Industry Update: the Latest Developments in Therapeutic Delivery

Abstract

The present Industry Update covers the period 16 May to 15 June 2011, with information sourced from company press releases, media newswires, regulatory agencies and relevant patent offices. This period was dominated to a significant extent by events taking place at the 47th Annual Meeting of the American Society of Clinical Oncology held on 3–7 June in Chicago (IL, USA) where results from some of the larger studies were published concomitantly in The New England Journal of Medicine. Notable amongst these were the positive results of the Roche Phase III BRIM3 study on vemurafenib subjects with BRAF V600 mutation-positive metastatic melanoma. The announcement that Roche and Bristol-Myers Squibb have entered into an agreement to evaluate Yervoy™, currently the only CTLA-4 inhibitor approved for metastatic melanoma, in combination with vemurafenib is further good news. In terms of journal publications, an exceptional study led by researchers at The University of Texas MD Anderson Cancer Center (TX, USA) was published in the Journal of Clinical Oncology, in which a lymphoma vaccine, uniquely tailored for each patient, was shown to extend disease-free survival by 14 months, with signs of an even better response for patients with a specific biological marker.

Business development

Acquisitions & mergers

Merck & Inspire Pharmaceuticals

On 16 May, Merck announced that it had completed its acquisition of Inspire Pharmaceuticals, Inc., a specialty pharmaceutical company focused on developing and commercializing ophthalmic products, for US$5.00 per share in cash. The $430 million transaction was originally signed in April 2011 [201,202]. The acquisition has resulted in the merging of Monarch Transaction Corp., a wholly owned subsidiary of Merck, with and into Inspire, with Inspire surviving as a new business unit of its parent company.

Development & manufacturing agreement

Radius & 3M

On 24 May, Radius Health, Inc. and 3M Drug Delivery Systems announced an agreement to collaborate on the development of a transdermal delivery option of BA058, Radius‘ novel, proprietary parathyroid hormone-related protein analog, for the treatment of osteoporosis [203]. The BA058 Microneedle Patch will use 3M‘s patented Microstructured Transdermal System microneedle technology to administer BA058 through the skin, as an alternative to subcutaneous injection. The BA058 patch is expected to combine the ease, convenience and self-administration attributes of a transdermal patch with the speed and efficiency of a traditional injection. Terms of the agreement were not disclosed. “Poor adherence to prescribed osteoporosis therapy is a common and serious problem. Patients who drop their treatment unknowingly place themselves at high risk of fracture, which exacts an enormous toll in terms of human and economic cost”, commented C Richard Lyttle, President and CEO of Radius, “by providing a more convenient treatment alternative to injections that can promote improved compliance, the BA058 Microneedle Patch will be well-positioned to drive expansion of the osteoporosis market”. Radius‘ BA058 Microneedle Patch product is currently undergoing Phase I clinical studies. The company‘s recently concluded Phase II human testing of an injectable form of BA058 showed that BA058 significantly increased bone mineral density at the lumbar spine and femoral neck (a common osteoporotic fracture site located in the hip joint) after 6 months of therapy, with greater bone mineral density gains relative to Forteo^®, the reference drug used in the study. “We are pleased to partner with Radius, a company with deep domain expertise in osteoporosis”, commented Jim Vaughan, Division Vice President and General Manager of 3M Drug Delivery Systems Division. “This collaboration continues the validation of 3M‘s microneedle patch technology and provides an excellent example of how our technology adds value for promising new therapeutic agents. We look forward to merging 3M‘s innovative microneedle technology with Radius‘ promising bone-building agent to bring this important new therapy to market”.

Licensing & collaboration agreements

Sanofi & Glenmark Pharmaceuticals

On 16 May, Sanofi announced that it had entered into a license agreement with Glenmark Pharmaceuticals SA, a wholly owned subsidiary of Glenmark Pharmaceuticals Ltd., India, for the development and commercialization of GBR500, a novel monoclonal antibody to treat Crohn‘s disease and other chronic autoimmune diseases [204,205]. GBR500 is an antagonist of the VLA-2 (α2-β1) integrin. It is a first-in-class therapeutic monoclonal antibody for chronic autoimmune disorders. GBR500 has completed a Phase I dosing study in the USA and has been well tolerated with a good pharmacokinetic profile. Under the terms of the agreement, Glenmark will receive an upfront payment of $50 million of which $25 million will be paid upon closing of the transaction, with $25 million contingent upon Sanofi‘s positive assessment of certain data to be provided by Glenmark. In addition, Glenmark could receive potential success-based development, regulatory and commercial milestone payments. The total of these payments could reach $613 million. Furthermore, Glenmark is eligible to receive double-digit royalties on net sales of products commercialized under the license. Sanofi will have exclusive marketing rights in North America, Europe, Japan, Mexico, Argentina, Chile and Uruguay, and co-marketing or co-promotion rights in Brazil, Russia, Australia and New Zealand. Glenmark will retain exclusive marketing rights in India and the rest of the world. VLA-2 integrin is a receptor that plays a role in lymphocyte adhesion at inflammation sites and in the downstream release of inflammatory cytokines. By targeting VLA-2, GBR500 can play a selective and critical role in treating inflammatory conditions. The goal of the partnership will be to advance GBR500 with the hope of providing better medicines for chronic inflammatory disorders.

