On April 7, 2014 ImmuNovo and VUmc reproted that they have received CCMO approval for Phase I with hVEGF26-104 vaccine in combination with the RFASE based adjuvant in the Department of Medical Oncology of VUmc Amsterdam headed by Professor Dr Henk Verheul (Press release Immunovo, APR 7, 2014, View Source [SID:1234500781]).
ImmuNovo’s CEO Joost van Bree PhD: ‘We are delighted to make this important step forward.’

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More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF). The VEGF family and their receptors (VEGFR) are receiving increasingly more attention in the field of neoplastic vascularization. VEGF is a powerful angiogenic agent in neoplastic tissues, as well as in normal tissues. Under the influence of certain cytokines and other growth factors, the VEGF family appears in cancerous tissue and the adjacent stroma, and plays an important role in neovascularization.

ImmuNovo and VUmc’s Medical Oncology are working on the development of hVEGF-trunc vaccine in combination with the RFASE based adjuvant for the treatment of cancer. A pro-angiogenic phenotype can be triggered by hypoxia resulting from the increasing distance between the growing tumor cells and the capillaries or from the inefficiency of new vessels. Hypoxia induces the expression of VEGF and its receptor via hypoxia-inducible factor-1α (HIF-1α). Tumor cells feed on the new blood vessels by producing VEGF and then secreting it into the surrounding tissue. Secreted VEGF binds its receptors (VEGFR1 and VEGFR2) on the outer surface of the endothelial cell. Once VEGF binds its receptor, a sequence of events follows that lead to angiogenesis. First, activated vascular endothelial cells produce matrix metalloproteinases (MMPs). MMPs cause degradation of the extracellular matrix (ECM). Next, the endothelial cells migrate into the surrounding tissues and begin to divide. Finally, the endothelial cells differentiate in order to form a functional blood vessel. ImmuNovo is working on the development of hVEGF26-104 vaccine in combination with the RFASE based adjuvant for the treatment of cancer.

The vaccine hVEGF26-104/RFASE consists of a truncated synthetic mimic of the human VEGF protein (hVEGF26-104) emulsified in the adjuvant RFASE. hVEGF26-104 is a new chemical entity based on Pepscan’s and ImmuNovo’s joint proprietary peptide technology. hVEGF26-104 consists of a continuous sequence out of the VEGF protein (residue 26-104) that covers the β1 to β6 and α2 region of the full protein sequence. Correct formation of the cys-knot fold gives both the β1/2/α2/β3 loop (first loop) and the β5/β6 loop (second loop) the correct 3D conformation that is required for a correct mimicry of the VEGF protein surface. In its oxidized form it is used as an antigen for VEGF directing the body’s subsequent polyclonal antibody response towards the active site of the VEGF molecule. The important issue is that antibodies raised against the synthetic molecule hVEGF26-104 strongly cross-react with endogenous VEGF and after binding of the antibodies to endogenous VEGF this hormone will no longer be able to bind to its receptors (VEGFR1 and VEGFR2) and consequently will no longer exert its angiogenic effect.

To enhance the immune response, RFASE will be used as an adjuvant. RFASE belongs to the adjuvant group of sulpholipopolysaccharides.

Preclinical data has already demonstrated the feasibility of this approach.

On April 7, 2014 Deciphera Pharmaceuticals reported the initiation of a Phase 1 clinical trial of its pan-RAF inhibitor LY3009120 (DP-4978), under development in collaboration with Eli Lilly (Press release Deciphera Pharmaceuticals, APR 7, 2014, View Source [SID:1234500371]). The Phase 1 trial will evaluate the safety, tolerability and initial efficacy of LY3009120 in cancer patients. Data demonstrating the preclinical activity of LY3009120 in cancer were recently presented at the New Drugs on the Horizon plenary session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) national meeting, held April 5-9, 2014 in San Diego. LY3009120 emerged from a collaboration between Eli Lilly and Deciphera Pharmaceuticals, LLC. Deciphera received a $6 million development milestone for initiation of Phase 1 studies.
LY3009120 is a small molecule kinase inhibitor that has been shown to inhibit known characterized RAF isoforms, and potentially blocks proliferation in both BRAF and RAS mutant cancer cells. LY3009120 broadly blocks signaling of cellular RAF homo/heterodimers including CRAF containing dimers, thus minimizing paradoxical pathway activation and resistance mechanisms associated with selective BRAF inhibitors. Such paradoxical pathway stimulation is associated with side effects of these selective B-RAF inhibiting drugs, including cutaneous squamous cell carcinoma and other hyperplasias. As a pan-RAF inhibitor, LY3009120 blocks aberrant cancer signaling through RAS protein mutations, known to be prevalent in approximately 30% of all human cancers.

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On April 7, 2014 Myriad Genetics reported that it has submitted the first module of a premarket approval (PMA) application to the Food and Drug Administration (FDA) for the use of BRACAnalysis testing as a companion diagnostic with olaparib (Press release Myriad Genetics, APR 7, 2014, View Source [SID:1234500382]). Olaparib is an investigational, orally active poly-ADP ribose polymerase (PARP) inhibitor being developed by AstraZeneca.
In 2012, Myriad made strides in developing BRACAnalysis as a companion diagnostic by retrospectively genotyping patients in a previously completed Phase 2 study of olaparib.

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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.

On April 4, 2014 Amgen reported top-line results from the primary overall survival (OS) analysis of a Phase 3 trial in melanoma, which evaluated the efficacy and safety of talimogene laherparepvec for the treatment of unresected stage IIIB, IIIC or IV melanoma compared to treatment with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) (Press release Amgen, APR 4, 2014, View Source;p=RssLanding&cat=news&id=1915897 [SID:1234500366]). Results showed that, while the primary end point of durable response rate was met (as previously reported), the secondary endpoint of OS was not met, although there was a strong trend in favor of talimogene laherparepvec (p=0.051). The estimated OS hazard ratio and improvement in median OS were similar to what was previously reported at the interim OS analysis.
Talimogene laherparepvec is an investigational oncolytic immunotherapy designed to selectively replicate in tumors and to initiate an immune response to target cancer that has metastasized, or spread to other areas of the body.
The global, randomized, open-label Phase 3 trial enrolled patients with unresected stage IIIB, IIIC or IV melanoma. Patients were randomized 2:1 to receive either talimogene laherparepvec every two weeks through direct tumor injection or GM-CSF subcutaneously for the first 14 days of each 28-day cycle, for up to 18 months.
The most frequent adverse events observed in this trial were fatigue, chills and pyrexia. The most common serious adverse events include disease progression, cellulitis and pyrexia.

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