On March 28, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported a corporate update and reported financial results for the fourth quarter and year-ended December 31, 2015 (Press release, Onconova, MAR 28, 2016, View Source [SID:1234510063]).

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"Onconova is focused on the execution of the global INSPIRE trial of IV rigosertib. This trial is now enrolling higher-risk MDS patients at multiple U.S. sites and in Europe, and we are initiating additional clinical centers in the U.S. and abroad. Patients have been enrolled in the U.S. and Europe, and we are pleased that our Japan/Korea partner SymBio Pharmaceuticals has announced plans to enroll patients in INSPIRE in Japan," said Ramesh Kumar, Ph.D., President and CEO of Onconova. "In addition, based on the encouraging Phase 2 results for oral rigosertib in combination with azacitidine presented in December 2015, we are planning to define a regulatory path forward with the FDA this year."

Recent Business Highlights:

Development of Rigosertib IV in Higher-Risk MDS (HR-MDS)

The global INSPIRE trial is now enrolling patients in the United States and Europe. INSPIRE will be conducted in the United States, Europe, Australia, Israel, and Japan. The first patient in Europe was enrolled this month and sites in Japan are expected to open shortly. The first patient in this trial was enrolled in December 2015 at the MD Anderson Cancer Center.

Results from Onconova’s ONTIME trial were published in the top-tier, peer-reviewed journal, Lancet Oncology. The article, titled, "Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial," appeared in the March 8, 2016 online edition of the journal.
Development of Oral Rigosertib in Combination with Azacitidine for MDS and AML Patients

The Phase 2 portion of an open label Phase 1/2 clinical trial, designated 09-08, evaluating oral rigosertib in combination with the approved dose of injectable azacitidine for patients with HR-MDS and AML is fully enrolled. The Phase 2 study included both front-line patients (i.e. not previously treated with HMAs) and patients after failure of treatment with an HMA. Positive interim data from the 09-08 trial were presented at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2015.

In the presentation at ASH (Free ASH Whitepaper), 30 MDS patients were evaluable for efficacy assessment per 2006 International Working Group, or IWG, criteria. Overall, 23 of 30 patients (77%) responded, including six patients who had complete remissions. Notably, 16 of 19 (84%) HMA-naïve patients had a response to the combination therapy and 7 of 11 (64%) patients whose disease had previously failed HMAs responded. Hematologic improvement was observed in 13 of 26 patients that were evaluable for this part of the analysis.

Patients received full dose (per label) of azacitidine and the recommended daily Phase 2 dose of oral rigosertib (560 mg in the morning and 280 mg in the afternoon). The combination of oral rigosertib and azacitidine was well tolerated, with a median duration of treatment of 4 months (range 1 to 27 months). Adverse events of Grade > 3 experienced across all cycles with the combination included thrombocytopenia (27%), neutropenia (22%), hypokalaemia (5%), hematuria (5%) and diarrhoea (3%).
Operational Update

On March 3, 2016, the Company received notice from Baxalta US Inc. of Baxalta’s election to terminate the September 2012 development and license agreement between Baxalta and the Company for convenience, effective August 30, 2016, following Baxalta’s reprioritization review. In accordance with the terms of the development and license agreement, upon termination, the rights that the Company had licensed to Baxalta will revert to the Company at no cost.

The Company recently cut its workforce by ~17% as an important step towards reducing its operating losses and cash expenditures. Additional cost-optimization measures are being considered for implementation over the next several months.
Upcoming Events

Enrollment of the first patient in the Phase 3 INSPIRE trial in Japan: 1H2016

Peer-reviewed publication of mechanism of action of rigosertib: 2Q2016

Presentation of updated Phase 2 data from oral rigosertib combination trial in MDS: 2Q2016

End of Phase 2 meeting with FDA to discuss data from oral rigosertib combination trial: 2H2016
2015 Financial Results

Cash, cash equivalents, and marketable securities as of December 31, 2015 totaled $19.8 million, compared to $43.6 million as of December 31, 2014. Onconova believes that its current cash and cash equivalents, together with anticipated contractual cost-sharing payments from Baxalta for a portion of the INSPIRE trial costs, and in consideration of the cost optimization measures previously noted, will be sufficient to fund its ongoing trials and operations into the first quarter of 2017.