AVEO Pharmaceuticals & Centocor Ortho Biotech Pharmaceuticals

On 31 May, AVEO Pharmaceuticals, Inc. announced it had entered into an exclusive license agreement with Centocor Ortho Biotech, Inc. for the worldwide development and commercialization of AVEO‘s internally discovered antibodies targeting the Recepteur d‘Origine Nantais (RON) receptor [206]. The RON pathway is believed to be involved in several aspects of cancer development including regulation of tumor growth, survival and metastasis, and bone disruption. In preclinical studies, AVEO‘s proprietary anti-RON antibodies have demonstrated strong antitumor activity. AVEO is initially receiving $15 million. Under the terms of the license agreement, AVEO will receive the first half of this amount as an up-front payment from Centocor Ortho Biotech. Through a separate equity private placement and stock purchase agreement, the second half will be received through the sale of newly issued shares of AVEO common stock to an affiliate of Centocor Ortho Biotech, Johnson & Johnson Development Corporation. Under the license agreement, AVEO is eligible to receive up to $540 million in milestone payments based upon the achievement of specified development, regulatory and commercialization goals. Upon commercialization, AVEO will be entitled to a tiered, double-digit royalty on net sales worldwide. Centocor Ortho Biotech will be responsible for all clinical development, manufacturing, and commercialization activities and costs. Centocor Ortho Biotech will also fund certain research conducted by AVEO, including translational research studies using its Human Response Platform™ to identify biomarkers for patients most likely to benefit from treatment with RON-targeted antibodies. Elan Ezickson, Executive Vice President and Chief Business Officer of AVEO commented, “We believe that the RON pathway is a promising novel target for combating cancer growth and progression. This license agreement highlights the broad potential of our unique monoclonal antibody R&D capabilities and further supports AVEO‘s strategy to maximize our proprietary cancer biology platform to build a sustainable cancer therapeutics company”. RON, or MST1R, receptor tyrosine kinase is a member of the c-MET RTK family. Published research has shown that overexpression of RON has been observed in multiple solid tumor types including breast, colorectal, non-small-cell lung, glioblastoma multiforme, prostate, pancreatic, ovarian and bladder cancers, and is associated with disease progression and metastasis. AVEO‘s research of RON biology has been aided by its novel, genetically defined, in vivo murine tumor models and related bioinformatics tools. In AVEO‘s proprietary in vivo models, both wild-type RON and RON160 have been shown to potently drive tumor growth, with AVEO‘s anti-RON antibodies demonstrating strong antitumor activity. AVEO has also utilized its unique bioinformatics tools for biomarker research and to generate a RON pathway gene index that quantifies the level of RON pathway activation. AVEO has used this index to identify human tumor cell lines with high RON pathway activity, and has demonstrated in preclinical models that the inhibition of RON function by anti-RON antibodies potently inhibited tumor cell growth and survival. These studies provided preclinical evidence of the potential benefits of RON inhibition and identified a genetic context in which RON inhibition may have therapeutic benefit. AVEO‘s lead product candidate, tivozanib, is currently being investigated in a global, randomized Phase III clinical trial called TIVO-1, comparing tivozanib to sorafenib in patients with advanced renal cell carcinoma, as well as additional clinical studies in other solid tumor types. AVEO‘s second most advanced product candidate, ficlatuzumab (AV-299), is a potent, functional anti-HGF/c-MET pathway antibody that is currently in Phase II clinical development. AVEO‘s proprietary Human Response Platform is designed to offer the company a unique advantage in cancer drug development and has provided a discovery engine for multiple therapeutic targets. This approach has resulted in a promising pipeline of monoclonal antibodies against novel targets including HGF, ErbB3, RON, Notch and FGFR.

Bristol-Myers Squibb & Roche

On 2 June, Bristol-Myers Squibb announced it had entered into a clinical collaboration agreement with Roche to evaluate the utility of Bristol-Myers Squibb‘s CTLA-4 inhibitor, Yervoy™ (ipilimumab), in combination with Roche‘s investigational oral BRAF inhibitor, vemurafenib, in treating patients with a specific type of metastatic melanoma [207,208]. Under the agreement, the two companies will conduct a Phase I/II study to evaluate the safety and efficacy of the combination. If appropriate, the companies may conduct further development of the combination. The agreement represents an important cross-company collaboration wherein the potential role of a combination regimen in the treatment of metastatic melanoma, the deadliest and most aggressive form of skin cancer, can be assessed. The US FDA approved ipilimumab for the treatment of patients with unresectable (inoperable) or metastatic melanoma on 25 March 2011 following its performance in a recent Phase III study [209]. Ipilimumab is a recombinant, human monoclonal antibody that blocks the cytotoxic T-lymphocyte antigen-4 (CTLA-4), a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab in patients with melanoma is indirect, possibly through T-cell-mediated antitumor immune responses. The recommended dose of ipilimumab is 3 mg/kg administered intravenously over 90 min every 3 weeks for a total of four doses. Vemurafenib is an investigational, oral, small molecule that is designed to selectively inhibit a cancer-driving mutated form of the BRAF protein. Vemurafenib is being co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, a member of the Daiichi Sankyo Group.

