Rockwell's Triferic Has Zero Clinical Relevance - Sell Ahead Of The Upcoming AdCom

| About: Rockwell Medical, (RMTI)

Summary

Rockwell Medical is awaiting a November 6th FDA Advisory Committee for its lead candidate Triferic – an iron replacement therapy for CKD patients receiving dialysis.

The protocols of the Triferic clinical trials conducted by Rockwell, as well as the results of those trials, lack any clinical meaning or relevance.

In the pivotal CRUISE studies, the effect of Triferic on hemoglobin levels wasn’t clinically different from placebo, and the Triferic arm exhibited very high dropout rates.

In the PRIME study, not only did Triferic treatment fail to lower ESA dose requirement, but 24% of Triferic-treated patients required rescue i.v. iron administration.

Given the above, we expect very harsh and critical briefing documents, followed by a negative AdCom recommendation.

Introduction

Rockwell Medical (NASDAQ:RMTI) is currently awaiting an FDA Advisory Committee hearing on its lead candidate Triferic (Soluble Ferric Pyrophosphate, or SFP) intended for delivering iron to patients who are receiving dialysis treatments via dialysate, rather than intravenously or orally. Since presenting the results of several Triferic studies at the 2013 ASN Conference, Rockwell has been generating hype amongst investors, having gained nearly 50% on its share price since the release.

On the surface, Triferic's FDA approval appears to be a walk in the park. The drug's studies to date met all clinical endpoints with statistical significance, while demonstrating a sound safety profile. In reality, however, Triferic results may be deluding investors. Whilst the trial protocols devised by Rockwell may have yielded statistically strong results, they have no clinical relevance. The scenario in which Triferic was shown to be effective is neither realistic for a real-world clinical context nor did it adhere to any procedures which are commonly used in dialysis clinically. In fact, the questionable trial protocols set up by Rockwell have never been used before in studies involving any equivalent-indication iron supplement which has reached the market. It is uncertain how and indeed if the FDA was ever in agreement with the drug's study design.

In addition, the company's dubious and shareholder-unfriendly conduct casts a shadow over the general credibility of information the company supplies to investors. The full results of the two pivotal CRUISE studies have still never been made publicly available, an open-label extension safety study completely lacks results, and the company's CEO has consistently made claims of Triferic's superiority to existing treatments when in fact Rockwell has provided almost zero proof to back such claims.

We believe that, whether or not Triferic is an effective iron treatment, Rockwell has not provided sufficient proof of its efficacy, safety, equivalence to current standard of care, and most importantly - clinical relevance. We are confident that many of these issues will be raised in the FDA briefing documents that will be released on November 4th in advance of Triferic's November 6th FDA Advisory Committee hearing, and that the FDA will be unable to approve the drug based on the current information Rockwell has supplied.

Rockwell Medical and Triferic: Background

Rockwell Medical has been operating as a dialysis concentrate manufacturer and supplier since 1996 and has recently joined the specialty pharma niche. The company's first and only innovative candidate is Triferic, intended to be delivered to hemodialysis patients via dialysate, replacing iron that is lost during a dialysis treatment. Triferic was invented and patented by Dr. Ajay Gupta, and was subsequently licensed by Rockwell in 2002. Gupta is now Rockwell's Chief Scientific Officer and is in charge of developing Triferic.

Triferic is a salt form of soluble iron which is strongly complexed by pyrophosphate and theoretically does not cause toxicity during systemic administration due to the fact that it lacks carbohydrate and is not treated as a foreign particle in the body. According to RMTI, Triferic also never reaches the liver, binding to apotransferrin directly in the blood, subsequently directly reaching the bone marrow.

Triferic is indicated for the treatment of iron loss or iron deficiency to maintain hemoglobin in adult patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD 5HD) and to reduce the prescribed dose of erythropoiesis stimulating agents (ESAs) required to maintain desired hemoglobin levels.

Rockwell filed a New Drug Application (NDA) with the FDA on May 28 '14 and is awaiting an FDA Advisory Committee hearing on November 6th. The AdCom's briefing documents should become available on November 4th. Triferic's PDUFA is booked for January 24th, 2015.

