On March 30, 2020 AstraZeneca reported that Imfinzi (durvalumab) has been approved in the US as a 1st-line treatment for adult patients with extensive-stage small cell lung cancer (ES-SCLC) in combination with standard-of-care (SoC) chemotherapies, etoposide plus either carboplatin or cisplatin (platinum-etoposide) (Press release, AstraZeneca, MAR 30, 2020, View Source [SID1234555971]).

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The approval by the Food and Drug Administration was based on positive results from the Phase III CASPIAN trial showing Imfinzi in combination with SoC platinum-etoposide demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus SoC alone.

SCLC is a highly aggressive, fast-growing form of lung cancer that typically recurs and progresses rapidly despite initial response to chemotherapy.1,2

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "The US approval of Imfinzi brings a new medicine to extensive-stage small cell lung cancer patients in urgent need of new options. Imfinzi is the only immunotherapy to show both a significant survival benefit and improved response rate in combination with chemotherapy for these patients, an important step forward in treating this devastating disease."

Jonathan Goldman, MD, Associate Professor of Hematology & Oncology, UCLA Medical Center, Santa Monica, California and a lead investigator in the Phase III CASPIAN trial, said: "Patients with extensive-stage small cell lung cancer continue to face a poor prognosis, and finding new medicines to improve outcomes in this setting has been a formidable challenge. The CASPIAN trial enables clinicians to choose durvalumab in combination with etoposide and either carboplatin or cisplatin, making this an important new 1st-line treatment option for patients that is both effective and well-tolerated."

The Phase III CASPIAN trial had two primary endpoints comparing experimental arms to SoC. In the Imfinzi plus SoC arm, the risk of death was reduced by 27% (equal to a hazard ratio of 0.73; 95% CI 0.59-0.91; p=0.0047), with median OS of 13.0 months versus 10.3 months for SoC alone. Results also showed an increased confirmed objective response rate in the Imfinzi plus SoC arm (68% versus 58% for SoC alone). The safety and tolerability for Imfinzi plus SoC was consistent with the known safety profiles of these medicines. The Imfinzi plus SoC data from the CASPIAN trial were published in The Lancet.3

The second experimental arm testing tremelimumab added to Imfinzi and SoC recently completed, but did not meet its primary endpoint. Details will be presented at a forthcoming medical meeting.

The CASPIAN trial used a fixed dose of Imfinzi (1500mg) administered every three weeks for four cycles while in combination with chemotherapy and then every four weeks until disease progression. As part of a broad development programme, Imfinzi is also being tested following concurrent chemoradiation therapy in patients with limited-stage SCLC in the Phase III ADRIATIC trial with data anticipated in 2021.

Imfinzi received its first approval based on the Phase III CASPIAN trial in Singapore for patients with ES-SCLC in February 2020. Imfinzi in combination with etoposide and either carboplatin or cisplatin is currently under regulatory review for the treatment of ES-SCLC in the 1st-line setting based on the Phase III CASPIAN trial in the EU and Japan.

Small cell lung cancer

Lung cancer is the leading cause of cancer death among both men and women and accounts for about one fifth of all cancer deaths.4 Lung cancer is broadly split into non-small cell lung cancer (NSCLC) and SCLC, with about 15% classified as SCLC.5 About two thirds of SCLC patients are diagnosed with ES-SCLC, in which the cancer has spread widely through the lung or to other parts of the body.6 Prognosis is particularly poor, as only 6% of all SCLC patients will be alive five years after diagnosis.6

CASPIAN

CASPIAN was a randomised, open-label, multi-centre, global, Phase III trial in the 1st-line treatment of 805 patients with ES-SCLC. The trial compared Imfinzi in combination with etoposide and either carboplatin or cisplatin chemotherapy, or Imfinzi and chemotherapy with the addition of a second immunotherapy, tremelimumab, versus chemotherapy alone. In the experimental arms, patients were treated with four cycles of chemotherapy. In comparison, the control arm allowed up to six cycles of chemotherapy and optional prophylactic cranial irradiation. The trial was conducted in more than 200 centres across 23 countries, including the US, in Europe, South America, Asia and the Middle East. The primary endpoint was OS in each of the two experimental arms.

Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is approved in the curative-intent setting of unresectable, Stage III NSCLC after chemoradiation therapy in the US, Japan, China, across the EU and in many other countries, based on the Phase III PACIFIC trial. Imfinzi is approved for the 1st-line treatment of ES-SCLC in combination with SoC chemotherapy in the US and Singapore. Imfinzi is also approved for previously treated patients with advanced bladder cancer in the US and a small number of other countries.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, SCLC, bladder cancer, head and neck cancer, liver cancer, biliary tract cancer, cervical cancer and other solid tumours.

Tremelimumab

Tremelimumab is a human monoclonal antibody and potential new medicine that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Tremelimumab blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death. Tremelimumab is being tested in a clinical trial programme in combination with Imfinzi in NSCLC, SCLC, bladder cancer, head and neck cancer and liver cancer.

AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage development for the treatment of different forms of lung cancer spanning different histologies, several stages of disease, lines of therapy and modes of action. We aim to address the unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with the approved medicines Iressa (gefitinib) and Tagrisso (osimertinib), and its ongoing Phase III trials ADAURA, LAURA, and FLAURA2.7-9 We are also committed to addressing tumour mechanisms of resistance through the ongoing Phase II trials SAVANNAH and ORCHARD which test Tagrisso in combination with savolitinib, a selective inhibitor of c-MET receptor tyrosine kinase, along with other potential new medicines. Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate is in development for metastatic non-squamous HER2-overexpressing or HER2-mutated NSCLC including trials in combination with other anticancer treatments.

An extensive late-stage Immuno-Oncology programme focuses on lung cancer patients without a targetable genetic mutation which represents up to three-quarters of all patients with lung cancer.10 Imfinzi, an anti-PDL1 antibody, is in development for patients with advanced disease (Phase III trials POSEIDON and PEARL) and for patients in earlier stages of disease including potentially-curative settings (Phase III trials AEGEAN, ADJUVANT BR.31, PACIFIC-2, PACIFIC-4, PACIFIC-5, and ADRIATIC) both as monotherapy and in combination with tremelimumab and/or chemotherapy. Imfinzi is also in development in the Phase II combination trials NeoCOAST, COAST and HUDSON in combination with potential new medicines from the early-stage pipeline.

AstraZeneca’s approach to Immuno-Oncology (IO)

Immuno-oncology (IO) is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. AstraZeneca believes that IO-based therapies offer the potential for life-changing cancer treatments for the clear majority of patients.

The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a monotherapy and in combination with tremelimumab in multiple tumour types, stages of disease, and lines of therapy, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine the IO portfolio with radiation, chemotherapy, small targeted molecules from across AstraZeneca’s Oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On March 29, 2020 Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported its annual results for the year ended December 31, 2019 (Press release, Ascentage Pharma, MAR 29, 2020, View Source [SID1234555966]). During the reported period, Ascentage Pharma further increased its investments in innovation, and achieved significant progress in clinical development, external collaborations, intellectual property rights, and the building of its manufacturing capabilities. In 2020, Ascentage Pharma plans to submit its first New Drug Application (NDA).

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Achieving significant progress with drug candidates while advancing global clinical development

As of December 31, 2019, Ascentage Pharma has developed a robust pipeline of eight clinical-stage small molecule drug candidates, currently being evaluated in more than 30 Phase I or II clinical trials in the United States, Australia, and China. The Company’s pipeline consists of inhibitors that target key proteins in the apoptotic pathways, including the Bcl-2, IAP, and MDM2-p53 pathways, to restore normal apoptotic functions; and next-generation tyrosine kinase inhibitors (TKIs) that target mutant kinases in cancers.

With increased investments in innovation, the Company’s research and development expenses for the year ended December 31, 2019, totaled RMB464 million. During the reported period, Ascentage Pharma achieved significant progress with the global clinical development of its drug candidates.