Net loss was $24.0 million for the year ended December 31, 2015, compared to $63.8 million for the year ended December 31, 2014 due primarily to a 45% reduction in operating expenses and the recognition of deferred revenue in 2015.

Research and development expenses were $25.9 million for the year ended December 31, 2015, compared to $49.4 million for the year ended December 31, 2014,

General and administrative expenses were $9.5 million for the year ended December 31, 2015, compared to $15.1 million for the year ended December 31, 2014.

On March 28, 2016 Diffusion Pharmaceuticals Inc. (OTCQX:DFFN) a clinical stage biotechnology company focused on the development of novel small molecule therapeutics for cancer, reported financial results for the year ended December 31, 2015 and provided an overview of recent operational highlights (Press release, Diffusion Pharmaceuticals, MAR 28, 2016, View Source [SID:1234510058]).

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David Kalergis, Chairman and Chief Executive Officer of Diffusion Pharmaceuticals, said, "2015 was a transformational year for Diffusion. In May, we completed the Phase 2 trial of our lead drug trans sodium crocetinate (TSC) in glioblastoma (GBM) brain cancer with positive top-line results. In August, we received the FDA’s agreement on a Phase 3 clinical trial plan, which could support registration of TSC based on a single pivotal trial. In December, we entered into a merger agreement with RestorGenex Corporation (now known as Diffusion Pharmaceuticals Inc.) and, upon the merger’s closing on January 8, 2016, became a public company. Looking further ahead into this coming year, we have assembled a clinical trial advisory committee of global experts to guide us through our upcoming discussions with the FDA regarding expansion of the use of TSC from GBM into pancreatic cancer, one of the most devastating of all the cancers."

Operational Highlights

On January 8, 2016, Diffusion Pharmaceuticals LLC completed a reverse merger with RestorGenex Corporation in an all-stock transaction. Following the close of the reverse merger, RestorGenex was renamed Diffusion Pharmaceuticals Inc. and the Company’s ticker symbol was changed to "DFFN". In conjunction with the merger, holders of outstanding units of Diffusion Pharmaceuticals LLC were issued approximately 83.0 million shares of common stock in the renamed publicly traded company, bringing the total number of shares outstanding to approximately 101.6 million. The issuance of the 83.0 million new shares thus allowed the Company to add an FDA Phase 3-ready asset to what had previously been a preclinical drug development pipeline.
As a result of the new stock issuance, former equity holders of Diffusion Pharmaceuticals LLC owned approximately 84.1% of the Common Stock and the shareholders of former RestorGenex owned approximately 15.9% of the Common Stock immediately following the merger’s closing on a fully-diluted basis (subject to certain exceptions and adjustments). The 83.0 million newly issued shares of Diffusion Pharmaceuticals Inc., now belonging to former Diffusion Pharmaceuticals LLC holders, have not been registered with the SEC and therefore are not eligible for public trading at this time. The Company has agreed to file a registration statement covering the resale of these shares within 270 days of the merger closing.

Lead Candidate: Diffusion is continuing to advance the clinical development of its lead candidate TSC. TSC has demonstrated positive results in a Phase 2 clinical trial in patients with newly diagnosed GBM. The U.S. Food and Drug Administration (FDA) has granted orphan drug designation for TSC for the treatment of GBM. At the End-of-Phase-2 meeting with the FDA in August 2015, Diffusion reached an agreement with the agency on the design of a single Phase 3 study which, if successful, would be sufficient to support registration. The Company intends to commence the Phase 3 trial within the next 12 months, contingent on the availability of financial resources and the completion of certain manufacturing and animal toxicology guidelines mandated by the FDA agreement.

Pancreatic Cancer Indication: Diffusion is currently in discussions with the FDA regarding a planned Phase 2/3 clinical trial for TSC in pancreatic cancer. The Company has assembled a clinical advisory committee of key opinion leaders in the field of pancreatic cancer to facilitate the development of the program. The Company anticipates commencing the trial in the first half of 2017, assuming the availability of financial resources.

Metastatic Brain Cancer Indication: The Company is also planning a Phase 2/3 clinical trial program with TSC in metastatic brain cancer, an indication for which it has also received orphan drug designation.

