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Developed by Keryx

An orally active alkyl-phosphocholine compound with potential antineoplastic activity. Targeting cellular membranes, perifosine modulates membrane permeability, membrane lipid composition, phospholipid metabolism, and mitogenic signal transduction, resulting in cell differentiation and inhibition of cell growth. This agent also inhibits the anti-apoptotic mitogen-activated protein kinase (MAPK) pathway and modulates the balance between the MAPK and pro-apoptotic stress-activated protein kinase (SAPK/JNK) pathways, thereby inducing apoptosis. Perifosine has a lower gastrointestinal toxicity profile than the related agent miltefosine.

Current Status

In trial phase II as of March 2007, expected to end December 2007. Has shown some signs of working on Renal Cell Carcinoma

Other Links

Keryx Biopharmaceuticals, Inc.

To view the Main/Home Web Site of Keryx Biopharmaceuticals, Inc. Click Here


09-Nov-2007 - Perifosine (KRX-0401) in Patients with Advanced Renal Cell Carcinoma

Phase 1 & 2 Data of Perifosine (KRX-0401) in Patients with Advanced Renal Cell Carcinoma Presented Today at the 25th Annual Chemotherapy Foundation Symposium

Oral Presentation by Dr. Robert Figlin Highlights Phase 2 Data Showing 31% Partial Response Rate and a 62% Overall Clinical Benefit Rate to Perifosine Used as a Single Agent and Phase 1 Data Showing No Evidence of Increased Toxicity When Combined with Sorafenib

NEW YORK, Nov. 9 /PRNewswire-FirstCall/ -- Keryx Biopharmaceuticals, Inc. today announced positive phase 1 & 2 data of Perifosine (KRX-0401) in patients with advanced renal cell carcinoma (RCC). In an oral presentation entitled "PERIFOSINE: AN ORAL, AKT INHIBITOR WITH CLINICAL ACTIVITY IN ADVANCED RENAL CELL CARCINOMA," Dr. Robert Figlin, Medical Oncology Chair and Professor of Medicine, City of Hope National Medical Center in Duarte, CA provided an update on the clinical activity of single agent Perifosine from a phase 2 trial (Protocol 207), and reported on the safety and efficacy of Perifosine in combination with sorafenib from an ongoing phase I study (Protocol 124).

Phase 2 Single Agent in RCC - Protocol 207

Twenty-four patients with advanced renal cell carcinoma (RCC) were randomized to either the daily (50 mg or 100mg) or weekly (900mg or 1200mg) dose of Perifosine. Patients with measurable disease who received at least 2 courses of Perifosine and at least one Tumour measurement after initiation of Perifosine, were considered evaluable for response using RECIST criteria. Thirteen were evaluable for response. Four of these (31%) had a partial response and an additional 4 patients (31%) achieved long-term stable disease for a 62% overall clinical benefit rate. Five patients progressed. One of the responding patients had previously failed to respond to both sorafenib and sunitinib. The results are as follows:

                                                               50      1200
                                                               or       or
                                                             100 mg   900 mg
   Protocol 207 RCC Update               All Patients         Daily   Weekly
   Enrolled, all tumor types                 416               205     211
   Renal Cell Carcinoma                       24                12      12
   Evaluable for response                     13                 7       6
   Partial responses (RECIST)  4 (Duration 4, 6.5, 9, 12 mo's)   2       2
   Time to Progression > 6 mo's   4 (10, 13, 14, 18+ mo's)       3       1

Times with '+' meaning patient still stable or responding at time of analysis.

Additional renal patients will be enrolled on this study, including patients with prior exposure to sorafenib and sunitinib. Keryx also has two multi-center phase 2 trials underway evaluating perifosine 100 mg as a single agent in pts who have failed a prior TKI (sunitinib or sorafenib), with one of the studies allowing pts who have also failed prior mTOR. Data from these phase 2 TKI failure studies will be presented at upcoming meetings.

Phase 1 Combination Perifosine + Sorafenib - Protocol 124

Eighteen patients with advanced cancers were enrolled in one of four cohorts. Ten of these patients had advanced RCC with some patients having received a prior TKI. No grade 4 toxicities were reported and 1 grade 3 hand/foot syndrome has been seen. The combination has been generally well tolerated. The phase I will enroll an additional 20 patients to confirm the selected MTD.

"The data presented here today further demonstrates Perifosine's promising activity as a single agent. The combination of Perifosine with sorafenib is of great interest and further exploration with this combination in patients who fail a prior TKI is warranted," stated Dr. Robert Figlin, who continued, "We are anxious to further explore the potential of Perifosine, either in comparison to, or in combination with sorafenib, in patients with advanced RCC."