Chronic Kidney Disease Standard of Care

Over 2.5 million of CKD patients globally undergo regular kidney dialysis. These patients often suffer from iron deficiency anemia caused by "leakage" of 5-7mg of iron during the dialysis treatment and are commonly supplemented with iron to bring hemoglobin levels to the standard recommended range of 10 - 11 g/dl (previously 10 - 12 g/dl). Such supplementation requires co-administration of ESAs - kidney hormones which induce the bone marrow to produce red blood cells. This co-administrative treatment has limitations in that a compound called hepcidin traps the foreign iron in the liver, eventually causing toxicity and the need for higher doses of ESAs, which are pricey.

Dialysis Procedures and Current Iron Treatments

Currently, iron is delivered to dialysis patients orally or, most commonly via injection or infusion. The frequency of dosing will vary on individual blood parameters and is commonly re-adjusted in response to amounts of markers, such as ferritin or transferritin. A common clinical-setting dialysis ESA/iron adjustment procedure is outlined here.

In theory, Triferic appears to be an ideal iron supplement for dialysis patients because iron delivery via dialysis seems convenient, direct, real-time and supposedly cheaper and safer than other forms of iron. Dialysate iron would eliminate the need for extra intravenous/oral administration and potential unwanted GI and hepatic toxicity side effects.

PART 1: TRIFERIC STUDIES PROVIDED CLINICALLY MEANINGLESS DATA

To date, Rockwell ran a Phase IIa and a IIb dose-escalating studies, two identical Phase III efficacy studies called CRUISE-1 and CRUISE-2 and a Phase II PRIME study aimed to demonstrate Triferic's effect on diminishing the necessary dose of ESAs in maintaining hemoglobin levels. The company also ran a Phase III safety study on 718 HD-CKD patients for which Rockwell never released full results. None of the studies paint a convincing picture about Triferic's efficacy or clinical relevance:

1. The Phase III CRUISE Studies were conducted according to a Clinically Irrelevant Protocol

The two CRUISE studies are likely to form the focus of the FDA AdCom hearing. Their protocol is outlined in table 1.

Table 1. Protocol description of CRUISE-1 and CRUISE-2

CRUISE-1

CRUISE-2

Description

A randomized, placebo-controlled, Phase III study to confirm the safety and efficacy of TRIFERIC dialysate solution in maintaining iron delivery for erythropoiesis in anemic adult patients with CKD receiving hemodialysis.

Initiation date

March 2011

April 2011

Duration

48 weeks unless withdrawn/removed prematurely

No. of patients

305

294

Active drug arm

TRIFERIC - 11 micrograms of iron / deciliter ((dl)) of dialysate 3-4 times a week

Placebo arm drug

Zero-iron standard dialysate 3-4 times a week

Run-in period

1-4 weeks of no oral/IV iron, no changes in dose/route of ESA allowed

Primary endpoint

Mean change from baseline in hemoglobin (Hgb)

Secondary Endpoints

Decrease in Hgb to < 9 g/dl sustained for ≥ 2 consecutive weeks;

Decrease in Hgb of ≥ 1 g/dl from baseline sustained for ≥ 2 consecutive weeks;

Decrease in ferritin to < 100 µg/l sustained for ≥ 2 consecutive weeks;

Hgb concentration in the range of ≥ 9.5 to ≤ 11.5 g/dl;

TSAT in the range of 20-50%;

Ferritin in the range of 200-800 µg/dl

Removal Criteria

Patients were removed from the study if: 1. There was a need to change ESA dose for low or high (< 90 or > 120 g/l) hemoglobin values; 2. There was a rapidly rising hemoglobin defined as > 115 g/L and an increase of 10 g/l over 4 weeks; or 3. serum ferritin was < 100 µg/l

The CRUISE Protocol raises red flags which are not likely to slip past the FDA:

1. Placebo patients were given absolutely no iron for up to 48 weeks, and were removed from the study as soon as their hemoglobin levels reached dangerously low levels. Aside from the potential risks to the placebo patients, it is also extremely uncommon, unnecessary and not clinically relevant, as no patient would be receiving zero iron in a realistic clinical setting.

Such a study protocol, whereby placebo patients receive no iron at all, has never been run by any of Rockwell's competitors (Amag, Sanofi, Vifor). All of the FDA-approved iron supplements were tested alongside another form of iron supplementation (most commonly oral iron). It is likely that Rockwell was well aware of this, but chose to utilize a controversial study protocol because Triferic would not reach any endpoint with statistical significance alongside another form of iron due to its weak effect (described below).