Affectis Pharmaceuticals & Merck Serono

On 8 June, Affectis Pharmaceuticals announced that an exclusive licensing agreement was signed with Merck Serono, a division of Merck KGaA, for the development and commercialization of oral compounds targeting P2X7 receptors [210]. These receptors are believed to be involved in neuroinflammation observed in some neurodegenerative diseases. Under the terms of the agreement, Merck Serono will have worldwide exclusive rights to develop and commercialize selected compounds. The contract also includes a research collaboration focusing on P2X7 antagonist optimization. Affectis will receive EUR€2.4 million in upfront payment and research funding, and could receive up to €277 million in milestones for the first three products to come out of the collaboration, as well as undisclosed royalties. Manfred Ruediger, CEO of Affectis Pharmaceuticals, commented, “This agreement validates Affectis‘ strategy to focus on small molecules that potentially target the neuroinflammatory aspect of some neurodegenerative diseases. We look forward to collaborating with Merck Serono, an industry leader in the field”. Michael Boes, CSO of Affectis added, “Affectis‘ chemistry expertise puts special emphasis on brain penetration, which supports our development of oral P2X7 antagonists for the potential treatment of CNS diseases”. Bernhard Kirschbaum, Executive Vice President for Global Research and Development at Merck Serono commented, “We are pleased to announce this collaboration with Affectis Pharmaceuticals, a company with robust experience in drug discovery in the CNS area. This partnership with Affectis reflects our long-term commitment to developing innovative treatments for neurodegenerative diseases, where unmet medical need still remains”. P2X7 is an ATP-gated ion channel receptor, which is essential for the maturation and release of the proinflammatory cytokines. P2X7 is found on brain cells, which are activated by high levels of ATP in conditions of neuroinflammation.

Merck & Hanwha Chemical Corporation

On 13 June, Merck and Hanwha Chemical Corporation announced that they had entered into an exclusive global agreement to develop and commercialize a candidate biosimilar form of the TNF inhibitor Enbrel^® (etanercept) [211]. Under the terms of the agreement, the parties will work together to develop and commercialize HD203, a candidate biosimilar form of etanercept developed by Hanwha. Merck will conduct clinical development and be responsible for manufacturing. In addition, upon marketing approval, Merck will commercialize HD203 globally, except for in Korea and Turkey where Hanwha has retained marketing rights. In return, Hanwha receives an upfront payment from Merck and will be eligible for additional payments associated with milestones for technology transfer and regulatory progress as well as tiered royalties on sales. Specific financial terms of the agreement were not disclosed. HD203 is currently being evaluated in Korea, in a randomized double-blind active-controlled parallel group Phase III clinical trial to evaluate the equivalence in efficacy and safety of HD203 and etanercept in combination with methotrexate in patients with rheumatoid arthritis. Clinical trials are yet to be initiated in the USA.

Vertex & Alios BioPharma

On 13 June, Vertex Pharmaceuticals, Inc. and Alios BioPharma, Inc. announced an exclusive worldwide licensing agreement that will add two distinct nucleotide analogues to Vertex‘s hepatitis C portfolio [212]. The compounds discovered by Alios, known as ALS-2200 and ALS-2158, are highly potent nucleotide analogues that, in vitro, appear to have a high barrier to drug resistance and the potential to be dosed once daily. Both compounds are designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. Each compound has its own unique mechanism of action, which supports the potential for developing these compounds together as a dual nucleotide regimen and as part of combination therapy regimens with Vertex‘s other approved and investigational medicines for chronic hepatitis C, including Incivek™ (telaprevir), a hepatitis C protease inhibitor recently approved by the FDA [213], and VX-222, an investigational hepatitis C non-nucleoside polymerase inhibitor. Data from in vitro studies demonstrated that both ALS-2200 and ALS-2158 had a synergistic effect when combined together and with telaprevir and VX-222. Additionally, both compounds showed antiviral activity across all genotypes of the hepatitis C virus, including genotypes more prevalent outside of the USA. The addition of these compounds provides Vertex with multiple opportunities to develop potentially, new, all-oral combination regimens for chronic hepatitis C; ALS-2200 and ALS-2158 are expected to enter clinical development later this year. As part of the agreement, Alios will receive a $60 million up-front payment from Vertex for the worldwide rights to ALS-2200 and ALS-2158. Vertex is responsible for development costs related to ALS-2200 and ALS-2158 and will also provide research funding to Alios who, in addition, will be eligible to receive R&D milestone payments up to $715 million if both compounds are approved. Vertex expects to pay approximately $35 million in development milestones in 2011. Alios is eligible to receive up to $750 million in sales milestones on sales of all approved medicines under the collaboration; the agreement also includes tiered royalties on product sales.

