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 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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On April 3, 2014 Amgen reported that it would end an agreement with GlaxoSmithKline Plc for the marketing of its osteoporosis drug in some regions outside the United States (Press release, Amgen, APR 3, 2014, View Source [SID:1234502170]).

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Amgen said it would take over the marketing of the drug, sold under the brand name Prolia, in most areas under the agreement, including the European Union, Switzerland, Norway, Russia and Mexico, by Dec. 31.

GSK will continue to market the drug in Australia, Amgen said in a regulatory filing.

"GSK and Amgen have reached a mutual agreement to end their existing agreement…," a GSK spokesman said in an emailed statement, adding, "This new arrangement will allow GSK to increase focus on executing important new product launches over the next few years."

Amgen said it would pay GSK $275 million over the rest of the year and reimburse the British drugmaker $15 million for costs incurred during the transition period.

Prolia generated worldwide sales of $744 million in 2013, a 58 percent increase from a year earlier. (link.reuters.com/mux28v)

According to the agreement signed in July 2009, Amgen retained the rights to market the drug in the United States and Canada as a treatment for osteoporosis and other conditions and as a treatment for cancer in Europe, Australia, New Zealand and Mexico.

Amgen also said on Thursday that GSK would continue to market the drug as a treatment for conditions other than osteoporosis in countries such as China, Brazil, India and South Korea.

GSK holds the marketing rights in these regions until 2024, according to Amgen’s annual report.

Amgen is developing the drug in late-stage studies as a treatment for other forms of osteoporosis, including glucocorticoid-induced osteoporosis and male osteoporosis.

The company is also testing the drug, denosumab, as a treatment for cancer-related bone damage.

Denosumab is sold under the brand name Prolia as a treatment for three conditions, including postmenopausal osteoporosis in women at high risk of fracture.

The drug is approved in the United States as a treatment for giant cell tumor of the bone and is sold under the brand name Xgeva. (Reporting by Vrinda Manocha in Bangalore; Editing by Simon Jennings)

On April 2, 2014 Patrys reported that data on the production of PAT-SM6 in an easy-to-grow plant manufacturing system have been published in the leading peer-reviewed journal Proceedings of the National Academy of Sciences (PNAS) (Press release Patrys, APR 2, 2014, View Source [SID:1234500550]). The article titled "Expression and glycoengineering of functionally active hetero-multimeric IgM in plants" is currently available online ahead of a future print edition of the journal.
The study was the result of a research collaboration involving Patrys and the University of Natural Resources and Life Sciences, Vienna, Austria. The collaboration has focused on developing an alternative production system for the manufacture of IgM antibodies (using PAT-SM6) which might significantly reduce production costs while maintaining the quality and functionality of the antibody products.
The study found that relatively high quantities of PAT-SM6 IgM antibody can be made in an easy-to-grow plant manufacturing system. Further, functionality of antibodies very often depends on the attached sugars. It was shown that by modulating the properties of the plants, a process called in planta glycoengineering, this plant expression system can produce fully functional antibodies that are similar to the antibodies generated by the human body. The study demonstrated this novel plant-based process can be successfully applied to generate high yield, functional, human-like IgM antibodies.

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