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Rockwell Medical Technologies (RMTI)'s Iron Deficiency Drug Succeeds in Second Phase 3 Trial; Stock Rises +9.05% at Market Close (September 4, 2013)


9/4/2013 6:50:15 AM

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Rockwell Medical Announces SFP Meets Primary and Key Secondary Endpoints in Phase 3 CRUISE-2 Efficacy Study as a Treatment for Iron Replacement in Chronic Kidney Disease Patients on Dialysis

WIXOM, MI--(Marketwired - September 04, 2013) - Rockwell Medical (NASDAQ: RMTI), a fully-integrated biopharmaceutical company targeting end-stage renal disease (ESRD) and chronic kidney disease (CKD) with innovative products and services for the treatment of iron deficiency, secondary hyperparathyroidism and hemodialysis, today announced successful top-line results from the long-term CRUISE-2 Phase 3 efficacy study of SFP. SFP is the Company's late-stage investigational iron-delivery drug for the treatment of iron deficiency in chronic kidney disease patients receiving hemodialysis. In this study, SFP met the primary endpoint, demonstrating a statistically significant mean change in hemoglobin from baseline to End-of-Treatment. Additionally, SFP met key secondary endpoints, including maintenance of hemoglobin, maintenance of reticulocyte hemoglobin, and increase in serum iron pre-to-post treatment without an increase in ferritin. This long-term study is the second and final study of two identical Phase 3 efficacy studies to provide clinical data required for the Company to file a New Drug Application (NDA) with the U.S. FDA.

Rob Chioini, Founder, Chairman and CEO of Rockwell Medical stated, "As we were with CRUISE-1, we are thrilled with the successful outcome of this CRUISE-2 efficacy study. This second Phase 3 study produced identical results to the first in demonstrating statistical significance and meeting the primary efficacy endpoint. The data again shows that in place of IV iron, SFP appears safe and effective as an iron replacement therapy that consistently maintains hemoglobin levels without increasing iron stores. The demonstrated efficacy and excellent safety data from each of the two Phase 3 CRUISE efficacy studies gives us great confidence in obtaining FDA regulatory approval. These successful results, coupled with the recent positive PRIME study data demonstrating SFP's ability to significantly reduce ESA use, support our belief that SFP will establish a new paradigm in iron therapy treatment for hemodialysis patients. We believe that upon FDA approval, SFP will become the new standard of care in iron therapy."

Primary Efficacy Endpoint
The CRUISE-2 study successfully met its pre-defined primary efficacy endpoint, which was a change in hemoglobin from Baseline to End-of-Treatment between the SFP and placebo groups. The mean difference between SFP and placebo was 3.6 g/L (95% CI 0.8, 6.3) in favor of SFP, and was statistically significant (p=0.011).

At baseline the two groups had similar hemoglobin levels (109.6 g/L SFP and 109.3 g/L placebo). The mean adjusted change from baseline hemoglobin to the end of the randomized treatment period in the SFP group was -0.5 g/L (95% CI -2.6, 1.7). In placebo there was a statistically significant decline of -4.0 g/L (95% CI -6.2, -1.9).

Key Secondary Endpoints
The key secondary endpoints at End-of-Treatment showed statistically significant differences between the SFP and placebo groups, including the pre-dialysis reticulocyte hemoglobin (CHr) and serum ferritin. CHr, an early index and the best marker of iron-delivery to the bone marrow, was maintained at baseline levels in the SFP group during the randomized treatment, compared to a significant decrease in the placebo group. At End-of-Treatment, the difference between groups was a statistically significant 0.97% difference in favor of SFP (p=0.017). Serum ferritin, a marker of tissue iron stores, declined by 11.6% from baseline in the SFP arm while the placebo group ferritin level declined by 21.7%. The difference between groups was statistically significant (p < 0.001). These results indicate that hemodialysate containing 2 µM SFP iron delivers sufficient iron to maintain erythropoiesis and does not lead to tissue iron overload.