Regulatory news & approvals

Product approvals

Edurant™ (rilpivirine)

On 20 May, Johnson & Johnson announced that the FDA has approved Edurant (rilpivirine) tablets for use in combination with other antiretroviral agents in the treatment of HIV-1 in adults who have never taken HIV therapy [214,215]. Rilpivirine is a second-generation non-nucleoside reverse transcriptase inhibitor that works by blocking HIV viral replication and reducing viral load. The safety and effectiveness of rilpivirine is based on 48-week data from two Phase III clinical trials (ECHO and THRIVE) with 1368 adult subjects with HIV infection, and from a 96-week (with extension to 192 weeks) Phase IIb trial. Patients had not received prior HIV therapy and were selected to receive treatment with rilpivirine or efavirenz, another FDA-approved non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection. Both drugs were given in combination with other antiretroviral drugs. Rilpivirine was as effective as efavirenz in lowering viral load. In the rilpivirine and efavirenz groups, 83 and 80% of subjects, respectively, had undetectable amounts of HIV in their blood following 48 weeks of treatment.

Sutent^® (sunitinib malate)

On 20 March, Pfizer, Inc. announced that the FDA has approved Sutent (sunitinib malate) as the first anti-VEGF therapy to treat progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease [216]. Pancreatic neuroendocrine tumors is a rare cancer reported in two to four people per million annually worldwide [1]. The approval represents the third disease indication for sunitinib malate, which was approved by the FDA in 2006 for the treatment of patients with advanced kidney cancer and imatinib-resistant or intolerant gastrointestinal stromal tumor. The present approval represents a significant advancement for affected patients who have had limited treatment options for this rare and difficult-to-treat tumor. The FDA approval is based on data from the SUN 1111 pivotal Phase III trial that demonstrated a clinically significant improvement in progression-free survival (PFS) for sunitinib malate compared with placebo (10.2 vs 5.4 months; p = 0.000146). Treatment also yielded a statistically significant improvement in tumor response, with an objective response (OR; complete response and/or partial response) rate of 9.3% (95% CI: 3.2, 15.4; p = 0.0066). No ORs were observed with placebo. In addition, while overall survival (OS) was not mature at the time of final analysis, nine deaths were observed in patients enrolled in the sunitinib malate arm versus 21 deaths in patients enrolled in the placebo arm [2].

Incivek (telaprevir)

On 23 May, Vertex Pharmaceuticals, Inc. announced that the FDA had approved Incivek tablets for a broad group of people with genotype 1 chronic hepatitis C with compensated liver disease, including cirrhosis [213,217,218]. Telaprevir acts directly on the hepatitis C virus protease, an enzyme essential for viral replication, and is approved for people who are new to treatment, and for people who were treated previously but who did not achieve a viral cure. The current standard of care for patients with chronic hepatitis C infection is PEGylated interferon and ribavirin taken for 48 weeks; however, fewer than 50% of patients respond to this therapy. Approval of telaprevir was based on data from three Phase III studies involving approximately 2250 adult subjects. In all studies patients also received the drug with standard of care. In previously untreated patients, 79% of those receiving telaprevir experienced a sustained virologic response; specifically, the infection was no longer detected in the blood 24 weeks after stopping treatment compared with standard treatment alone. The sustained virologic response for patients treated with telaprevir across all studies, and across all patient groups, was 20–45% higher than current standard of care. The studies indicate that treatment with telaprevir can be shortened from 48 weeks to 24 weeks in most patients. In previously untreated patients, 60% achieved an early response and received only 24 weeks of treatment compared with the standard of care of 48 weeks. The sustained virologic response for these patients was 90%. When a person achieves a sustained virologic response after completing treatment, this suggests that the hepatitis C infection has been cured.

Xience nano™

On 24 May, Abbott announced it had received FDA approval for the Xience nano Everolimus Eluting Coronary Stent System for the treatment of coronary artery disease in small vessels [219]. Xience nano, which is based on the same platform as the Xience V^® Everolimus Eluting Coronary Stent System, offers physicians in the USA a new option for treating patients with coronary artery disease in vessels as small as 2.25 mm in diameter. Small blood vessels are associated with increased levels of restenosis following stent implantation. With its cobalt chromium stent design, high deliverability, and everolimus drug coating used to prevent abnormal tissue growth, Xience nano is designed to be an optimized treatment for coronary artery disease in patients who have small vessels. The FDA approval was supported by results from the SPIRIT Small Vessel clinical trial, which showed very low late loss (a measure of vessel re-narrowing) of 0.20 mm and a target lesion failure rate of 8.1%, which is comparable to results observed in the SPIRIT clinical trials with Xience V. The target lesion failure rate is a composite measure of important efficacy and safety outcomes for patients that include cardiac death, heart attack attributed to the target vessel and ischemia-driven target lesion revascularization.