HQP1351, Ascentage Pharma’s core drug candidate and a third-generation BCR-ABL/KIT inhibitor, has achieved several milestones during the reported period. As of December 31, 2019, the Company had completed enrollments for two pivotal Phase II clinical trials of HQP1351 in patients with chronic phase chronic myeloid leukemia (CP-CML) and accelerated phase CML (AP-CML) in China, and had initiated a third pivotal Phase II trial in CML patients resistant/intolerant to first and second-generation TKIs in China. Meanwhile, the development program of HQP1351 in the United States is also progressing well, with the Phase Ib trial having been initiated in July 2019 and the first patient dosed in January 2020. It is worth noting that results from the Phase I clinical trial of HQP1351 were selected for oral presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meetings two years in a row, and was nominated as "Best of ASH (Free ASH Whitepaper)" research in 2019. Ascentage Pharma plans to submit an NDA for HQP1351 in China in 2020 and expects HQP1351 to become the Company’s first commercialized product.

APG-2575, a key drug candidate in the Company’s pipeline targeting apoptosis, is a novel, orally administered Bcl-2 selective inhibitor that has also met numerous milestones with its global clinical programs during the reported period. In July 2019, APG-2575 dosed the first patient in the Phase I trial in China, and became the first China-developed Bcl-2 selective inhibitor entering clinical stage. Previously, the Company had already initiated a multi-center Phase I study of APG-2575 as a monotherapy for the treatment of hematologic malignancies in the United States and Australia. In March 2020, the Company obtained approvals from the U.S. Food and Drug Administration (FDA) for two global Phase Ib/II clinical trials of APG-2575, as a single agent and in combination with other agents, one study in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and another one in patients with Waldenström macroglobulinemia (WM). The Phase Ib/II study in patients with relapsed/refractory CLL/SLL has recently dosed its first patient in the United States. Upon receiving the recent approval from the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA), Ascentage Pharma will soon initiate a Phase Ib study of APG-2575 as a single agent or in combination for the treatment of relapsed/refractory acute myeloid leukemia (AML) in China.

In addition, the Company has further advanced the development of several other drug candidates, including APG-1252, a novel Bcl-2/Bcl-xL dual inhibitor; APG-115, a MDM2-p53 inhibitor; and APG-1387, an IAP inhibitor.

Building a global IP portfolio and expanding strategic partnerships to accelerate transition toward commercialization

Intellectual property rights are of vital importance to Ascentage Pharma, a China-based innovative biopharmaceutical company with a global footprint. Utilizing its robust R&D capabilities, Ascentage Pharma has strategically developed a global intellectual property portfolio. As of December 31, 2019, the Company has 80 issued patents and more than 200 patent applications globally, of which about 67 patents had been issued overseas.

While building a highly capable R&D team, Ascentage Pharma has cultivated partnerships with leading biotechnology and pharmaceutical companies, and academic institutions around the world. In April 2019, Ascentage Pharma entered into a clinical collaboration agreement with Junshi Biosciences to explore the synergies of the IAP inhibitor, APG-1387, and Junshi Biosciences’ anti-PD-1 therapy, toripalimab, in clinical trials in solid and hematologic tumors in China. The clinical study has already been approved and initiated in China. In November 2019, the Company entered into a strategic collaboration with Shanghai Henlius Biotech, to conduct clinical trials of combination therapy between APG-2575, Ascentage Pharma’s novel, orally administered Bcl-2 selective inhibitor and 汉利康 (rituximab injection) for the treatment of CLL in China.

In the meantime, Ascentage Pharma has begun executing its industrialization strategies. In November 2019, Ascentage Pharma broke ground on its global headquarters, R&D center, and manufacturing facility in the Suzhou Industrial Park. At the new facility, which has a planned building area of approximately 10,000m2, the Company plans to produce drug products for clinical development or, in the future, commercial use. Ascentage Pharma expects this facility to consist of two oral-solid-dosage production lines, for both tablet and capsule formulations, and two parenteral liquid/lyophilization powder-for-injection production lines.

