On December 16, 2014 The Cancer Research Technology Pioneer Fund (CPF or the Fund) reported an additional £20m investor commitment from BACIT Limited (BACIT), taking the total fund to £70m (Press release, Cancer Research Technology, DEC 16, 2014, View Source [SID1234523215]).

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The news comes as the fund announces its fifth research investment, expanding its agreement with Chroma Therapeutics Ltd to develop drugs that use immune cells called macrophages – a type of white blood cell – to deliver drugs directly into tumours.

The CPF was established in 2012 by the European Investment Fund and Cancer Research Technology Ltd. It bridges the gap in cancer research between late discovery and Phase II clinical trials. Through its relationship with CRT, the Fund has access to drug discovery and development programmes funded by Cancer Research UK.

Today’s announcement takes the total capital now committed to the Fund to £70m which will allow the CPF to invest in a larger portfolio of cancer research projects and have the potential to develop existing projects further.

Today’s announcement includes an expansion of the license from Chroma to the CPF for all rights in oncology to its Esterase Sensitive Motif (ESM) technology*.

The ESM technology incorporates specific chemical motifs – such as cancer drugs – into active compounds, which are freely transported into cells. Once inside the cell, a specific enzyme found only in certain type of macrophage targeted at tumours, removes the motifs to create a compound that cannot easily exit the cell. Over time, the compound selectively accumulates in the macrophages to significant levels and it becomes active in fighting cancer cells.

Dr Robert James, managing partner of Sixth Element Capital, said: "We’re very excited to welcome BACIT as an additional investor. This enables us to create an even more diversified portfolio of novel world-class cancer therapeutics.

"The expansion of the Chroma agreement enables CPF to develop a portfolio of projects that modulate the immune system. Immunotherapy is an extremely exciting area in cancer research. Developing small molecules which activate the immune system to fight cancer could be of great importance to cancer patients."

Richard Bungay, chief executive of Chroma, said: "It is now widely accepted that modulation of a patients’ own immune system will be an important tool in the fight against cancer. Consequently, we are very pleased to have expanded our collaboration with CPF, which will facilitate further significant investment in our portfolio of novel immunotherapy treatments, and potentially expand the disease targets that the ESM macrophage-targeting technology is applied to."

Dr Piyush Unalkat, Principal – Equity Investments, commented: "I’m extremely pleased to see BACIT formalising its investment to CPF, bringing the fund to £70m. BACIT, CRT and EIF are long-term investors aligned in their mission to catalyse the development of new therapies to fight cancer, of which the ESM technology is a good example. The CPF is a cost efficient model and the additional resources shall allow for more investments than were originally foreseen."

Dr Keith Blundy, CEO of Cancer Research Technology, said: "BACIT’s investment in the CPF is warmly welcomed and will help us further accelerate drug discovery research to bring potential new treatments to patients sooner. Immunotherapy research is looking increasingly promising for the treatment of cancer, so I am delighted to see the progress that the CPF is making in attracting new investment to help bridge the UK’s innovation gap in this important area."

On December 15, 2014 Ignyta reported that it has entered into an amendment to its license agreement with Nerviano Medical Sciences, S.r.l. relating to its entrectinib (formerly RXDX-101) product candidate (Press release Ignyta, DEC 15, 2014, View Source [SID:1234501188]). The amendment modifies the milestones that would trigger the initial three milestone payments specified in the license agreement. Pursuant to the amendment, the initial milestone payment of $10 million will be due and payable to Nerviano by December 31, 2014, and the second and third milestone payments will be triggered by revised clinical and/or regulatory events relating to entrectinib or other licensed products. The amounts of such milestone payments have not changed.

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"The promising clinical data observed with entrectinib have spurred us to develop a more ambitious clinical development plan that enables us to accelerate development while also pursuing multiple opportunities in parallel for this exciting product candidate," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "Under the previous structure, there were future milestone payments that posed potential financial disincentives for Ignyta to accelerate the clinical development program or pursue multiple indications due to potential stacking of milestone payments. By accelerating the first payment, pushing back subsequent payments, and modifying the triggers for milestone payments under our agreement with Nerviano, we have better aligned the companies’ interests. Ignyta may now strategically accelerate the development and potential commercialization of entrectinib for the benefit of cancer patients."

The FDA has granted breakthrough therapy designation for Lucentis (ranibizumab; Genentech) for the treatment of diabetic retinopathy, according to a company statement (External Source Eyewire , Genentech, DEC 15, 2014, View Source [SID:1234501195]).

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A medicine may be designated as a breakthrough therapy by the FDA if it is intended to treat a serious or life-threatening disease or if preliminary clinical research suggests it will provide a significant improvement over existing therapies. The designation will expedite the development and review of Lucentis for diabetic retinopathy and reflects the unmet need for treatment options for diabetic retinopathy patients, according to Genentech.

In September, the FDA accepted the supplemental biologics license application for Lucentis and granted the medicine priority review for the treatment of diabetic retinopathy.

