Seattle Genetics starts phase 1/2 trial of vadastuximab talirine combination therapy for patients with untreated MDS

33A is an antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest technology, comprising an engineered cysteine antibody (EC-mAb) stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer.

Azacitidine is a hypomethylating agent (HMA) commonly used in the treatment of MDS. MDS is known to be a precursor to acute myeloid leukemia (AML), and broadly expresses CD33.

Seattle Genetics chief medical officer and executive vice president of research and development Jonathan Drachman said: "Most newly diagnosed patients with intermediate or high risk MDS are ineligible for allogeneic stem cell transplant due to age, comorbidities or lack of appropriate donor. For these patients, novel therapies are urgently needed to prolong survival and delay disease progression into AML.

"In our phase 1 AML clinical trial evaluating 33A plus HMAs (azacitidine or decitabine), we have observed encouraging tolerability and depletion of blasts from the bone marrow in many patients, and we recently presented preclinical data demonstrating synergistic activity of 33A plus HMAs. Expanding our clinical evaluation of 33A in MDS is part of a broad clinical development strategy to establish 33A as the foundation of care for patients with myeloid malignancies."

The phase 1/2, open-label, multi-center clinical trial is designed to evaluate the safety and activity of 33A administered in combination with azacitidine in patients with previously untreated International Prognostic Scoring System (IPSS) Intermediate-2 or high risk MDS. Phase 1 of the study will identify the recommended dose of 33A when combined with azacitidine in this patient population.

The phase 2 portion of the trial will be a randomized, double-blind, placebo-controlled study evaluating azacitidine with or without 33A.

The primary endpoint in phase 1 is determination of the recommended 33A dose in combination with azacitidine. The primary endpoint in phase 2 is to compare the overall response rate between the two treatment arms. The secondary endpoints include evaluation of safety, best response, duration of response, progression-free survival and overall survival. The phase 1/2 trial will enroll approximately 130 patients at approximately 35 centers in North America.

In addition to this MDS trial, Seattle Genetics is evaluating 33A broadly across multiple lines of therapy in patients with AML, including the following ongoing trials:

A phase 1 trial of 33A monotherapy and in combination with HMAs in AML patients who have relapsed/declined intensive frontline therapy or are newly diagnosed;
A phase 1b trial in combination with standard of care intensive chemotherapy, including cytarabine and daunorubicin, for younger fit patients with AML; and,
A phase 1/2 trial in patients with relapsed or refractory AML evaluating 33A monotherapy as a pre-conditioning regimen prior to an allogeneic stem cell transplant and also for use as maintenance therapy following transplant.

Additionally, a phase 3 clinical trial to evaluate 33A in combination with HMAs in previously untreated older AML patients is planned to begin by the third quarter of 2016.

More information about SGN-CD33A and ongoing clinical trials can be found at www.ADC-CD33.com.

With more than 15 years of experience and innovation, Seattle Genetics is the leader in developing ADCs. ADCs are monoclonal antibodies that are designed to selectively deliver cell-killing agents to tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

About Myelodysplastic Syndrome

Myelodysplastic Syndromes (MDS) are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells. MDS is often referred to as a "bone marrow failure disorder". MDS is a disorder that starts when abnormal progenitor cells in the bone marrow are damaged and have problems making new blood cells.

Blood cells formed by the abnormal bone marrow cells are defective. Defective cells often have reduced survival and function, resulting in low blood counts and abnormal behavior. In advanced MDS, blasts are detectable in the bone marrow and usually express CD33.

In about one-third of patients, MDS can progress to a rapidly growing cancer of the bone marrow cells called acute myeloid leukemia, or AML. According to the American Cancer Society, in 2016 more than 19,500 new cases of MDS will be diagnosed and more than 10,000 deaths will occur from MDS.

About Vadastuximab Talirine (SGN-CD33A)

Vadastuximab talirine (SGN-CD33A; 33A) is a novel ADC targeted to CD33 utilizing Seattle Genetics’ newest ADC technology. CD33 is expressed on most AML and MDS blast cells. The CD33 antibody is attached to a highly potent DNA binding agent, a pyrrolobenzodiazepine (PBD) dimer, via a proprietary site-specific conjugation technology to a monoclonal antibody with engineered cysteines (EC-mAb).

PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology (EC-mAb) allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody.

The ADC is designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD33-expressing cells. 33A is being evaluated in ongoing phase 1 and phase 1/2 clinical trials in AML and MDS and a planned pivotal phase 3 clinical trial for patients with AML.