing EGFR inhibitor-induced rash (treatment emergent group) made up one group. The second group consisted of subjects about to begin EGFR inhibitor therapy (treatment pre-emergent group), and who are at risk for the rash. Subjects applied Menadione Topical Lotion (MTL) and placebo lotion twice daily to the right and left sides of the face, neck, and chest in a double blinded fashion, allowing each subject to serve as her/his own control. Treatment emergent subjects initiated MTL and placebo lotion application when, after starting treatment with an EGFR inhibitor, acute signs and symptoms of rash on the face/neck and/or upper chest were noted. Treatment pre-emergent subjects initiated MTL and placebo lotion application one day prior to the beginning of EGFR inhibitor treatment. Lotion strength reduction and reduced lotion application frequency were allowed in response to signs and/or symptoms of lotion intolerance.

Summary of results:

MTL was generally safe and well tolerated
The apparent maximum tolerated MTL strength was 0.1%
There was negligible systemic menadione exposure
Preliminary evidence of rash mitigation activity from MTL 0.1%

HBS 702
Title: A Phase 1, Single-Center, Single-Blind, Modified Dose Escalation, Placebo Controlled Study Evaluating the Safety, Tolerability and Systemic Absorption of Menadione Topical Lotion 0.05%, 0.1% and 0.2% in Healthy Normal Volunteers after Single and Multiple Doses

A phase 1, single blind, multi-dose, placebo-controlled, single-center study was conducted to assess the bioavailability, safety, and tolerability of three concentrations (0.05%, 0.1% and 0.2%) of Menadione Topical Lotion (MTL). Normal healthy subjects applied the different concentrations of MTL and matching placebo lotion twice daily to the entire face, neck, upper chest and upper arms for 3.5 day periods of time, every 7 days, over a 28 day period. Photographs were taken at each dose. The pharmacokinetic parameters of MTL were assessed in blood and tissue. Potential response biomarkers p27, p63 and pEGFR, were measured in skin. Twelve normal healthy subjects, 6 male and 6 female, with a median age of 43 years (range, 30-52) were entered into the study.

Summary of results:

MTL was universally well tolerated at the 0.05% and 0.1% lotion strengths
There was negligible systemic menadione exposure at all lotion strengths
Normal skin architecture and signaling were normal after menadione exposure

BRAKIVA™

HBS 601
Title: A Phase 1 Study of Topotecan Liposomes Injection (TLI) in Subjects with Small Cell Lung Cancer (SCLC), Ovarian Cancer and Other Advanced Solid Tumors

A Phase 1 multi-center, open-label, two-arm, dose-escalation study is being conducted in up to 50 adult patients. Eligible patients have advanced solid tumors that have relapsed, or are refractory to standard therapy, or for whom there is no standard therapy available. The study is designed to evaluate safety, tolerability, and to determine the maximum tolerated dose (MTD). Subjects receive TLI intravenously as a 30 minute infusion under one of two dosing regimens. Arm A subjects began TLI dosing on Days 1 and 8 of a 21-day treatment cycle (Starting dose: 1 mg/m2) and arm B subjects started TLI dosing on Day 1 of a 21-day treatment cycle (Starting dose: 2 mg/m2).

Status:
This study is ongoing

ALOCREST™

HBS 501
Title: A Phase 1 Study of Vinorelbine Liposomes Injection (VLI) for Treatment in Patients with Advanced Solid Tumors, Non-Hodgkin's Lymphoma or Hodgkin's Disease

A Phase 1, multi-center, open-label, dose-escalation study was conducted in 30 subjects with solid tumors refractory to standard therapy or for which no standard therapy was known to exist, or relapsed/refractory NHL or Hodgkin 's disease. Subjects were treated with vinorelbine liposomes injection (Alocrest) administered intravenously on Days 1 and 8 of a 21-day cycle, starting at 2 mg/m2. The study assessed the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and preliminary tumor response to therapy. The study also characterized the pharmacokinetic profile of Alocrest. Responses were based on Response Evaluation Criteria in Solid tumors (RECIST) and NHL International workshop criteria.

Summary of results:

The MTD of Alocrest in primarily heavily pretreated subjects was determined to be 28 mg/m2 administered on days 1 and 8 of a 21 day cycle
Alocrest was generally well-tolerated, with neutropenia of short duration being the chief drug-related toxicity
Liposome encapsulation of vinorelbine imparted no new toxicity
Alocrest resulted in a disease control rate of 47% including 3 of 4 Non Small Cell Lung Cancer (NSCLC) subjects
No subjects on study experienced an injection site reaction

Talon Product Portfolio

Marqibo®

Menadione Topical Lotion

Brakiva™

Alocrest™

Completed Trials Summary

Pipeline