There are currently no approved ocular medications for diabetic retinopathy, which is estimated to affect 7.7 million Americans.

The FDA decision is based on the phase 3 RISE/RIDE trials, which showed meaningful improvements in diabetic retinopathy in a clinically significant proportion of patients treated with Lucentis at 2 years compared to patients treated with sham injections. Benefits of Lucentis treatment were maintained during year 3 of treatment. The safety in the RISE and RIDE phase 3 trials was consistent with previous studies.

The FDA’s confirmed action date for its biologics license application is February 6, 2015.

On December 12, 2014 Novartis reported on results of the BOLERO-1 (Breast cancer trials of OraL EveROlimus-1) trial of Afinitor (everolimus) tablets in combination with trastuzumab (Herceptin*) and paclitaxel as a first-line treatment in women with human epidermal growth factor receptor-2 positive (HER2+) advanced breast cancer at the 2014 San Antonio Breast Cancer Symposium (SABCS) (Press release Novartis, DEC 12, 2014, View Source [SID:1234501181]).

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The trial was conducted in HER2+ advanced breast cancer patients, a population that represents approximately 20% of advanced breast cancers and differs from the hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer patients for whom Afinitor in combination with exemestane following a non-steroidal aromatase inhibitor is approved worldwide. The study did not meet the threshold of statistical significance for the primary objectives of progression-free survival (PFS) among women with HER2+ advanced breast cancer or the pre-defined hormone-receptor negative, human epidermal growth factor receptor-2 positive (HR-/HER2+) subgroup.

"For more than two years, Afinitor has positively impacted the HR positive treatment landscape as an important therapy for women living with advanced breast cancer," said Alessandro Riva, Global Head, Oncology Development and Medical Affairs, Novartis Oncology. "The results of this trial in HER2 positive support our research approach of investigating various treatment combinations targeting the PI3K/AKT/mTOR pathway in advanced breast cancer and we thank all of the researchers and patients who participated in the BOLERO-1 study."

The results of BOLERO-1, a Phase III, randomized, double-blind, placebo-controlled multicenter trial of 719 patients with HER2+ locally advanced or metastatic breast cancer, showed that the median PFS with everolimus plus trastuzumab and paclitaxel was 15.0 months versus 14.5 months with placebo plus trastuzumab and paclitaxel, a difference of 0.5 months (hazard ratio=0.89 [95% CI: 0.73 to 1.08]; p=0.1166).

In the HR- subgroup of women with HER2+ advanced breast cancer, a second primary objective, everolimus plus trastuzumab and paclitaxel treatment demonstrated benefit over the placebo arm prolonging median PFS by 7.2 months. The median PFS was 20.3 months with everolimus plus trastuzumab and paclitaxel and 13.1 months with placebo plus trastuzumab and paclitaxel. While this difference was clinically relevant, the results did not demonstrate statistical significance.

The combination of everolimus, trastuzumab and paclitaxel was generally well-tolerated. Adverse events were consistent with the known safety profile of everolimus with the most common all-grade adverse reactions (incidence >= 35%) being stomatitis, diarrhea, alopecia, rash, cough, pyrexia, neutropenia and fatigue. The most common Grade 3-4 adverse reactions (incidence >= 2%) were neutropenia, stomatitis, diarrhea, anemia, hypokalaemia, leukopenia, hyperglycemia, fatigue, pyrexia and dyspnea.

Afinitor is currently approved in more than 90 countries across the globe, including the countries of the European Union and the United States, to treat postmenopausal women with HR+/HER2- advanced breast cancer in combination with exemestane after recurrence or progression following a non-steroidal aromatase inhibitor. The specific indications vary by country. HR+/HER2- advanced breast cancer is the most common form of the disease. Approximately 70% of all invasive breast cancers are positive for HR expression at the time of diagnosis.

On December 12, 2014 Oncothyreon reported that the positive preliminary data from two ongoing Phase 1b trials of ONT-380 (ARRY-380), an orally active, reversible and selective small molecule HER2 inhibitor, will be presented at the San Antonio Breast Cancer Symposium (Press release Oncothyreon, DEC 12, 2014, View Source [SID:1234501172]).

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The first trial (ClinicalTrials.gov Identifier NCT02025192) is a parallel dose-escalation study of ONT-380 in combination with Xeloda (capecitabine) and/or Herceptin (trastuzumab) in patients previously treated with Herceptin and Kadcyla (ado-trastuzumab emtansine or TDM-1) for metastatic breast cancer. Interim data will be presented for 21 patients, including seven in the ONT-380 plus Xeloda cohort, eight in the ONT-380 plus Herceptin cohort, four in the ONT-380 plus Xeloda and Herceptin cohort, and two in an ongoing expansion cohort in patients with untreated or progressive central nervous system (CNS) metastases, both treated with ONT-380 plus Herceptin.

