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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Controversy exists as to whether erectile response to phosphodiesterase type 5 inhibitors is compromised in men with low total testosterone (TT) levels. This is amplified by reports of improved response to phosphodiesterase type 5 inhibitor therapy after coadministration of testosterone replacement therapy in hypogonadal men unresponsive to phosphodiesterase type 5 inhibitors.
To determine whether TT and luteinizing hormone levels influence efficacy of tadalafil for erectile dysfunction in men with concomitant lower urinary tract symptoms and benign prostatic hyperplasia.
This integrated analysis included 1,075 men randomized to once-daily tadalafil 5 mg (n = 540) or placebo (n = 535) for 12 weeks in three prospective clinical trials who had not received concomitant testosterone replacement therapy. Subjects were categorized at baseline by low vs normal TT levels (n = 1,049; <300 vs ≥300 ng/dL) and normal vs high luteinizing hormone levels (n = 1,058; ≤9.4 vs >9.4 mIU/mL). Treatment-group differences in International Index of Erectile Function (IIEF) by hormone subgroups were assessed using analysis of covariance.
Changes in IIEF erectile function domain and other domain scores.
The overall study population was comprised primarily of white men (>86%) with a mean age range of 64 to 70 years. Median baseline TT level in the integrated population was 355 ng/dL; levels were lower than 300 ng/dL (cutoff for normal) in 32.4% of men. Men with low TT levels reported diabetes (21.8%), cardiovascular disease (54.1%), and hypertension (49.1%) numerically more often than men with normal TT levels (10.6%, 43.2%, and 36.7%, respectively). Low TT and high luteinizing hormone levels were associated with numerically, but not statistically significantly, lower 12-week IIEF domain scores compared with those with normal levels. Changes in most 12-week IIEF domain scores showed that tadalafil was significantly more effective than placebo (P < .02).
Low TT levels at baseline did not negatively influence response to tadalafil in men of advancing age with concomitant lower urinary tract symptoms and benign prostatic hyperplasia and erectile dysfunction.
Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

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