Abarelix for the Treatment of Prostate Cancer

PRAECIS PHARMACEUTICALS INCORPORATED (PRAECIS) is pleased to submit these comments in response to the Centers for Medicare & Medicaid Services’ (CMS) draft decision memo regarding coverage of abarelix (Plenaxis®) in the treatment of patients with advanced symptomatic prostate cancer.* As the manufacturer of Plenaxis®, we have been engaged with CMS in the national coverage determination (NCD) process for Plenaxis® since the agency accepted our request for such a determination in June 2004. We have found this process to be open and collaborative and would particularly like to thank Dr. Steve Phurrough, Dr. Louis Jacques, Dr. Carlos Cano, Elizabeth Truong, Gay Burton and other members of the Coverage and Analysis Group for the time and attention they have devoted to our request.

We would like to commend CMS on its thoughtful and thorough discussion of Plenaxis® and its role in treating patients with advanced symptomatic prostate cancer. We support CMS’ proposal to cover, at this time, only uses of Plenaxis® that are consistent with its label. Plenaxis® is subject to marketing restrictions to ensure its safe use in the indicated population. We believe the draft decision memo furthers our goal of ensuring compliance with such restrictions while also making Plenaxis® available to beneficiaries who need it most. We also believe the draft decision memo, if adopted as the final NCD, will provide consistency in coverage at the local level which will support the Phase 4 and other safety monitoring elements of the risk minimization action plan associated with Plenaxis®. For these reasons, we are supportive of the draft decision memo proposed by CMS.

We look forward to continuing to work with CMS as the draft decision memo becomes final and appreciate the opportunity to provide the agency with the comments discussed below.

Our comments are organized as follows:

I. Discussion of the desirability of establishing continuing authority for reimbursement under protocol as a part of the NCD for Plenaxis® for clinical trials that would benefit the public health;

II. Clarification of certain facts related to Plenaxis®;

III. Clarification of certain facts related to the general clinical endocrine management of prostate cancer; and

IV. Conclusion

I. Addition to the NCD of Continuing Authority for Reimbursement under Protocol

As mentioned above, given the marketing restrictions placed on Plenaxis®, we are supportive of CMS’ decision to restrict coverage of off-label uses. We are, furthermore, supportive of CMS’ proposal to retain sole authority to determine appropriate off-label reimbursement for Plenaxis®. However, we urge CMS to revise the decision memorandum to include for itself a continuing authority to cover off-label uses of Plenaxis® in the context of clinical trials that the agency deems useful and appropriate over time. Such clinical trials would allow important new data of particular importance to Medicare beneficiaries and the provider community to be collected in a controlled fashion. Such data could then serve as the basis for subsequent decisions by CMS for non-protocol, off-label coverage.

We would like to work with CMS and, as appropriate, other federal healthcare agencies, such as the FDA, in developing clinical trials that could benefit the public health, but particularly Medicare beneficiaries who are disproportionately affected by prostate cancer. Below we have described in broad terms examples of two clinical trials that we believe may be of interest to CMS and the FDA that we would like to discuss with CMS further. For purposes of the NCD, however, we are hopeful that CMS will simply reserve the right to cover Plenaxis® in the context of clinical trials that are approved by CMS. We do not necessarily expect that CMS will be in a position to commit to any particular trial at this time.

As mentioned above, the following will discuss broadly two clinical trials that may be of interest to CMS. These proposed trials are merely examples. The first proposed study would test Plenaxis® against the leading, commercially available luteinizing hormone-releasing hormone (LHRH) agonist(s) to determine the effect of testosterone surge and other differential endocrinological effects on disease progression, survival and other health outcomes. The second proposed trial would study Plenaxis® against chemotherapy in patients with androgen independent prostate cancer (AIPC).

A. Use of Plenaxis® in a Practical Clinical Trial in Intermediate and High Risk Populations to Study the Effect of Testosterone Surge and other Differential Endocrinological Effects, among other Factors, on Time to Progression, Survival and other Health Outcomes

PRAECIS proposes that CMS cover under protocol the use and administration of Plenaxis® in studies of prostate cancer patients with a high risk of failure from relapse in a long-term, multicenter, open label, randomized study of Plenaxis® versus the leading commercially available LHRH agonist(s) to determine relative disease progression, survival and other health outcomes. In clinical practice today, LHRH agonists are already reimbursed when used for the patient population contemplated by this study.