Seventeen of the patients were evaluable for best overall response using RECIST 1.1 criteria. In the ONT-380 plus Xeloda cohort, four patients had a partial response (PR) and three patients had stable disease (SD), for an overall clinical benefit rate of 100 percent (defined as either PR/CR or stable disease for > 6 months). In the ONT-380 plus Herceptin cohort, best response has been a complete response (CR) in one patient, PR in two patients, SD in four patients, and progressive disease (PD) in one patient. Two patients in the ONT-380 plus Xeloda and Herceptin cohort are currently evaluable, one of whom had a PR and one PD. One patient in the CNS expansion cohort had a PR and the other SD.

Fourteen of the 21 patients in this trial had a history of CNS metastases, of whom six had evaluable target lesions per modified RECIST 1.1 at the time of entry into the trial. Of these, best initial response has been SD, with decreases in CNS target lesions in four patients. Five of these six patients remain active on study.

The second trial (ClinicalTrials.gov Identifier NCT01983501) is a dose-escalation study of ONT-380 in combination with Kadcyla in patients who have been previously treated with Herceptin and a taxane for metastatic breast cancer. Data will be presented for 17 patients, of whom 16 were evaluable for response. Patients in this trial were heavily pre-treated, having received a median of two prior systemic treatments for metastatic disease, including prior pertuzumab in six, and prior lapatinib in five. Best overall response has been PR in five patients, SD in seven patients, and PD in four patients. Nine patients in this trial had a history of CNS metastases, of whom four had measurable disease per modified RECIST 1.1 at the time of entry into the trial. Three of these four patients have SD in the CNS and remain active on the study, including two with decreases in measurable target lesions.

ONT-380 was well-tolerated in both studies and in all combinations tested. The most common adverse events included nausea and vomiting, diarrhea, fatigue and elevated liver function tests. Most adverse events were grade 1 or 2 in severity. Elevated liver function tests were more common in patients also receiving Kadcyla. No grade 3 diarrhea was seen in either trial; anti-diarrheal prophylaxis was not a study requirement.

A maximally tolerated dose (MTD) for ONT-380 has not been identified to date in any of the combinations tested in either trial. An improved tablet formulation of ONT-380 with increased absorption was used in these trials compared to the powder in capsule formulation used in the previously reported Phase 1 trial. All patients in both current trials received an initial dose of 300 mg twice per day. At that dose, measured drug levels were similar to those seen with 600 mg twice per day (the single agent MTD) of the prior formulation. Drug exposure in the current trials was well above the level needed for 90 percent inhibition of HER2.

"The preliminary signs of efficacy in both of these trials are encouraging for the further development of ONT-380," said Stacy Moulder, M.D., Associate Professor, Breast Medical Oncology, University of Texas MD Anderson Cancer Center. "These patients were heavily pre-treated, with the majority already having a history of CNS metastases. Nevertheless, meaningful responses and prolonged stable disease have been observed and many patients currently remain on study. Importantly, ONT-380 has been well-tolerated, with a toxicity profile that facilitates its combination with other agents."

"We are continuing to enroll patients in both of these Phase 1b trials," said Diana Hausman, M.D., Chief Medical Officer of Oncothyreon. "We are currently testing an increased dose level of ONT-380 of 350 mg twice daily in both trials. We are also enrolling cohorts of patients in both trials with CNS metastases from HER2+ breast cancer that are either asymptomatic and untreated or progressive following treatment to better define the potential role of ONT-380 in treating patients with this serious unmet medical need."

About ONT-380

ONT-380 is an orally active, reversible and selective HER2 inhibitor invented at Array BioPharma Inc. In multiple preclinical tumor models, ONT-380 was well tolerated and demonstrated significant dose-related tumor growth inhibition that was superior to Herceptin (trastuzumab) and Tykerb (lapatinib). Additionally, in these models, ONT-380 demonstrated synergistic or additive tumor growth inhibition when dosed in combination with the standard-of-care therapeutics Herceptin or Taxotere (docetaxel). ONT-380 has also demonstrated superior activity, based on overall survival, compared to Tykerb and to the investigational drug, neratinib, in an intracranial HER2 positive breast cancer xenograft model.

A Phase 1 trial of ONT-380, with both dose-escalation and expansion components, has been completed in 50 patients, 43 of whom had HER2 positive metastatic breast cancer. All HER2 positive breast cancer patients had progressed on a Herceptin-containing regimen. In addition, over 80 percent had been treated with Tykerb, with many having progressed on therapy. In this study, ONT-380 demonstrated an acceptable safety profile; treatment-related adverse events were primarily Grade 1. Because ONT-380 is selective for HER2 and does not inhibit EGFR, there was a low incidence and severity of treatment-related diarrhea, rash and fatigue. Additionally, there were no treatment-related cardiac events or Grade 4 treatment-related adverse events reported. Twenty-two HER2 positive breast cancer patients with measurable disease were treated with ONT-380 at doses greater than or equal to 600 mg BID. In this heavily pretreated patient population, there was a clinical benefit rate (partial response [n = 3] plus stable disease for at least 6 months [n = 3]) of 27 percent.