2. In addition, despite lowered ESA/hemoglobin levels recommendations released by the FDA in June of 2011, Rockwell did not make the recommended changes to the "high hemoglobin" threshold value of 12g/dl which was part of the CRUISE protocol, and which should have become 11g/dl. Throughout the 48-week study, many patients were potentially put at risk by receiving ESA treatments when they reached what was now considered dangerously high levels of hemoglobin. The failure to change the protocol in line with FDA recommendations also renders the results of Triferic studies not relevant to a modern clinical setting.

2. The CRUISE trials' results raise questions about Triferic's clinical relevance

The results from the CRUISE-1 and 2 studies were announced on July 11, 2013 and Sept 4, 2013, respectively. The company presented the studies' results as positive, stating that both studies "Met Primary and Key Secondary Endpoints…as a Treatment for Iron Replacement in Chronic Kidney Disease Patients on Dialysis."

However, when going over the available data, clear and pressing issues emerge that suggest lack of activity by Triferic:

Rockwell may have deliberately tried to conceal a weak clinical effect by converting standard hemoglobin units

1. The effect of Triferic on Hemoglobin level is too small to have any clinical meaning

2. Surprisingly high dropout/withdrawal rate in the Triferic arm

Triferic showed no clinical effect beyond standard Hemoglobin cycling

Rockwell never made the full results of CRUISE 1 and 2 available to the public, instead releasing excerpts of the findings in press announcements. The results of the two CRUISE studies are shown in Table 2.

Despite the fact that every single trial protocol registered by Rockwell featured the standard hemoglobin measurement units of g/dl, the CRUISE results were suddenly and without warning released to the press in g/l units. The sole purpose of such a change would be to deliberately make each result measurement appear 10-fold higher (a 0.6g/dl measurement is equivalent to 6g/l).

The results in table 2 have been converted back to g/dl units (in parentheses) in order to demonstrate the actual minimal changes achieved in the studies.

Table 2. Results of CRUISE-1 and CRUISE-2 trials

CRUISE-1

CRUISE-2

TRIFERIC

Placebo

TRIFERIC

Placebo

Mean difference in Hgb change from baseline between placebo and TRIFERIC

3.6 g/l
(0.36 g/dl)

3.6 g/l
(0.36 g/dl)

Baseline Hgb readings

109.6 g/l
(10.96 g/dl)

109.0 g/l
(10.90 g/dl)

109.6 g/l
(10.96 g/dl)

109.3 g/l
(10.93 g/dl)

Change from baseline

0.6g/l
(0.06g/dl)

-3.0g/l
(-0.3g/dl)

-0.5 g/l
(-0.05 g/dl)

-4.0 g/l
(-0.4g/dl)

Terminations

Safety reasons (related to Hbg levels)

69

83

68

90

Iron or ESA administration

19

22

14

22

Blood Transfusions

1

7

5

5

Total

89 (59%)

112 (73%)

87 (61%)

117 (81%)

What the results are showing is in fact that there is no clinically relevant difference between placebo and Triferic readings (see figure 1 for graphic illustration):

1. The mean difference in change from baseline between placebo and Triferic was 0.36g/dl out of a range of 3g/dl (the allowed hemoglobin range of 9-12 g/dl for patients throughout the study).

2. Moreover, the end of treatment hemoglobin readings achieved in both the placebo arm and drug arm fall perfectly within the normal hemoglobin range guidelines, with the placebo reading well above the lower limit.

3. Another emphasis to the irrelevance of the 0.36g/dl difference between the placebo and Triferic arms is provided by the fact that the laboratory variation of hemoglobin measurement amounts to 0.5 g/dl within a given blood sample. This 0.5 gr/dl measurement error finding is based on samples collected from over 65,000 dialysis patients, which and also revealed that hemoglobin levels fluctuate by >1 g/dl within 6-month periods (source). 90% of patients undergo such frequent hemoglobin fluctuations when receiving ESA treatment.

Unfortunately, Rockwell never released full weekly data which could have demonstrated a hemoglobin cycling pattern in the placebo group. Based on the fact that according to end of treatment readings alone, study groups can't be clinically differentiated, the results of the CRUISE trials lack clinical meaning.