Hormonal therapies are frequently used in the management of prostate cancer patients with clinical and pathological features that predict a high likelihood of PSA (biochemical) failure within five years of the initial diagnosis of prostate cancer. One useful scheme for assessing such a risk profile includes the clinical T (tumor) stage, PSA and Gleason pathological score of the prostate cancer. Intermediate risk patients are those defined as individuals with a 50% likelihood of biochemical free survival (i.e., no evidence of PSA failure within 5 years of diagnosis) with the following baseline features: (1) PSA 10-20 ng/mL; (2) Gleason score 7; and (3) clinical T stage of T2b. Those with so-called high risk features have a 33% likelihood of biochemical free survival within 5 years of diagnosis and have the following features: (1) T2c; (2) PSA >20ng/mL; and (3) Gleason score of 8 or greater.1/

The proposed study would randomize patients that exhibit intermediate or high risk features of biochemical failure within 5 years of diagnosis who are to receive hormonal therapy as part of their overall treatment program. Patients would be randomized to one of two treatments – Plenaxis® or an LHRH agonist. Stratifications would be made according to risk category, duration of hormonal therapy, and other prostate cancer interventions (e.g., radical prostatectomy or radiation therapy). This practical clinical study would reflect the “real-world” use of hormonal therapy among diverse groups of patients, treated by a diverse group of physicians, using a diverse group of treatment programs and treatment durations. Specific study endpoints would include: (1) time to first event, defined as either: (a) a biochemical (PSA) failure following initial PSA reduction; (b) demonstration of first evidence of metastatic disease by radiographic evidence (X-ray, computerized scan or radionuclide scan); or (c) progression free survival at prespecified time points such as 2, 4 and 6 years following initiation of therapy; or (2) overall survival at additional prespecified time points.

In addition, an early evaluation would be incorporated to measure any early events occurring within the first 12 months of treatment. Based upon the unique mechanism of action of Plenaxis® compared to LHRH agonists 2/- 3/, it is possible that 1) the avoidance of testosterone surge, leading to more rapid medical castration in these patient populations and 2) the more durable suppression of follicle- stimulating hormone (FSH), among other differential endocrinological effects may be reflected in both an improvement in local, biochemical, or metastatic events, as measured by 12 months of treatment. The study would be powered to consider both the stratifications in outcomes listed above at 12 months. This study would incorporate early stopping rules if the analyses of “event” outcomes differ between Plenaxis® and LHRH agonist arms. Other endpoints particularly relevant to CMS and its beneficiaries, such as quality of life measures, would also be incorporated into the study design to facilitate CMS’ decision-making for more enduring, post-study coverage.

B. Randomized Study of Plenaxis® vs. Chemotherapy in Androgen Independent Prostate Cancer (AIPC)

One of the most critical unmet medical needs facing patients with advanced prostate cancer is the treatment of androgen independent disease. While the majority of men who are diagnosed with prostate cancer will initially respond to androgen deprivation, nearly 30,000 men annually will succumb to the disease. Most of these patients will have developed androgen independent disease, where the prostate cancer is no longer responsive to the effects of lowered testosterone.

While testosterone has been the most studied factor driving the growth of prostate cancer, recent evidence suggests that other hormones, such as FSH, may have independent properties that stimulate the proliferation of prostate cancer cells. Randomized studies have conclusively shown that FSH levels are consistently and significantly higher following surgical castration (the highest levels) or LHRH agonist therapy when compared to Plenaxis® treatment.4/- 6/ By targeting FSH with Plenaxis® in the context of AIPC, one can theoretically interrupt and decrease a growth factor that is not being affected with current hormonal treatments. Preliminary evidence suggests that when Plenaxis® is used in patients with AIPC, anti-cancer activity may result (as determined by declines in PSA levels).