"2019 marked some major milestones for Ascentage Pharma, as we pressed ahead with the implementation of our innovation strategies globally. In the past year, we made tremendous headways with our drug candidates, including HQP1351, a core drug candidate in our pipeline, advanced several global clinical programs, which further elevated Ascentage Pharma’s influence in the global medical and scientific community. We continued to increase investments in R&D, which strengthened our innovation capabilities. Our effort to expand external collaborations led to the partnerships with Unity, Junshi Biosciences, and Shanghai Henlius Biotech. By commencing the construction of the Company’s global headquarters, R&D center, and manufacturing facility in Suzhou, Ascentage Pharma has begun its transition toward manufacturing," said Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma. "Moving forward, we will continue to boost our R&D capabilities, accelerate clinical development programs, and prepare ourselves for the first NDA submission and product commercialization, in fulfilling our mission of ‘addressing unmet clinical needs in China and around the world’."

On March 28, 2020 Ryvu Therapeutics (WSE: RVU), a clinical-stage biopharmaceutical company developing novel small molecule therapies that address emerging targets in oncology, reported that the U.S. Food and Drug Administration (FDA) has granted an orphan drug designation (ODD) to Ryvu’s SEL120, for the treatment of patients with acute myeloid leukemia (AML) (Press release, Ryvu Therapeutics, MAR 28, 2020, View Source [SID1234555967]).

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SEL120 is an oral, selective inhibitor of CDK8 kinase which is implicated in the development of hematological malignancies and solid tumors. A clinical phase 1b study of SEL120 is currently enrolling in 6 investigational sites in USA, investigating safety and preliminary efficacy of SEL120 in treatment of patients with relapsed or refractory AML or high-risk myelodysplastic syndrome (HR-MDS).

"The FDA’s granting orphan drug designation to SEL120, is a significant encouragement for advancement of our clinical strategic plan addressing the unmet medical needs in the area of AML treatment, a disease where patients still face poor prognosis" said Setareh Shamsili, MD, PhD, Chief Medical Officer and Executive VP at Ryvu Therapeutics. "SEL120 has shown strong proof of concept in the preclinical studies and has received a strategic support from The Leukemia & Lymphoma Society (LLS) through its Therapy Acceleration Program (TAP). SEL120 may have the potential to offer an important therapeutic benefit in AML and in particular to those refractory/relapsed AML patients with the poorest prognosis, worldwide."

Orphan drug status (ODD) is intended to advance drug development for rare diseases. The FDA provides ODD to drugs and biologics that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions that affect fewer than 200,000 people in the U.S. The FDA’s orphan drug designation allows the drug for the designated indication to be eligible for requesting a seven-year period of U.S. marketing exclusivity upon approval of the drug, as well as potential of other development assistance and financial incentives: View Source

About SEL120

SEL120 is an oral, selective inhibitor of CDK8, a kinase which is a part of the mediator complex and is essential for the activity of super-enhancers important to the regulation of RNA transcription. CDK8 kinase is implicated in the development of hematological malignancies and solid tumors. SEL120 was discovered with the Ryvu Therapeutics discovery engine platform and is currently in Phase 1b study in adult patients with AML or HR-MDS who are refractory to treatment or have relapsed after previous therapies. Patients are enrolled in the study independent of specific tumor mutational burden. The study will also assess pharmacokinetic and pharmacodynamic parameters of SEL120.

SEL120 has received support from The Leukemia & Lymphoma Society Therapy Acceleration Program (TAP), a strategic initiative to partner directly with innovative biotechnology companies and leading research institutions to accelerate the development of promising new therapies for blood cancers. More information about TAP program is available at: View Source

About Acute Myeloid Leukemia

Acute myelogenous leukemia or acute myeloid leukemia (AML) is a heterogenous hematological malignancy involving the clonal expansion of myeloid blasts in the bone marrow and peripheral blood with possible spread to liver and spleen. It is estimated that there are around 90 000 cases of AML worldwide each year, and American Cancer Society estimates that approximately 20 000 of these in U.S. only. The median age at diagnosis is 66 years, with 54% patients over 65 years, and 33% over 75 years. Of those diagnosed at a later age, the diagnosis is often associated with underlying myelodysplastic syndromes (MDS), sometimes linked to cancer chemotherapy and radiotherapy exposure.

On March 27, 2020 Bonnie J Addario Lung Cancer Foundation reported the Food and Drug Administration approved durvalumab (IMFINZI, AstraZeneca) in combination with etoposide and either carboplatin or cisplatin as first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC) (Press release, Bonnie J Addario Lung Cancer Foundation, MAR 27, 2020, View Source [SID1234555996]).