Nulojix^® (belatacept)

On 15 June, the FDA approved Nulojix (belatacept), the first selective T-cell costimulation blocker indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant, in combination with basiliximab induction, mycophenolate mofetil and corticosteroids [220,221]. Belatacept is a soluble fusion protein that binds to CD80 and CD86 on antigen-presenting cells thereby blocking CD28-mediated costimulation of T cells. In vitro, belatacept inhibits T-lymphocyte proliferation and the production of the cytokines IL-2, IFN-γ, IL-4 and TNF-α. Activated T cells are the predominant mediators of immunologic rejection. Belatacept was evaluated in two open-label, randomized, multicenter, controlled Phase III studies that enrolled more than 1200 patients and compared two dose regimens of belatacept with another immunosuppressant, cyclosporine. These trials demonstrated that the recommended belatacept regimen is safe and effective for the prevention of acute organ rejection.

Clinical trials

Zytiga™ (abiraterone acetate)

On 25 May, Johnson & Johnson announced that a study entitled ‘Abiraterone and increased survival in metastatic prostate cancer‘ would be published in the 26 May online edition of The New England Journal of Medicine[3,222]. The COU-AA-301 study was sponsored by Ortho Biotech Oncology Research & Development, a unit of Cougar Biotechnology, Inc. Abiraterone acetate is an oral androgen biosynthesis inhibitor that works by selectively inhibiting the CYP17 enzyme complex, the latter being required for the production of androgens. Although required for the development of secondary sexual characteristics, in cases of prostate cancer, androgens serve to promote tumor growth. Moreover, the tumor tissue itself is an additional source of androgens. The present study evaluated abiraterone acetate in combination with prednisone in a Phase III, randomized, placebo-controlled, multicenter clinical study in patients who had received prior chemotherapy containing a taxane such as docetaxel. A total of 1195 patients were randomized 2:1 to receive abiraterone acetate (1000 mg daily) in combination with prednisone (5 mg twice daily) or placebo in combination with prednisone (5 mg twice daily); the primary end point was OS. Results showed that at a prespecified interim analysis, treatment with abiraterone acetate in combination with prednisone resulted in a 35.4% reduction in the risk of death (14.8 vs 10.9 months (hazard ratio [HR]: 0.65; 95% CI: 0.54, 0.77; p < 0.001) and a 3.9 month difference in median survival compared with placebo plus prednisone. Adverse events associated with elevated mineralocorticoid levels due to CYP17 inhibition (fluid retention and edema, hypokalemia and hypertension), as well as cardiac disorders and liver-function test abnormalities were deemed of special interest and were more common in the abiraterone acetate arm. The FDA approved Zytiga on 28 April 2011 for the treatment of men with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel [223].

Vemurafenib (RG7204, PLX4032)

On 5 June, Roche announced the results of a Phase III study (BRIM3) that showed vemurafenib significantly improved OS in people with previously untreated BRAF V600 mutation-positive metastatic melanoma, compared with chemotherapy [224–226]. In the study, the risk of death was reduced by 63% for people who received vemurafenib compared with those who received chemotherapy (HR: 0.37; p < 0.0001). In addition, vemurafenib significantly reduced PFS, a co-primary end point, by 74% compared with chemotherapy (HR: 0.26; p < 0.0001). The safety profile of vemurafenib was consistent with previous clinical studies. Vemurafenib is a personalized investigational medicine designed to specifically inhibit the activity of the mutant BRAF protein that is found in approximately half of all cases of melanoma, the deadliest and most aggressive form of skin cancer. People were enrolled into the study based on BRAF mutation status as determined by the cobas 4800 BRAF V600 Mutation Test, an investigational diagnostic from Roche. The results were presented at the 47^th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago (IL, USA) and published on the same day in the online edition of The New England Journal of Medicine[4]. BRIM3 is a global, randomized, open-label, controlled, multicenter, Phase III study that compared vemurafenib with dacarbazine chemotherapy, a current standard of care, in 675 patients with previously untreated BRAF V600 mutation-positive, unresected locally advanced or metastatic melanoma. Co-primary end points were OS and PFS. Secondary end points included response rate, response duration and safety profile.

Analysis of the BRIM3 data showed the response rate (those who experienced tumor shrinkage) in the group of patients who received vemurafenib (48.4%) was nearly nine-times higher than in the group who received chemotherapy (5.5%; p < 0.0001). After 6 months, 84% of patients who received vemurafenib were alive compared with 64% who received chemotherapy. The improvement in OS, PFS and tumor shrinkage with vemurafenib was seen in patients regardless of age, gender or disease risk factor. In January 2011, an independent data monitoring board reviewed data from a planned interim analysis of BRIM3 and recommended the release of study results due to compelling efficacy. The board also recommended that patients in the chemotherapy arm be permitted to crossover or receive vemurafenib instead of chemotherapy. Median OS estimates when BRIM3 met the co-primary end point in January 2011 were 9.2 months in patients receiving vemurafenib and 7.8 months in those receiving chemotherapy; an additional 2 months of follow-up showed an estimated median OS of 10.5 months for patients receiving vemurafenib, while the median OS estimate for patients receiving chemotherapy remained at 7.8 months. While Roche seeks regulatory approval of vemurafenib, a global Expanded Access Programme is available for people with previously treated or untreated BRAF V600 mutation-positive metastatic melanoma.

