On October 1, 2015 Merck, a leading company for innovative and top-quality high-tech products in healthcare, life science and performance materials, reported an update on key immuno-oncology and oncology research and development projects, illustrating visible progress across all pipeline stages (Press release, Merck KGaA, OCT 1, 2015, View Source [SID:1234507627]).

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Among others, the company announced that it started investigating a novel, potential first-in-class bi-functional immunotherapy in clinical trials with the potential to offer an alternative therapy to anti-PD-1/anti-PD-L1 and other immunotherapies. Merck also showed good progress in its avelumab development program, which it is driving together with Pfizer. If successful, the companies expect the first potential commercial launch for avelumab in 2017, and are working toward at least one additional potential launch per year through 2022.

"We have a focused and differentiated pipeline in immuno-oncology, oncology and immunology that has the potential to make a substantial difference in the lives of patients," said Luciano Rossetti, Head of Global R&D at the biopharmaceutical business, Merck Serono, in an investor call following presentations at this year’s European Cancer Congress (ECC) in Vienna, which took place Sept. 25 – 29. "Our priorities include accelerating high-priority programs and ensuring launch success to secure long-term growth."

Merck has been rebuilding its research and development organization over the past four years, with new leadership and improved R&D operating model. Rigorous project prioritization, increased efficiency and more agile decision making has allowed the company to progress its R&D productivity. Merck is on track to deliver a continuous flow of innovative specialty medicines in areas of high unmet medical need, including several promising earlier stage assets.

Merck expects more than 3,000 patients treated with Avelumab by 2016
Regarding the avelumab clinical development program, Merck said it is on track to meet its 2015 goals of collaborating on up to 20 clinical programs, including initiating up to six pivotal trials. By the end of 2016, Merck expects more than 3,000 patients to be treated across more than 15 tumor types and lines of therapy.

In September, the US Food and Drug Administration (FDA) granted Orphan Drug Designation (ODD) for avelumab in Merkel cell carcinoma (MCC). MCC is a very rare disease in which malignant (cancer) cells form in the skin. This orphan drug designation does not guarantee market approval, but could imply seven years of market exclusivity upon approval and other incentives.

Beyond avelumab, Merck today also disclosed details on other key immuno-oncology programs aimed at helping patients fight difficult-to-treat cancers. These projects include its CAR-T/Intrexon T-cell therapies, which could form the next cornerstone of cancer immunotherapy. The innovative chimeric antigen receptor t-cell treatments modulate the immune system’s natural ability to fight tumors.

In addition, Merck gave details on its investigational molecule, M7824, for which it has initiated and treated the first patient in a phase I, open-label, multiple-ascending clinical trial, targeting to enroll 106 patients. This potential first-in-class bi-functional immunotherapy is designed to simultaneously block two immuno-inhibitory pathways that are commonly used by cancer cells to evade the immune system, thereby controlling tumor growth by restoring and enhancing anti-tumor immune responses.

"The initiation of the M7824 clinical trial marks the next milestone in Merck’s strategy to build an innovative portfolio of cancer immunotherapies that may work synergistically to potentially maximize patient benefit," Rossetti said. "This is the first phase I trial industry-wide for this class of molecule and we expect to see key data during the second half of 2016."

In the broader field of oncology, Merck reiterated that it expects to have key data on its oncology treatment evofosfamide, a hypoxia-activated pro drug currently tested in clinical phase III trials in soft tissue sarcoma and pancreatic cancer, during the fourth quarter of 2015. In addition, the company disclosed details of its tepotinib program, an investigational small molecule inhibitor of the c-met receptor tyrosine kinase, as well as its DNA-PK inhibitor M3814, which has the potential for a first-in-class orally administered selective DNA-PK inhibitor.

The webcast can be followed live here (starting at 14:00 CEST), the presentation will be available at the Investor Relations section of our website.

On October 1, 2015 XOMA Corporation (Nasdaq:XOMA), a leader in the discovery and development of therapeutic antibodies, reported it has exclusively licensed the global development and commercialization rights to its anti-transforming growth factor-beta (TGFb) antibody program to Novartis. Under the terms of the agreement, XOMA will receive $37.0 million in the form of an upfront payment and is eligible to receive up to $480.0 million if all development, regulatory, and commercial milestones are met (Press release, Xoma, OCT 1, 2015, View Source [SID:1234507625]).

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In addition, XOMA is eligible to receive royalties on product sales that range from the mid-single digits to the low double digits. In connection with this license agreement, Novartis has agreed to extend the maturity date on the approximately $13.5 million of outstanding debt under the secured note agreement, which bears interest at the six-month LIBOR plus 2% (currently 2.53%), to September 30, 2020. XOMA has also agreed to reduce the royalty rate to XOMA associated with Novartis’ clinical stage anti-CD40 antibodies.

"XOMA and Novartis have worked closely together for several years to develop new product candidates. When they expressed interest in our anti-TGFb program, we knew Novartis was the best company to bring this exciting potential therapy to the patients whom it may help," stated John Varian, Chief Executive Officer of XOMA. "Novartis is recognized as a leader in oncology, where an anti-TGFb molecule has real potential either as monotherapy or in combination with other therapeutic options.