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Efficacy of this combination in patients with previously untreated ES-SCLC was investigated in CASPIAN, a randomized, multicenter, active-controlled, open-label, trial (NCT03043872). The evaluation was based on the comparison of patients randomized to durvalumab plus chemotherapy vs. chemotherapy alone. The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR), per RECIST v1.1.

Median OS was 13.0 months (95% CI: 11.5, 14.8) in the durvalumab plus chemotherapy arm compared with 10.3 months (95% CI: 9.3, 11.2) in the chemotherapy alone arm (hazard ratio 0.73; 95% CI: 0.59, 0.91; p=0.0047).

Investigator-assessed PFS (96% of total planned events) showed a HR of 0.78 (95% CI: 0.65, 0.94), with median PFS of 5.1 months (95% CI: 4.7, 6.2) in the durvalumab plus chemotherapy arm and 5.4 months (95% CI: 4.8, 6.2) in the chemotherapy alone arm. The investigator-assessed confirmed ORR was 68% (95% CI: 62%, 73%) in the durvalumab plus chemotherapy arm and 58% (95% CI: 52%, 63%) in the chemotherapy alone arm.

The most common adverse reactions (≥20%) in patients with ES-SCLC were nausea, fatigue/asthenia, and alopecia.

For ES-SCLC, durvalumab is to be administered prior to chemotherapy on the same day. The recommended durvalumab dose when administered with etoposide and either carboplatin or cisplatin is 1500 mg every 3 weeks prior to chemotherapy and then every 4 weeks as a single agent.

View full prescribing information for IMFINZI.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

FDA granted this application priority review and granted durvalumab orphan drug designation for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

On March 27, 2020 Merrimack Pharmaceuticals, Inc. (the "Company") reported that it has entered into an Asset Purchase Agreement (the "Asset Purchase Agreement") with Celator Pharmaceuticals, Inc. (the "Buyer"), pursuant to which the Buyer agreed to purchase certain assets (the "Transferred Assets") relating to certain of the Company’s preclinical nanoliposome programs (the "Transaction") (Filing, 8-K, Merrimack, MAR 27, 2020, View Source [SID1234555983]). The Company and the Buyer completed the Transaction simultaneously with the execution of the Asset Purchase Agreement. Under the terms of the Asset Purchase Agreement, the Buyer agreed to pay to the Company upfront cash payment of $2.25 million, and also agreed to reimburse the Company for certain specified expenses and to assume certain liabilities with respect to the acquired assets.

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Pursuant to the Asset Purchase Agreement, the Company assigned to the Buyer the previously disclosed intellectual property license agreement among the Company, Ipsen S.A. and Ipsen Biopharm Ltd. (together with Ipsen S.A., "Ipsen"), dated as of April 3, 2017, pursuant to which Ipsen granted the Company licenses to certain patents. On March 27, 2020, the Company and the Buyer also entered into an intellectual property license agreement pursuant to which the Buyer granted to the Company an exclusive license to certain specified know-how included in the Transferred Assets and an exclusive sublicense to the patents which are the subject of the license agreement with Ipsen, in each case to exploit certain specified nanoliposome products.

Both the Company and the Buyer have agreed to indemnify the other for losses arising from certain breaches of the Asset Purchase Agreement and for certain other potential liabilities, subject to certain limitations. The Asset Purchase Agreement also contains customary representations and warranties and covenants. The assertions embodied in those representations and warranties were made solely for purposes of the Asset Purchase Agreement and may be subject to important qualifications and limitations agreed to by the Company and the Buyer in connection with negotiating its terms. Moreover, the representations and warranties may be subject to a contractual standard of materiality that may be different from what may be viewed as material to stockholders or may have been used for the purpose of allocating risk between the Company and the Buyer rather than establishing matters as facts. For the foregoing reasons, no person should rely on such representations and warranties as statements of factual information at the time they were made or otherwise.

The foregoing description of the Asset Purchase Agreement does not purport to be complete and is qualified in its entirety by reference to the terms of the Asset Purchase Agreement, a copy of which is filed as Exhibit 2.1 hereto and incorporated herein by reference.