Yervoy (ipilimumab)

On 5 June, Bristol-Myers Squibb announced results from a second Phase III multinational, randomized, double-blind study (Study 024) demonstrating that ipilimumab prolonged the lives of patients with metastatic melanoma [227]. As was the case with Roche and vemurafenib, the data were presented at the Annual Meeting of the ASCO in Chicago and published on the same day in the online edition of The New England Journal of Medicine[5,227]. As previously stated, ipilimumab is a recombinant human monoclonal antibody and the first FDA-approved cancer immunotherapy that blocks the CTLA-4, a negative regulator of T-cell activation. Study 024 evaluated the safety and efficacy of ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m²) versus dacarbazine alone in treatment-naive patients with stage III unresectable or stage IV metastatic melanoma. Patients who received prior adjuvant therapy were allowed in the trial. Patients were randomly assigned in a 1:1 ratio to receive either ipilimumab plus dacarbazine (n = 250) or dacarbazine plus placebo (n = 252) at weeks 1, 4, 7 and 10, followed by dacarbazine alone every 3 weeks through to week 22 (induction phase). If drug intolerance or progressive disease was noted during weeks 12–24, treatment was discontinued. At week 24, patients who had stable disease or an OR during induction with no dose-limiting toxicity could enter a maintenance phase in which they received placebo or ipilimumab every 12 weeks until progressive disease, drug intolerance or end of study. The primary study end point was OS; secondary end points included PFS, disease control rate, best overall response rate by modified WHO criteria, time to response, response duration and safety. Analysis of the study data revealed a significant improvement in OS (HR: 0.72; p = 0.0009) in the ipilimumab plus dacarbazine arm versus the dacarbazine alone arm. The estimated rates of OS in the ipilimumab plus dacarbazine arm compared with the dacarbazine alone arm were 47.3 versus 36.3% at 1 year, 28.5 versus 17.9% at 2 years and 20.8 versus 12.2% at 3 years (3 years was analyzed post hoc). Median OS in the ipilimumab plus dacarbazine arm was 11.2 months (95% CI: 9.4, 13.6) compared with 9.1 months (95% CI: 7.8, 10.5) in the dacarbazine alone arm. The best OR rate was 15.2% in the ipilimumab plus dacarbazine arm and 10.3% in the dacarbazine alone arm. The median duration of response in those patients who achieved an OR was 19.3 months (95% CI: 12.1, 26.1) in the ipilimumab plus dacarbazine arm (n = 38) and 8.1 months (95% CI: 5.19, 19.8) in the dacarbazine alone arm (n = 26). Jedd Wolchok of the Memorial Sloan-Kettering Cancer Center who presented the results at the ASCO meeting in Chicago commented, “We now have Phase III data demonstrating that ipilimumab improved survival in patients with metastatic melanoma in both the first- and second-line settings”. It should be noted that the presently described combination of dacarbazine with ipilimumab is not an FDA-approved regimen, nor was the present study designed to compare the safety and efficacy of the FDA-approved monotherapy dose of 3 mg/kg for unresectable or metastatic melanoma versus the investigational dose of 10 mg/kg. Nonetheless, Bristol-Myers Squibb intends to conduct a head-to-head Phase III study comparing the safety and efficacy of these two doses given as a monotherapy in patients with unresectable or metastatic melanoma.

Ridaforolimus (AP23573, MK-8669)

On 6 June, Merck and Ariad Pharmaceuticals, Inc. announced detailed results from the Phase III SUCCEED clinical trial presented at the Annual Meeting of the ASCO in Chicago [228]. The SUCCEED trial was a randomized (1:1), placebo-controlled, double-blind study of oral ridaforolimus administered at 40 mg/day (5 out of 7 days per week) in patients with metastatic soft-tissue or bone sarcomas who previously had a favorable response to chemotherapy. Ridaforolimus is an investigational targeted and potent small-molecule inhibitor of the protein mTOR, a protein that acts as a central regulator of protein synthesis, cell proliferation, cell-cycle progression and cell survival, integrating signals from proteins, such as PI3K, AKT and PTEN, that are known to be important to malignancy. Based on 552 PFS events in 711 patients, (ridaforolimus [n = 347], placebo [n = 364]) determined by an independent radiological review committee, the study achieved its primary end point of improvement in PFS, with a statistically significant (p = 0.0001) 28% reduction in the risk of progression or death observed in those treated with ridaforolimus compared with placebo (HR: 0.72). Median PFS was 17.7 weeks for those treated with ridaforolimus compared with 14.6 weeks in the placebo group. Furthermore, based on the full analysis of PFS determined by investigator assessment, there was a statistically significant (p < 0.0001) 31% reduction by ridaforolimus in the risk of progression or death compared with placebo (HR: 0.69). In the investigator assessment analysis, median PFS was 22.4 weeks for those treated with ridaforolimus compared with 14.7 weeks in the placebo group. The independent radiological committee review analysis showed that the proportion of patients alive and free from disease progression in the ridaforolimus group compared with placebo was greater after 3 months (70 vs 54%), and 6 months (34 vs 23%). Secondary end points were trends in OS, best target lesion response, assessment of cancer-related symptoms, and safety and tolerability. Follow-up for OS is ongoing, and the current trend favors ridaforolimus: results at the most recent data cut-off (386 OS events) showed a median OS of 21.4 months for the oral ridaforolimus group compared with 19.2 months for the placebo arm (HR: 0.88; p = 0.2256). For the best target lesion response, the oral ridaforolimus group showed an average target tumor lesion size reduction of 1.3%; whereas the placebo group showed an average target tumor lesion size increase of 10.3% (p < 0.0001). Data from the SUCCEED trial show that ridaforolimus maintained the benefit of prior conventional chemotherapy. The study met the primary end point of PFS, showing a clinically meaningful and statistically significant improvement in PFS in those patients treated with oral ridaforolimus. Harvey Berger, CEO of ARIAD, commented, “These updated data illustrate how challenging metastatic sarcomas can be, even in patients who have responded favorably to chemotherapy”. As part of the exclusive license agreement with ARIAD, Merck is responsible for the development and worldwide commercialization of ridaforolimus in oncology. Based on the results, Merck plans to submit an NDA for ridaforolimus to the FDA and a marketing application in the EU this year.

