On April 7, 2014 MEI Pharma reported the presentation of new pre-clinical data showing the ability of its lead drug candidate Pracinostat to inhibit bladder cancer cell growth and induce activated transcription factor 3 (ATF-3) expression, a potential marker of tumor response (Press release MEI Pharma, APR 7, 2014, View Source [SID:1234500372]). The data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in San Diego.
Previous studies have shown that decreased ATF-3 expression is associated with tumor progression and reduced rate of survival in patients with bladder cancer. This study, conducted in collaboration with the Centre for Cancer Research, MIMR-PHI Institute of Medical Research in Melbourne, Australia, demonstrated that ATF-3 expression is reactivated in bladder cancer cells treated with Pracinostat in vitro. In addition, the study showed that Pracinostat treatment induced reactivation of ATF-3 in xenograft tumor samples.
Poster is available here, View Source .
Ambit Announces Initiation Of Phase 2 Cohort In MD Anderson Sponsored Study Of Quizartinib In AML And High Risk MDS
On April 7, 2014 Ambit Biosciences reported the initiation of the Phase 2 cohort of the MD Anderson Cancer Center-sponsored Phase 1/2 study of quizartinib in combination with either 5-azacitidine or low dose cytarabine for previously untreated FLT3-ITD positive acute myeloid leukemia (AML) patients age 60 or older, or FLT3-ITD positive AML patients 18 years of age or older in first relapse (Press release Ambit Biosciences, APR 7, 2014, View Source [SID:1234500370]).
The trial is being conducted under the principal direction of Jorge Cortes, M.D., of The University of Texas MD Anderson Cancer Center. Dr. Cortes is also the principal investigator of the upcoming Phase 3 QUANTUM-R trial, the Company’s randomized trial comparing quizartinib to standard chemotherapy in FLT3-ITD positive AML patients over the age of 18 who have relapsed from, or are refractory to, frontline chemotherapy, including those patients relapsing following a hematopoietic stem cell transplant (HSCT).
The Phase 2 cohort follows completion of the Phase 1 open-label, two-arm portion which included twelve total patients, six in each arm. Phase 1 included patients who were 18 years of age or older and who had relapsed AML or myelodysplastic syndrome (MDS) and were treated with quizartinib in combination with either 5-azacitidine or cytarabine. Up to a total of 64 patients are planned to be treated in this clinical trial. The regimen was found to be generally well tolerated, and there were no early mortalities. Despite limited follow up, evidence of anti-leukemia activity has been observed in a number of patients. Full results, including data from the Phase 2 cohort, are expected to be submitted to a medical conference in 2014.
8-K – Current report
On April 6, 2014 Agios Pharmaceuticals announced that data from its lead, first-in-class program AG-221 will be presented at a Clinical Trials Symposium titled “Novel Immune and Targeted Therapies for Hematological Malignancies and Solid Tumors” at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2014 (Filing 8K, Agios Pharmaceuticals, APR 7, 2014, View Source [SID:1234500369]). These preliminary data demonstrate the clinical activity, tolerability and unique mechanism of action of AG-221 in patients with advanced hematologic malignancies with an isocitrate dehydrogenase-2 (IDH2) mutation.
The preliminary data to be presented by Dr. Stein show that in the first two cohorts of the Phase 1 trial of AG-221 (NCT01915498), six of seven evaluable patients had objective responses, including three complete remissions (CR) and two complete remissions with incomplete platelet recovery (CRp). AG-221 also substantially lowered plasma levels of the oncometabolite 2-hydroxyglutarate (2HG) with a favorable exposure profile and good tolerability to date.
AG-221 is an orally available, selective, potent inhibitor of the mutated IDH2 protein. As of March 20, 2014, this ongoing Phase 1 dose-escalation study had enrolled 22 patients with acute myeloid leukemia (AML) or myelodysplastic syndrome, all of whose cancers harbored an IDH2 mutation. Patient cohorts received AG-221 administered at 30 mg twice a day, 50 mg twice a day, 75 mg twice a day or 100 mg once a day.