"We had said we did not plan to raise equity capital at our recent stock price in order to fund the development of our very exciting endocrine portfolio. With this non-dilutive liquidity of essentially $50.5 million, we currently project this capital, in combination with our planned cost savings measures, will fund operations into 2017. We remain on track to begin our XOMA 358 Phase 2 clinical program this fall and fully anticipate we will have the data from these studies during that timeframe," concluded Mr. Varian.

About TGF-beta

Transforming growth factor-beta (TGFb) is a potent immune suppressive cytokine that is involved in many cellular processes, including inhibition of cell growth and immune suppression. While TGFb is essential for normal tissue homeostasis, elevated levels of TGFb may drive the progression of numerous diseases, including advanced metastatic cancer and fibrosis.

Three isoforms of TGFb exist in humans: TGFb1, 2 and 3. TGFb1 is overexpressed in many cancers and is believed to increase the likelihood of metastasis. Inhibiting TGFb1 and 2 while sparing TGFb3 may reduce tumor-protecting regulatory T cells, while allowing for the development of cytotoxic immune responses enhanced by TGFb3, improving the therapeutic index of TGFb inhibitors. Given the role of the TGFb pathway in cancer, it has become an attractive target for cancer drug development.

About XOMA 089

Discovering the TGFb antibody program was made possible because of XOMA’s proprietary antibody discovery technology platform. XOMA 089 is a fully human, high-affinity, late preclinical monoclonal antibody that neutralizes TGFb1 and 2 while sparing TGFb3. Data have shown this compound to be both active against tumor growth in preclinical models of head and neck cancer as well as breast cancer and breast cancer metastasis. Preclinical data also suggest that it may be synergistic with PD1 inhibition and work highlighting these results was recently presented at the 2015 FASEB meeting on the TGFb Superfamily: Signaling in Development and Disease. XOMA has made significant progress regarding this lead compound on both the understanding of its activity, mechanism of action, as well as preclinical toxicology and manufacturing. Other antibodies included in this license agreement inhibit TGFb1, which may be a more appropriate approach to certain indications. These antibodies have potential in immuno-oncology either as a monotherapy and may be particularly amenable to combination therapies, especially with immune checkpoint inhibitors.

On October 1, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, and DNAtrix reported they have entered into an oncology clinical study collaboration to evaluate the efficacy and safety of DNX-2401, DNAtrix’s oncolytic immunotherapy, in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in a Phase 2, multi-centered study of patients with recurrent glioblastoma, the most aggressive form of brain cancer for which there is no cure (Press release, Merck & Co, OCT 1, 2015, View Source [SID:1234507624]).

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DNX-2401 is a conditionally replicative oncolytic adenovirus designed to specifically target cells defective in the Retinoblastoma (Rb) pathway, which is present in many cancers. Several DNX-2401 clinical studies have demonstrated a favorable safety profile and strong tumor-killing potential in patients with recurrent glioblastoma. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 and PD-L2. KEYTRUDA is currently approved in the United States for certain types of advanced metastatic melanoma.

"We are excited to enter into this important collaboration with Merck as we investigate the potential anti-tumor effect that combining our two immunotherapies – DNX-2401 and KEYTRUDA – may offer patients with this aggressive disease," said Frank Tufaro, Ph.D., chief executive officer of DNAtrix.

"The collaboration with DNAtrix further strengthens our efforts to progress the field of immuno-oncology and identify potential combinations that will significantly advance the care of people with cancers for which there have been few advancements," said Dr. Eric Rubin, vice president and therapeutic area head, oncology early-stage development, Merck Research Laboratories. "We look forward to studying the potential synergistic effects that combining DNX-2401 and KEYTRUDA could have in the treatment of patients with recurrent glioblastoma."

The agreement is between DNAtrix and Merck, through a subsidiary. Additional details of the collaboration were not disclosed.

About Glioblastoma

Glioblastoma is a type of glioma, which are tumors that arise from glial cells, or supportive brain cells that help to keep neurons in place and functioning well. Glioblastoma is highly malignant because the cells reproduce quickly and are supported by a large network of blood vessels. While glioblastoma rarely spreads elsewhere in the body, these tumors arise from normal brain cells, so it is easy for them to invade and live within normal brain tissue. Glioblastoma represents 17 percent of all primary brain tumors and 54 percent of all gliomas.

About DNX-2401

DNX-2401 is an investigational oncolytic immunotherapy designed to treat high grade gliomas. Upon tumor injection, DNX-2401 sets off a chain reaction of tumor cell killing by selectively replicating within glioma cells (but not normal cells), causing tumor destruction and further spread of the oncolytic virus to adjacent tumor cells. This process can also trigger an anti-tumor immune response. DNX-2401 is currently being investigated in several clinical studies and has been well tolerated in all settings. Compelling results from Phase I clinical studies in recurrent glioblastoma indicate that DNX-2401 can (1) replicate in human brain tumors for a period of weeks to months (2) trigger immune cell infiltration into the tumor (3) cause ongoing tumor destruction detectable by MRI and (4) induce durable responses to therapy. In these studies, patient survival has been prolonged in a subset of patients, including in those achieving a complete response.

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA in cases of severe hyperglycemia until metabolic control is achieved.

Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant immune-mediated adverse reactions occurred in patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, severe dermatitis including bullous pemphigoid, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.