Intellectual property

NexGenix Pharmaceuticals

On 19 May, NexGenix Pharmaceuticals, Inc. announced that the USPTO has issued a Notice of Allowance for Patent Application Serial No. 11/891652, a key patent for a platform of heat shock protein 90 (Hsp90) inhibitors based on derivatives of the naturally occurring pochonin family, Pochonia chlamydospora[101,229].The platform of fully synthetic small molecules covered by this composition of matter patent was developed in the laboratory of N Winssinger at the University of Strasbourg (France) and is exclusively licensed to NexGenix. The patent, entitled ‘Macrocyclic Compounds Useful as Inhibitors of Kinases and Hsp90‘, provides an exclusivity period until August 2027. The patent specifically covers the proprietary scaffold and its composition along with a large library of compounds, including NexGenix‘s lead Hsp90 inhibitors aimed at cancer and neurodegenerative indications. The pochonin scaffold represents an advancement in Hsp90 inhibition beyond several molecules developed over the last decade based on radicicol and geldanamycin derivative (17-AAG), which have been shown to exhibit highly potent antitumor activity in numerous preclinical and clinical studies. X-ray crystallography studies have demonstrated deeper binding of NexGenix‘s molecules to the Hsp90 ATP binding pocket compared with other small-molecule Hsp90 inhibitor compounds for which crystallography has been published. This generally translates to interaction deep in the protein-binding pocket with the molecule remaining longer and thus inhibiting the protein for longer periods. Another major key differentiating point of the platform is that a subset of the library of over 500 molecules developed to date has the ability to cross the blood–brain barrier and the blood spinal cord barrier, making them particularly attractive candidate therapeutics for CNS indications, such as primary and secondary tumors of the CNS and neurodegenerative disorders.

Syndax Pharmaceuticals

On 2 June, Syndax Pharmaceuticals, a clinical-stage epigenetics oncology company, announced allowance by the USPTO of Patent Application Serial No. 12/549458 entitled: ‘N-(2-aminophenyl)-4-[N-(pyridine-3-yl)-methoxycarbonyl-aminomethyl]-benzamide (MS-275) polymorph B‘ [230]. Entinostat is an orally bioavailable, highly selective, class I histone deacetylase (HDAC) inhibitor with a long half-life that allows for weekly or every-other-week dosing. A recent randomized, placebo-controlled Phase II study showed a 4-month survival advantage when entinostat was added to erlotinib in a subset of patients with non-small-cell lung cancers expressing high levels of E-cadherin [231]. Research has shown that HDACs are involved in the expression of various genes, such as the estrogen receptor, which regulates cell growth, differentiation and apoptosis. Such genes are frequently silenced in cancer cells through the overexpression of enzymes including HDACs. HDACs are therefore recognized as promising targets for cancer treatment. Furthermore, studies have demonstrated that HDAC inhibition can significantly enhance anticancer activity when used in combination with a broad range of anticancer agents. The potential therefore exists to overcome tumor resistance to targeted agents. The patent covers the novel polymorph form B of entinostat [102], being developed by Syndax for combination therapy with aromatase inhibitors for metastatic breast cancer and erlotinib for advanced non-small-cell lung cancer. Joanna Horobin, President and CEO of Syndax commented, “This US allowance comes at a strategic time for Syndax and the development of entinostat since we now have the results of our randomized Phase II placebo-controlled study in metastatic breast cancer in hand, and we are advancing entinostat in to Phase III studies. With patent life extending through 2029, we are looking forward to maximizing the opportunities to develop entinostat in multiple indications”.