Clinically, once AIPC develops, patients are generally treated palliatively for symptoms, or given chemotherapy. Chemotherapy, though recently shown to have a very modest benefit in prolonging survival in a population of AIPC patients, carries with it significant and substantial toxicity, especially in the elderly population already suffering from co- morbidities.

PRAECIS proposes that CMS cover under protocol the use and administration of Plenaxis® when studied in a population of AIPC patients who are candidates for chemotherapy.

The proposed study would randomize men with AIPC with demonstrable radiographic metastatic disease (as opposed to biochemical - i.e., PSA-only failure) whose next treatment option would be best supportive treatment or chemotherapy. The randomization would be: (1) Plenaxis® alone; (2) chemotherapy with docetaxel/prednisone; or (3) the combination of Plenaxis® with docetaxel/prednisone. Docetaxel/prednisone is approved as a combination therapy for androgen independent metastatic prostate cancer.7/ Recent study results have shown that, when given with prednisone, docetaxel treatment every three weeks led to superior survival and improved rates of response as compared with mitoxantrone plus prednisone.8/ Such a study would evaluate the relative role of the FSH suppression induced with Plenaxis®, as well as the importance of this factor in continued hormonal therapy in addition to chemotherapy. The primary endpoint would be overall survival. Additional parameters that evaluate time to progression, rate of PSA change, and quality of life measures would also be incorporated.

This study could potentially demonstrate a survival benefit of significance to the public health, particularly the Medicare population. Additionally, if the study demonstrated equivalence in survival between Plenaxis® and available chemotherapy, this population of men could potentially avoid the significant toxicities of combination chemotherapy. By selecting men with demonstrated metastatic disease for the study, the medial duration of survival is predicted to be approximately 18 months. Thus, a survival endpoint is likely to be obtained in a relatively short time frame.

II. Clarification of Certain Facts Relating to Plenaxis®

We respectfully submit for your consideration the following clarification of facts cited in the draft decision memo (when printed):

Page 11, first full paragraph: The subject of Plenaxis® has been systematically reviewed in a peer review publication by Mongiat-Aartus and Teillac.9/

Page 13, second paragraph under “Safety”: During the conduct of all Plenaxis® and active comparator studies, elevation of transaminases were noted following both treatment with Plenaxis® and active comparator arms.10/ This characterization may be more accurate than hepatic toxicity.

Page 13, number 2 under “Safety”: An analysis provided to the FDA included a comparison of all elevations of transaminases that occurred with Plenaxis® and active comparator agents. This analysis demonstrated that the number of patients who met the criteria for protocol withdrawal for elevation of transaminases was 1.3% in the Plenaxis® arm compared to 2% of active comparator arms. The numbers cited in Section 2 of the safety discussion of the draft decision memo include only data from US studies, and do not include the pooled data that includes the European randomized trial of Plenaxis® versus Zoladex® and Casodex®.

Page 16, last paragraph: The term “high” is subject to differing meanings and interpretations. PRAECIS would respectfully request that the actual percentage be listed, thus avoiding the ambiguity of, and need to interpret, the term “high.”

Page 18, last paragraph: The same considerations regarding imprecision of wording noted immediately above are applicable to the term “serious.”

Page 20, first full paragraph: The avoidance of orchiectomy in the cited study was determined at 4 and 12 weeks of treatment, not at 8 weeks, as stated.11/

Page 20, second full paragraph: The randomized controlled studies of Plenaxis® to active comparators included a majority of patients with asymptomatic advanced prostate cancer. These populations included patients with stage D1 and D2 disease, those with a rising PSA following definitive localized treatment (so-called Stage D1.5), and those undergoing intermittent hormonal therapy. A minority of patients in these randomized studies had early stage disease.12/- 13/

General comment: There are several places in the draft decision memo that imply that the indicated patient population for Plenaxis® is those with metastatic disease. The majority of patients who served as the basis for the approval of Plenaxis® did indeed have metastatic disease; however, a substantial proportion had regionally advanced prostate cancer, generally characterized as cT3N0M0 or cT4N0M0 patients. These latter individuals had significant urinary difficulties, including urinary retention requiring a urinary catheter, but did not have documented radiographic metastases.10/ In general practice, these regionally advanced prostate cancer patients would typically be treated with Plenaxis® therapy for nine months to one year.