Sun Pharma to acquire Ranbaxy in a
US$ 4 billion landmark transaction
On April 6, 2014 Sun Pharmaceutical Industries Ltd. (Reuters: SUN.BO, Bloomberg: SUNP IN, NSE: SUNPHARMA, BSE: 524715) and Ranbaxy Laboratories Ltd (Reuters: RANB.BO, Bloomberg: RBXY IN, NSE: RANBAXY, BSE: 500359) reported that they have entered into definitive agreements pursuant to which Sun Pharma will acquire 100% of Ranbaxy in an all-stock transaction (Press release, Sun Pharma, APR 6, 2014, View Source [SID:1234513419]). Under these agreements, Ranbaxy shareholders will receive 0.8 share of Sun Pharma for each share of Ranbaxy. This exchange ratio represents an implied value of `457 for each Ranbaxy share, a premium of 18% to Ranbaxy’s 30-day volume-weighted average share price and a premium of 24.3% to Ranbaxy’s 60-day volume-weighted average share price, in each case, as of the close of business on April 4, 2014.
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The combination of Sun Pharma and Ranbaxy creates the fifth-largest specialty generics company in the world and the largest pharmaceutical company in India. The combined entity will have operations in 65 countries, 47 manufacturing facilities across 5 continents, and a significant platform of specialty and generic products marketed globally, including 629 ANDAs. On a pro forma basis, the combined entity’s revenues are estimated at US$ 4.2 billion with EBITDA of US$ 1.2 billion for the twelve month period ended December 31, 2013. The transaction value implies a revenue multiple of 2.2 based on 12 months ended December 31, 2013.
Dilip Shanghvi, Managing Director of Sun Pharma said, "Ranbaxy has a significant presence in the Indian pharma market and in the US where it offers a broad portfolio of ANDAs and first-to-file opportunities. In high-growth emerging markets, it provides a strong platform which is highly complementary to Sun Pharma’s strengths. We see tremendous growth opportunities and are excited with the prospects to create lasting value for both our shareholders through a successful combination of our franchises." 2
"We believe this transaction brings significant value to all Ranbaxy shareholders. Sun Pharma has a proven track record of creating significant long-term shareholder value and successfully integrating acquisitions into its growing portfolio of assets. We are confident that Sun Pharma is the ideal partner to help us realize our full potential and are excited to participate in future value creation opportunities," stated Arun Sahwney, Managing Director and Chief Executive Officer of Ranbaxy.
The proposed transaction has been unanimously approved by the Boards of Directors of Sun Pharma, Ranbaxy, and Ranbaxy’s controlling shareholder, Daiichi Sankyo. Ranbaxy’s board and Sun Pharma’s board have recommended approval of the transaction to their respective shareholders.
Diversified Specialty and Generic Portfolios
The combination will create a large specialty pharmaceutical company with strong capabilities in developing complex products and exploiting first to file opportunities. A combined Sun Pharma and Ranbaxy will have a diverse, highly complementary portfolio of specialty and generic products targeting a spectrum of chronic and acute treatments. The combined business will have a strong portfolio of specialty and generic products marketed globally, including 445 ANDAs. Additionally, the combination will create one of the leading dermatology platforms in the United States.
Enhanced Global Market Presence
The combination creates the fifth-largest generic company in the world and the largest pharmaceutical entity in India. The combined entity will have 47 manufacturing facilities across 5 continents. The transaction will combine Sun Pharma’s proven complex product capabilities with Ranbaxy’s strong global footprint, leading to significant value creation opportunities. Additionally, the combined entity will have increased exposure to emerging economies while also bolstering Sun Pharma’s commercial and manufacturing presence in the United States and India. It will have an established presence in key high-growth emerging markets. In India, it will be ranked No. 1 by prescriptions amongst 13 different classes of specialist doctors.
Financially Compelling Transaction
The acquisition is expected to be accretive to Sun Pharma’s cash earnings per share in the first full year. Additionally, Ranbaxy’s shareholders will participate in the value creation of the combined company through their ownership of Sun Pharma shares. Sun Pharma expects to realize revenue and operating synergies of US$ 250 million by third year post closing of the transaction. These synergies are expected to result primarily from topline growth, efficient procurement and supply chain efficiencies. As part of the transaction, Sun Pharma intends to leverage the human capital that has supported both companies, in order to drive future growth.