I. Craig Henderson, MD, President of Keryx Biopharmaceuticals, commented, "Perifosine is clearly an active drug in the treatment of renal cell cancer. Now it's time for us to determine how active and to better define the patient populations that will most benefit from Perifosine treatment, either alone or with other drugs."

Based on the promising data in renal cell carcinoma with Perifosine as a single agent and in combination with sorafenib, Keryx Biopharmaceuticals plans to launch a phase 2/3 clinical program in the 1st half of 2008.

About the Phase 2 Trial Design

This company-sponsored, exploratory trial was designed to evaluate the safety and efficacy of two schedules of Perifosine (KRX-0401) in patients with a variety of Tumour types. From February 2005 to May 2007, 416 patients at over 30 centers across the US were first randomized to receive either 50 mg of Perifosine once daily or 1200 mg on a weekly dose schedule and later to either 100 mg daily or 900 mg weekly. Because the daily doses appear to be as effective and clearly less toxic, enrollment continues with randomization between 50 and 100 mg daily. The protocol was designed to accrue 11 patients in a given tumor type and then expand that cohort to 26 patients if a favorable outcome is seen in at least 1 of the first 11 patients. The responses we have seen in this advanced renal cell carcinoma cohort did not appear dose-dependent as partial responses and stable disease were noted in both dose groups. This is consistent with prior data with Perifosine where responses have been equally distributed between higher and lower dose groups.

About the Phase 1 Trial Design - Perifosine + Sorafenib

This company-sponsored trial was designed to evaluate the safety (Part 1) of Perifosine in combination with sorafenib for patients with advanced cancers. Perifosine is escalated from 50 mg qd to 50 mg tid while sorafenib is escalated from 400 mg qd to 400 mg bid. From September 2006 to October 2007, 17 patients at 6 centers across the US were enrolled into one of the four cohorts. No DLT's were observed and extra patients were enrolled to confirm the last two cohorts. The study will move into Part 2 where an additional group of up to 20 patients will be accrued and treated at the determined MTD in order to determine a Phase II dose that will allow patients to remain on-study for at least 12 weeks. The effects of the combination of Perifosine and sorafenib will be evaluated for response rate and time to progression in both parts of the study.


Both, the 50 mg and 100 mg dose have been well tolerated. The main toxicities are nausea, vomiting, diarrhea, and fatigue. In a pooled analysis, % of patients on the continuous daily dose of 50 mg or 100 mg with no GI toxicity was as follows:

                    % with NO Gastrointestinal Toxicity
                         50 mg Daily   100 mg Daily
   Adverse Event           N = 141         N = 68
   Nausea                    57%            63%
   Vomiting                  70%            74%
   Diarrhea                  61%            69%

Perifosine (KRX-0401) Mechanism of Action and Profile

Perifosine has been shown to inhibit or otherwise modify signaling through a number of different signal transduction pathways including Akt, MAPK, and JNK. Akt isoforms have been found to be overexpressed in renal, breast, prostate, and pancreatic cancers. Elevated levels of pAkt have been correlated with poor prognosis in patients with gastric, hepatocellular, endometrial, prostate, renal cell and head and neck cancers, as well as glioblastoma. The majority of Tumours expressing high levels of pAkt were high-grade, advanced stage or had other features associated with poor prognosis.

The effects of Perifosine on Akt are of particular interest because of 1) the importance of this pathway in the development of most cancers; 2) the evidence that it is often activated in tumors that are resistant to other forms of anticancer therapy; and 3) and the difficulty encountered thus far in the discovery of drugs that will inhibit this pathway without causing excessive toxicity.

To date, over 1,500 patients have been treated with Perifosine in trials conducted both in the US and Europe. Its safety profile is distinctly different from that of most cytotoxic agents. It does not cause myelosuppression (depression of the immune system) or alopecia (hair loss) like many currently available treatments for cancer. In phase 1/2 trials it has induced Tumour regressions and/or caused disease stabilization in a variety of Tumour types. Responding patients, including stable disease, have been treated for months to almost 3 years, on both the daily and weekly schedule.

KRX-0401 (Perifosine) is in-licensed by Keryx from Aeterna Zentaris, Inc. in the United States, Canada and Mexico.

About Renal Cell Carcinoma

In 2007, an estimated 51,000 new cases of RCC and 13,000 deaths attributable to RCC are expected in the US. The National Cancer Institute reports a rising incidence of RCC at a rate of approximately 2% per decade. The disease occurs predominantly in the seventh and eighth decades in life, and it affects nearly twice as many men as women.

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