Figure 1. Placebo and Triferic patients' hemoglobin levels relative to FDA-recommended boundaries (CRUISE-1)

High dropout/withdrawal rate in the Triferic group

Another major issue with the under-performance of the Triferic arm is related to unimpressive discontinuation rate: the CRUISE trials were planned as withdrawal studies, with a set of pre-specified removal criteria based on hemoglobin/iron levels (see in table 1). Since only patients in the Triferic arm were receiving iron (placebo arm did not receive any iron), it was expected that the dropout rate from the Triferic arm would be minimal.

Surprisingly, that was not the case, as 59%-61% of patients in the Triferic arms were not able to complete the study, in contrast with 73%-81% of placebo patients (CRIUSE 1 and 2, respectively; Table 2). Most commonly, the patients dropped out because they needed ESA adjustments (due to unsafe hemoglobin levels), which were not permitted per study protocol.

What the termination rates show is that in ~60% of patients receiving Triferic, hemoglobin levels were not balanced and that patients required either lower or higher ESA doses than they were receiving. In a conference call discussing the issue, Rockwell's CSO, Ajay Gupta, has produced contradictory (see below) claims that this was due to Triferic's strong efficacy in raising hemoglobin levels: "You would expect that in the Triferic group, the patients' hemoglobin would rise. And once the hemoglobin rises above 12 [g/dl], we cannot keep the patient in the study because the ESA dose is clamped. And for safety reasons, the ESA has to be reduced, and therefore, these patients are not dropped out. They are actually removed from the study because of high hemoglobin so that the ESA dose can be titrated."

This claim was never supported by data published by the company. Importantly, this claim seems to directly contradict the results of the PRIME study described below.

3. The PRIME study showed that Triferic requires higher ESA dosing

The PRIME study was a Phase II, randomized, placebo-controlled, multi-center study that enrolled 108 patients. A total of 103 patients received Triferic treatment or placebo (Triferic = 51, placebo = 52). Treatment was dialysate containing Triferic, and placebo was conventional dialysate without additional iron over a 36-week period. The patients in the Triferic group received iron via dialysate during each of the 3-4 weekly dialysis sessions, placebo patients received ESA treatment in order to stay within a 9.5-11.5 g/dl hemoglobin range. Rescue IV iron was administered if a patient's ferritin levels fell to <200 μg/L and/or TSAT fell to <15%.

The PRIME study was seemingly meant to be the most impressive Triferic study, and showed that patients receiving placebo required 35-37% higher doses of ESAs than did the Triferic arm. However, as in the CRUISE studies, the PRIME study's results yet again demonstrated serious issues with the design and results.

The results of the PRIME study, which are presented in table 3 indicated that:

1. Triferic treatment did not result in lower necessary doses of ESA treatment, as Rockwell's CSO suggested. In fact, it required an additional 1000 unit/week at end of treatment compared to baseline dose.

2. The difference in end of treatment ESA doses between the study arms was driven almost purely by the expected increased ESA requirement in the placebo arm (which was deprived of any iron supplementation).

3. A substantial number of Triferic patients (24%) also required rescue IV iron administration.

Table 3. Results of the PRIME study

TRIFERIC group (n=51)

Placebo (n=52)

Baseline Hgb readings

10.9 g/dl

11.1 g/dl

Baseline ESA dose

9448 U/wk

9049 U/wk

End-of-treatment ESA dose

10557 U/wk

13345 U/wk

Rescue iron administration

12

20

Discontinuation(s)

11

11

Discontinuations due to serious adverse events

2

3

The results of the PRIME study demonstrated a clear lack of Triferic efficacy

The study protocol utilized in the PRIME study, while conforming to clinical recommendations, did not follow a common clinical protocol and was not clinically relevant. In essence, the protocol was tweaked to create an imbalance between iron and ESA dosing, which ultimately led to a marked increase in ESA administration to those patients whose iron levels were not maintained regularly.

In fact, if iron is properly maintained during dialysis, ESA dosing should also follow a stable path. Patients receiving placebo in the study were administered iron only when their ferritin levels fell to <200 μg/L and/or their TSAT fell to <15%. In the clinical setting, such patients' ferritin levels should have been maintained at 500 - 1000 μg/L, and TSAT values maintained at 22 - 50%.