Transaction Details
Under the agreements, Ranbaxy shareholders will receive 0.8 shares of Sun Pharma for each share of Ranbaxy. This exchange ratio represents an implied value of Rs 457 for each Ranbaxy share, a premium of 18% to Ranbaxy’s 30-day volume-weighted average share price and a premium of 24.3% to Ranbaxy’s 60-day volume-weighted average share price, in each case, as of the close of business on April 4, 2014.The transaction has a total equity value of approximately US$ 3.2 billion.
The transaction is expected to represent a tax-free exchange to Ranbaxy shareholders, who are expected to own approximately 14% of the combined company on a pro forma basis. Upon closing, 3 Daiichi Sankyo will become a significant shareholder of Sun Pharma and will have the right to nominate one director to Sun Pharma’s Board of Directors.
Ranbaxy has recently received a subpoena from the United States Attorney for the District of New Jersey requesting that Ranbaxy produce certain documents relating to issues previously raised by the FDA with respect to Ranbaxy’s Toansa facility. In connection with the transaction, Daiichi Sankyo has agreed to indemnify Sun Pharma and Ranbaxy for, among other things, certain costs and expenses that may arise from the subpoena.
Approvals and Timing
The transaction will need approval by majority in number representing 75% in value of the shares present and voting at the shareholder meetings of each of Sun Pharma and Ranbaxy. Both Daiichi Sankyo (which holds approximately 63.4% of the outstanding shares of Ranbaxy) and promoters of Sun Pharma (who hold approximately 63.7% of the outstanding shares thereof), have irrevocably agreed to vote in favor of the transaction.
Additionally, the closing of the transaction will be subject to customary closing conditions, including approval by the Indian Central Government, approval by the High Courts of Gujarat and Punjab and Haryana, approval by the Competition Commission of India and expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvement Act in the United States. Pending approvals, Sun Pharma anticipates that the transaction will close by the end of calendar year 2014.
Pfizer’s Novel CDK 4/6 Inhibitor Palbociclib plus Letrozole Significantly Prolonged Progression-Free Survival in Patients with Advanced Breast Cancer
On April 6, 2014 Pfizer reported detailed results from the PALOMA-1 study (NCT00721409), a randomized Phase 2 study of palbociclib (PD-0332991) in combination with letrozole (Press release Pfizer, APR 6, 2014, View Source [SID:1234500368]). PALOMA-1 achieved its primary endpoint by significantly prolonging progression-free survival (PFS) compared with letrozole alone in post-menopausal women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer. For women treated with the combination of palbociclib plus letrozole, the median PFS was 20.2 months, a statistically significant improvement compared to the 10.2 months of PFS in women who received letrozole alone (HR=0.488 [95% CI: 0.319, 0.748]; p=0.0004). These data at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2014 in San Diego (Abstract #CT101).
Final results for the secondary efficacy endpoints of duration of treatment and clinical benefit rate demonstrated superiority in the palbociclib plus letrozole arm compared to the letrozole-only arm. Per the PALOMA-1 trial protocol, an initial assessment of overall survival (OS), a secondary endpoint, was also performed. Based on the events at the time of the assessment, a median OS of 37.5 months was observed in the combination arm versus 33.3 months for those who received letrozole alone, a difference of 4.2 months (HR = 0.813, 95% CI: 0.492, 1.345). This OS observation at the time of final PFS analysis was not statistically significant. A follow-up OS analysis will be conducted following the accrual of additional events.
The combination of palbociclib and letrozole was generally well-tolerated and the safety profile of the combination was consistent with previously reported data. The most common adverse events in the palbociclib plus letrozole arm were neutropenia (a decrease of the neutrophil count), leukopenia, fatigue and anemia. The neutropenia observed with the combination in this study was non-cumulative and clinically manageable. No cases of febrile neutropenia were reported in either arm of the study. Neutropenia is an on-target, anti-proliferative side effect of palbociclib and signifies inhibition of CDK4 and its effect on bone marrow.
Palbociclib received Breakthrough Therapy designation from the United States Food and Drug Administration (FDA) in April 2013, for the initial treatment of women with advanced or metastatic ER+, HER2- breast cancer. This designation was based on interim data from the PALOMA-1 trial. Pfizer continues to work with the FDA and other regulatory authorities to define the appropriate regulatory path forward for palbociclib.