Safety
Overall, the adverse events reported were consistent with what are expected in the chronic hemodialysis population. There were no differences in frequency or severity between the SFP and placebo groups with respect to AEs or serious adverse events. Importantly, the incidence of intradialytic hypotension, infections, and cardiac events in the SFP group was similar to that observed in the placebo group. There were no events of anaphylaxis reported with dialysis administrations of SFP.

----------------------------------------------------------------------------
                                              SFP N=149       Placebo N=151 
             Adverse Events                     N (%)             N (%)     
----------------------------------------------------------------------------
Procedural (Intradialytic) Hypotension       20     (14.0)     16     (11.0)
----------------------------------------------------------------------------
AVF complication                             14      (9.8)     15     (10.3)
----------------------------------------------------------------------------
Hemodialysis induced Symptom                 10      (7.0)      8      (5.5)
----------------------------------------------------------------------------
AVF Hemorrhage or Thrombosis                 12      (8.4)      4      (2.8)
----------------------------------------------------------------------------
AVG complication or Thrombosis                2      (1.4)      4      (2.8)
----------------------------------------------------------------------------
Infections                                   38     (26.6)     38     (26.6)
----------------------------------------------------------------------------
Cardiac Disorders                            20     (14.0)     19     (13.3)
----------------------------------------------------------------------------

Dr. Raymond Pratt, Chief Medical Officer of Rockwell Medical, commented on the results, "We are extremely pleased again to see outstanding clinical results for safety and efficacy in this second Phase 3 study. We congratulate the investigators and our clinical team for their dedication and work. The successful achievement of meeting the CRUISE-1 and CRUISE-2 primary efficacy endpoints with statistical significance confirms our belief that SFP, administered via dialysate, safely and effectively replaces the iron loss experienced by hemodialysis patients. The positive CHr and ferritin data are impressive, and demonstrate that iron from SFP is directed primarily to erythropoiesis and not to the RE system. The safety profile for SFP, which is again similar to placebo treated patients, is excellent and to date we have not identified a single safety issue directly attributable to SFP administration. The CRUISE 2 study confirms the results of the CRUISE -1 and PRIME studies and increases our confidence that Rockwell will achieve the goal of making this iron product available as a maintenance treatment for patients with CKD-HD."

Dr. Ajay Gupta, Chief Scientific Officer of Rockwell Medical added, "This successful CRUISE-2 study data confirms our belief that SFP is an extremely safe drug that consistently maintains hemoglobin and that can effectively replace the need for general IV iron administration in dialysis patients. The two Phase 3 CRUISE studies are together the first demonstration of an iron therapy preventing the development of the iron deficient state and iron deficiency anemia in hemodialysis dependent CKD patients. The increasing safety concerns centered on IV iron, with tissue iron overload, infections, and anaphylactic reactions, highlight the importance of the strong safety profile SFP has demonstrated in our large clinical program, comprising close to 100,000 human doses of SFP iron. In contrast to the rapid bolus administration of IV iron, SFP delivers iron slowly and continuously in a physiologic manner during every hemodialysis session replacing dialytic iron loss. SFP has the potential to be the first and only iron product indicated for maintenance of hemoglobin and reducing ESA utilization, and we fully expect SFP to become the new standard of care for iron management in CKD-HD patients."

Study Design
The CRUISE-2 study was a single-blind, placebo controlled, parallel group study comparing SFP (2µM [110 µg iron/L] delivered via hemodialysate concentrate) to placebo (standard hemodialysate concentrate). Adult patients with chronic kidney disease on regular hemodialysis, who were receiving stable doses of erythropoiesis stimulating agents (ESAs) and who were iron replete (as measured by serum transferrin saturation between 15% to 40% and serum ferritin between 200 to 800 µg/L), were eligible for randomization. The study consisted of 3 stages: run-in, randomization and open-label extension.