Journal publications

Marker identifies breast cancer patients likely to respond to tamoxifen

On 19 May, an international team of collaborators reported the discovery of a biomarker in breast cancer that may help identify which women will respond to anti-estrogen therapy [232]; the work was initially published in the 16 May online issue of the Journal of Clinical Oncology[6]. Anti-estrogen drugs, most notably tamoxifen, are widely used in patients diagnosed with estrogen receptor-positive breast cancer. However, as many as a third of the women given tamoxifen fail to respond. In the new study, investigators found that women whose tumors retain the active form of the protein STAT5 have an increased likelihood of responding to tamoxifen. By contrast, women treated with tamoxifen whose tumors lacked active STAT5 had up to a 20-fold increased risk of dying from breast cancer after adjustment for effects of standard hormone receptor markers and other pathology data. Identification of predictive biomarkers in oncology is expected to drive improvements in individualized therapies. In this specific case, the absence of the active form of STAT5 may facilitate identification of ‘non-responders‘ who could be offered alternative treatment regimens. STAT5 is a DNA-binding factor that regulates expression of certain genes, many of which remain unknown. During pregnancy, STAT5 is activated by the hormone prolactin, and stimulates milk production in the breast. Active STAT5 is also detectable at lower levels in healthy breast tissue of nonpregnant women. The present study involved retrospective pathological analysis of archived tissues from five independent cohorts containing over 1000 subjects. Consistently favorable breast cancer outcomes were observed when tumors retained active STAT5. Furthermore, the assay for STAT5 is simple, inexpensive and lends itself to rapid automation for routine analysis.

Vaccine increases disease-free survival for follicular lymphoma patients

On 31 May, a study led by researchers at The University of Texas MD Anderson Cancer Center (TX, USA) was published in the online version of Journal of Clinical Oncology in which a lymphoma vaccine, uniquely tailored for each patient, was shown to extend disease-free survival by 14 months, with signs of an even better response for patients with a specific biological marker [7,233]. The multicenter study is the first successful Phase III trial of a lymphoma vaccine and one of the first of a personalized cancer therapy agent. To make the vaccine, unique proteins from each patient‘s tumor are isolated and combined with a delivery agent and a growth factor; this mixture is then injected back into the patient. Earlier studies showed this approach induces antitumor immune responses with few side effects in most lymphoma patients. Communicating author, Larry Kwak, commented, “Even if two patients have the same type of lymphoma, their tumors will still have different proteins”. In the USA, more than 74,000 people were diagnosed with non-Hodgkin‘s lymphoma in 2010. Follicular lymphoma accounts for 22% of non-Hodgkin‘s lymphomas worldwide. The 234 patients in this trial first were treated with a chemotherapy combination known as PACE. Of these patients, 117 went into complete remission or had a complete response for at least 6 months; they then received either the vaccine or a placebo. During a median follow-up period of 55.6 months, median time to relapse for the 76 vaccinated patients was 44.2 months, compared with 30.6 months for the 41 who received placebo. However, an unplanned subgroup analysis showed that patients with a certain biological marker had an even more profound response, extending disease-free survival time from 28.7 months to 52.9 months. While those results need to be confirmed in randomized studies, they suggest the potential for further targeting the vaccine. Moreover, these findings may be applicable to other types of cancers, as well as a broader range of lymphoma patients. A next-generation lymphoma vaccine is due to enter clinical testing within the next 12 months. The NCI advanced the vaccine by sponsoring its first randomized Phase III clinical trial with the intention of handing the trial off to a corporate partner. BioVest International prevailed in a competitive process to collaborate with the NCI and took over the trial in 2004. BioVest is developing the vaccine under the brand name BioVaxID™. The company is moving forward to secure FDA approval of the vaccine.

NIH scientists reactivate immune cells exhausted by chronic HIV

On 3 June, a study published by researchers at the National Institute of Allergy and Infectious Diseases in the Journal of Clinical Investigation demonstrated why certain immune cells chronically exposed to HIV shut down, and how they can be reactivated [8,234]. Healthy B cells have a balanced mix of surface proteins that the immune system can use either to activate the cell or to damp down its activity. However, in people with long-term HIV infection, who have not begun antiretroviral therapy, the B cells display a surplus of inhibitory receptors. It was hypothesized that this observation might explain why B cells become ‘exhausted‘ and essentially shut down in people who are HIV-infected but treatment-naive. The researchers consequently employed siRNAs, which act at the genetic level to prevent exhausted B cells from replenishing inhibitory receptors. After treatment with siRNAs, the exhausted cells responded more normally to conditions that would typically spur a B cell into action, such as the presence of a virus, demonstrating that the excess of inhibitory receptors may explain why exhausted B cells are so unresponsive. Since B cells generally are difficult to manipulate, the new siRNA-based approach may hold promise for scientists seeking to develop therapies to improve the human antibody response against HIV and other pathogens by altering the expression of specific B-cell genes.

Financial & competing interests disclosure

The author is employed by Genesis Oral Biosciences and has, in the past, received compensation from GlaxoSmithKline in respect of consultancy and scientific writing services. The author is a named inventor on four patents assigned to GlaxoSmithKline, and owns shares in the company. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript.

No writing assistance was utilized in the production of this manuscript.