If Triferic was an effective iron replacement treatment, the active-arm patients should not have reached the low-end ferritin and TSAT readings, and in fact should not have required higher dosing of ESA. Instead, 24% of patients who were regularly administered Triferic eventually needed iron rescue. The whole Triferic patient arm also needed increased dosing of ESA, which does not commonly happen in the clinical setting when iron levels are sufficiently maintained. In fact, treatment guidelines suggest that the initial ESA level should be gradually decreased to ~75% of the starting dose over the maintenance period.

What the PRIME study actually demonstrated is that Triferic did not provide enough iron to maintain a stable iron-ESA relationship, and that the company's claim (following the CRUISE studies) that the use of Triferic leads to lowered ESA dosing is factually incorrect.

All in all, it would appear that regular administration of Triferic via dialysate is simply not a good enough iron replacement drug.

PART 2: ROCKWELL'S MANAGEMENT IS NOT ACTING IN SHAREHOLDERS' INTERESTS

In our view, Rockwell's management has consistently exhibited shareholder-unfriendly conduct. In addition to the fact that the timeline for Triferic's clinical development has been consistently pushed back (it is now >1.5 years behind schedule), several lingering issues with the company's management seriously undermine Rockwell's overall credibility:

1. Rockwell Continues to Imply Unfounded Efficacy Superiority Claims

In a 2002 press release, Rockwell's CEO Robert Chioini released the following statement: "ferric pyrophosphate administered via dialysate is a safer, more effective and less costly method to deliver the needed iron to the dialysis patient." This was once again reiterated in 2005, "Rockwell's iron-delivery product provides a safer, more effective and less costly delivery of iron to the dialysis patient." The company continues to attest that Triferic "significantly reduces ESA dose."

To date, the company has done absolutely nothing to prove beyond sheer theoretical speculation that Triferic is indeed a more effective or safer method of iron delivery to dialysis patients than available treatments on the market. Despite this, the company continues to release factually incorrect information to investors under the continued pretense that Triferic has somehow demonstrated superiority to existing treatments.

2. Rockwell has consistently withheld detailed clinical data from investors

It is common practice, conducted by most reputable pharmaceutical companies, to publish the full data set of their clinical studies in medical conferences or scientific journals. For all but two dose-ranging studies, the detailed information for Triferic is missing. The most detailed information the company has ever released was contained in the posters, presentations and abstracts made available to attendees of the ASN Conference in 2013.

Results of one study, TRIFERIC-6, which was a Phase III 718 CKD-HD-patient-extension study of the CRUISE trials, were never made available even in top-line form. The most information investors received on the study was a very general press release containing a mere "We continue to be impressed with Triferic and its safety profile," by Rockwell's CMO.

The lack of detailed trial information is not only suspicious but also constitutes poor conduct towards investors.

Conclusion

All in all, we predict harsh and negative FDA briefing documents will be posted in light of the following:

None of Triferic's major studies had a clinically realistic or relevant protocol:

1. The Phase III CRUISE studies were designed to "drain" placebo patients of iron

2. The PRIME study did not follow proper ESA dosing and did not utilize standard clinical blood marker parameters

Triferic has not demonstrated any clinically meaningful efficacy:

1. Results of the CRUISE studies were nothing more than standard and expected fluctuations in hemoglobin levels in response to ESA treatment

2. No clinically significant difference between the Triferic and placebo arms was apparent in the CRUISE studies

3. The PRIME study has not demonstrated that Triferic lowers the required ESA dosing. It only showed that dialysis-dependent CKD patients, put on an improper clinical protocol (withheld iron replacement), required elevated ESA dosing.

Rockwell has other issues outside the direct scope of clinical trials which create added risk and undermine the credibility of the company's management

We are confident that the FDA Advisory Committee will not vote in favor of Triferic's approval, and that Triferic's chances of reaching the market without additional FDA-requested studies are extremely low. Such additional studies would cause an 18-24 months setback for the company towards resubmission of the Triferic NDA. Given the company's low revenues and very small profit margin, such a scenario should send RMTI's stock price to the $3-4 range.

The report can be downloaded from the Phase Five Research website.

Disclosure: The author is short RMTI.

The author wrote this article themselves, and it expresses their own opinions. The author is not receiving compensation for it. The author has no business relationship with any company whose stock is mentioned in this article.

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