Patients who met the inclusion criteria entered a run-in period of 1 to 4 weeks. During the run-in, no study drug was administered, and no changes in the dose or route of administration of ESA were allowed. IV and oral iron products were not allowed from run-in through the end of randomized treatment.

Patients who continued to meet inclusion criteria during the run-in period were randomized 1:1 to receive either SFP via dialysate or placebo (standard dialysate) in a blinded manner for up to 48 weeks. Patients received the designated study drug at each dialysis session during the randomized treatment period. Hemoglobin, the measurement for the primary endpoint, was assessed weekly, along with iron parameters every two weeks.

During the run in and randomized treatment stages, patients were not permitted to have their ESA dose adjusted from baseline dose, and were not permitted IV or oral iron. Patients advanced to the open-label stage of the study when they required a change in anemia management based on predefined criteria. The change in anemia management criteria to initiate advancement to open-label stage included: 1) a need to change ESA dose for low or high ( < 90 or > 120 g/L) hemoglobin values, 2) rapidly rising hemoglobin defined as > 115 g/L and an increase of 10 g/L over 4 weeks, or 3) serum ferritin < 100 µg/L. By withholding iron and not allowing ESA dose adjustment during the study period, the study was designed to transition the majority of patients to open-label stage prior to the 48 week study duration, while demonstrating a statistically significant change in hemoglobin from Baseline to End-of-Treatment between the SFP and placebo groups. All patients' hemoglobin values, were included in the primary endpoint calculation. Seventy three (73%) of randomized patients were transitioned to the ongoing open-label extension study.

The primary study population was the modified Intent-to-Treat (mITT) population, defined as all patients who were randomized, and received at least one dose of study drug, and had at least one post-baseline hemoglobin value during the randomized treatment period.

The primary outcome measure for this study was the mean change in hemoglobin level from baseline to the End-of-Treatment. End-of-Treatment was defined as the average of the hemoglobin levels during the last 1/6th of the time each patient was in the randomized treatment period. A minimum of at least two on-study hemoglobin values were necessary for inclusion in the analysis. The primary outcome statistic was provided by an analysis of covariance (ANCOVA) for the change from baseline hemoglobin between treatment groups, using baseline hemoglobin value as a covariate.

Secondary endpoints included the changes from baseline in pre-dialysis reticulocyte hemoglobin (CHr), ferritin and serum iron parameters. Safety endpoints included all treatment emergent adverse events (TEAEs), serious adverse events (TESAEs), intradialytic hypotension, cardiac events and anaphylactic/hypersensitivity events.

Baseline Characteristics
At baseline, the two treatment groups were well balanced with respect to age (mean 58 years), gender (40% female, 60% male), race (54% white, 40% black and 6% other) and ethnicity. The MITT population comprised 142 patients randomized to the SFP treatment arm and 144 patients to placebo. The mean duration of participation in the randomized treatment period was approximately 6 months (23 weeks). Patients transitioned to the extension study for anemia management changes included, 68 patients in the SFP arm and 90 in placebo. Non-protocol changes (in IV iron or ESA given) occurred in 14 patients in the SFP arm and 22 in placebo. Five (5) patients in the SFP arm and 5 patients in placebo were withdrawn due to blood transfusions. Other reasons for early termination were balanced between the groups.

Conference Call Information
Rockwell will host a conference call today, September 4, 2013 at 8:30am Eastern Time to present the top-line results from this Phase 3 CRUISE-2 study for SFP. To participate in the conference call, please call 1-877-383-7438 (U.S.), 1-678-894-3975 (outside the U.S.), call-in ID: 49150189. The call will be webcast simultaneously at http://ir.rockwellmed.com/events.cfm and will be available for replay at this link for 14 days.