Year End 2015 Results
The financial statements for the year ended December 31, 2015 filed Friday, March 25, 2016 via Form 10- K pertain solely to legacy RestorGenex’s operations. Financial statements filed Friday, March 25, 2016 via Form 8-K/A pertain to legacy Diffusion Pharmaceuticals LLC’s operations as of and for the year ended December 31, 2015 and pre-date the closing of the reverse merger on January 8, 2016. The financial results discussed below pertain to legacy Diffusion Pharmaceuticals LLC’s 2015 operations, as reported in the Form 8-K/A, which also includes pro-forma financial statements for the combined company.

Research and development expenses were $3.9 million for the year ended December 31, 2015, compared to $2.0 million in the prior year. The increase was attributable primarily to the clinical development activities for the TSC Phase 2 clinical trial in GBM that was completed in the second quarter 2015.

General and administrative expenses were $2.5 million for the year ended December 31, 2015, compared to $1.3 million for the year ended December 31, 2014. The increase was attributed primarily to costs associated with the merger transaction.

Net loss was $6.7 million for the year ended December 31, 2015, compared to a net loss of $3.5 million for the year ended December 31, 2014.

Cash, cash equivalents, and certificates of deposit were $2.0 million as of December 31, 2015, compared to $4.8 million as of December 31, 2014. On a pro forma combined basis in conjunction with the closing of the merger with RestorGenex, cash, cash equivalents, and certificates of deposit were $14.0 million for the year ended December 31, 2015.

Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan.
An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period.
Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups.
Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy.
View Source ; Identifier: JapicCTI-132398.

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Leuprorelin acetate, a luteinizing hormone-releasing hormone agonist, is used worldwide in premenopausal women with hormone receptor-positive breast cancer. This study was conducted to assess the non-inferiority of the 6-month depot formulation, TAP-144-SR (6M) 22.5 mg to the 3-month depot formulation, TAP-144-SR (3M) 11.25 mg in postoperative, premenopausal patients with hormone receptor-positive breast cancer.
This was a 96-week phase III, randomized, open-label, parallel-group comparative study. All patients concomitantly received oral tamoxifen (20 mg daily). The primary endpoint was the suppression rate of serum estradiol (E2) to the menopausal level (≤30 pg/mL) from Week 4 through Week 48.
In total, 167 patients were randomized to receive TAP-144-SR (6M) (n = 83) or TAP-144-SR (3M) (n = 84) and the E2 suppression rate was 97.6 and 96.4 %, respectively. The estimated between-group difference was 1.2 % (95 % confidence interval -5.2 to 7.8). The non-inferiority of TAP-144-SR (6M) to TAP-144-SR (3M) for E2 suppression was confirmed. As for safety, common adverse events were hot flush and injection site reactions including induration, pain, and erythema in both treatment groups, which were of ≤Grade 2 in severity and not serious. No significant between-group differences in safety profiles and tolerability were observed.
TAP-144-SR (6M) was not inferior to TAP-144-SR (3M) for its suppressive effect on serum E2. TAP-144-SR (6M) was also as well tolerated as TAP-144-SR (3M).

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The purpose of this analysis was to develop a population pharmacokinetic (PK) model for patritumab, a fully human monoclonal antibody that targets human epidermal growth factor receptor 3.
A total of 833 serum concentrations were included in this analysis; serum concentrations were obtained from 145 subjects (136 with non-small cell lung cancer, nine with solid tumors) treated with patritumab [9 or 18 mg/kg intravenously every 3 weeks (q3w)] in one phase 1 and one phase 1b/2 study. Data were analyzed by nonlinear mixed-effect modeling.
Patritumab PKs were best described through a two-compartment model with first-order elimination and interindividual variability on clearance (CL), volume of the central compartment (V c), distributional clearance, and volume of the peripheral compartment. In the final model, CL and V c were estimated as 0.0238 L/h and 3.62 L, respectively. Body weight (BW) and baseline albumin were found to be covariates for CL and BW was a covariate for V c. Covariates associated with hepatic and renal impairment were not significant on CL. Simulations showed that BW-based dosing reduced interindividual variability in patritumab exposure compared with fixed dosing.
The PK of patritumab was linear at the doses studied and well described by the two-compartment model. Hepatic and renal impairment did not appear to affect PK. Our results support BW-based dosing of patritumab on a q3w schedule.

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