About SFP
SFP is a unique iron compound that is delivered to the hemodialysis patient via dialysate, replacing the 5-7 mg of iron that is lost during a dialysis treatment. SFP is introduced into the sodium bicarbonate concentrate on-site at the dialysis clinic, which is subsequently mixed into dialysate. Once in the dialysate, SFP crosses the dialyzer membrane and enters the blood where it immediately binds to apo-transferrin and is taken to the bone marrow, similar to how dietary iron is processed in the human body. In completed clinical trials to date, SFP has demonstrated that it can safely and effectively deliver sufficient iron to the bone marrow, maintain hemoglobin and not increase iron stores (ferritin), while significantly reducing ESA dose.

About Rockwell Medical
Rockwell Medical is a fully-integrated biopharmaceutical company targeting end-stage renal disease (ESRD) and chronic kidney disease (CKD) with innovative products and services for the treatment of iron replacement, secondary hyperparathyroidism and hemodialysis.

Rockwell's lead drug candidate in late-stage clinical development is for the treatment of iron replacement in dialysis patients and is called Soluble Ferric Pyrophosphate (SFP). SFP delivers iron to the bone marrow of dialysis patients in a non-invasive, physiologic manner during their regular dialysis treatment, using dialysate as the delivery mechanism. In completed clinical trials to date, SFP has demonstrated that it can safely and effectively deliver sufficient iron to the bone marrow, maintain hemoglobin and not increase iron stores (ferritin), while significantly reducing ESA dose. SFP has completed the efficacy trials of its Phase 3 clinical study program (CRUISE-1 and CRUISE-2). SFP is expected to address an estimated $600M U.S. market.

Rockwell is preparing to launch its FDA approved generic drug Calcitriol, to treat secondary hyperparathyroidism in dialysis patients. Calcitriol (active vitamin D) injection is indicated in the management of hypocalcemia in patients undergoing chronic renal dialysis. It has been shown to significantly reduce elevated parathyroid hormone levels. Reduction of PTH has been shown to result in an improvement in renal osteodystrophy. Rockwell intends to launch Calcitriol once it receives FDA manufacturing approval, addressing an estimated $350M U.S. market.

Rockwell is also an established manufacturer and leader in delivering high-quality hemodialysis concentrates/dialysates to dialysis providers and distributors in the U.S. and abroad. As one of the two major suppliers in the U.S., Rockwell's products are used to maintain human life by removing toxins and replacing critical nutrients in the dialysis patient's bloodstream. Rockwell has three manufacturing/distribution facilities located in the U.S. and its operating infrastructure is a ready-made sales and distribution channel that is able to provide seamless integration into the commercial market for its drug products, Calcitriol and SFP upon FDA market approval.

Rockwell's exclusive renal drug therapies support disease management initiatives to improve the quality of life and care of dialysis patients and are intended to deliver safe and effective therapy, while decreasing drug administration costs and improving patient convenience. Rockwell Medical is developing a pipeline of drug therapies, including extensions of SFP for indications outside of hemodialysis. Please visit www.rockwellmed.com for more information. For a demonstration of SFP's unique mechanism of action in delivering iron via dialysate, please view the animation video at http://www.rockwellmed.com/collateral/documents/english-us/mode-of-action.html.

Certain statements in this press release constitute "forward-looking statements" within the meaning of the federal securities laws, including, but not limited to, Rockwell's intention to launch Calcitriol and SFP following FDA approval. Words such as "may," "might," "will," "should," "believe," "expect," "anticipate," "estimate," "continue," "predict," "forecast," "project," "plan", "intend" or similar expressions, or statements regarding intent, belief, or current expectations, are forward-looking statements. While Rockwell Medical believes these forward-looking statements are reasonable, undue reliance should not be placed on any such forward-looking statements, which are based on information available to us on the date of this release. These forward looking statements are based upon current estimates and assumptions and are subject to various risks and uncertainties, including without limitation those set forth in Rockwell Medical's SEC filings. Thus, actual results could be materially different. Rockwell Medical expressly disclaims any obligation to update or alter statements whether as a result of new information, future events or otherwise, except as required by law.

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