III. Clarification of Certain Facts Relating to the General Clinical Endocrine Management of Prostate Cancer

We respectfully submit for your consideration the following clarification of certain facts relating to the general clinical endocrine management of prostate cancer (as cited in the decision memo when printed):

Page 5, first full paragraph: The agonist induced surge of testosterone and dihydrotestosterone generally lasts between 14 to 21 days.14/-16/

Page 5, third full paragraph, second line: Greater clarification may be obtained by adding the term antagonist “of the androgen receptor” drugs.17/-18/

Page 5, third full paragraph: We respectfully disagree with the observation that antiandrogen monotherapy is an effective alternative to LHRH agonists for metastatic disease. Antiandrogen monotherapy is associated with a decreased survival in men treated adjuvantly for localized disease,19/ and bicalutamide monotherapy (150 mg) has been actively withdrawn from marketing in numerous countries due to this survival disadvantage.20/-21/ Antiandrogen monotherapy has never been approved for any form of prostate cancer treatment in the United States.

Page 16, first two paragraphs under “Clinical Considerations”; Page 18, first full paragraph under “CMS Appraisal”: There is indirect data to suggest that the avoidance of the testosterone surge may be associated with improvements in overall survival in men with prostate cancer.22/- 23/ The addition of an antiandrogen may provide some, but not complete, protection from many of the deleterious clinical consequences of the LHRH agonist induced testosterone surge.24/-25/ The addition of antiandrogens had only a partial effect on abrogating worsening bone pain induced by LHRH agonists.26/

PRAECIS again wishes to emphasize that the patient populations that are included in the Plenaxis® label are not specifically indicated in any commercially available hormonal therapies. The specific clinical characteristics of patients indicated for Plenaxis® (those at risk for developing disease worsening if treated with existing therapies) are addressed in the warnings and precautionary sections of every LHRH agonist product label 27/-28/ and are not listed as indicated populations in any of the approved non- steroidal antiandrogen product labels. 29/- 30/

IV. Conclusion

We commend CMS on the draft decision memorandum relating to Plenaxis®. We urge CMS to reserve the right to cover off-label uses of Plenaxis® in the context of clinical trials approved by CMS. We would like to work with the CMS and, as appropriate, other federal healthcare agencies, such as FDA, in developing clinical trials that would greatly benefit the public health, particularly Medicare beneficiaries. We also hope that CMS will consider our more technical comments relating to factual information on Plenaxis® and the general clinical endocrine management of prostate cancer. We look forward to working with CMS as the draft decision becomes final.

*These comments are not intended as promotional communication. We encourage anyone reviewing this communication who has not already done so to refer to the approved package insert including BOXED WARNING for Plenaxis® (available at www.plenaxis.com) for more detail regarding the approved Plenaxis® indication and important safety information.

Reference List

1/D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280(11):969-974.

2/Huirne JA, Lambalk CB. Gonadotropin-releasing- hormone-receptor antagonists. Lancet 2001; 358 (9295):1793-1803.

3/Weckermann D, Harzmann R. Hormone Therapy in Prostate Cancer: LHRH Antagonists versus LHRH Analogues. Eur Urol 2004; 46(3):279-284.

4/Garnick MB, Campion M. Abarelix Depot, a GnRH antagonist, v LHRH superagonists in prostate cancer: differential effects on follicle- stimulating hormone. Abarelix Depot study group. Mol Urol 2000; 4(3):275-277.

5/Beer TM, Garzotto M, Eilers KM, Lemmon D, Wersinger EM. Targeting FSH in androgen- independent prostate cancer: abarelix for prostate cancer progressing after orchiectomy. Urology 2004; 63(2):342-347.

6/Beer TM, Garzotto M, Eilers KM, Lemmon D. Phase II study of abarelix depot for androgen independent prostate cancer progression during gonadotropin-releasing hormone agonist therapy. J Urol 2003; 169(5):1738-1741.

7/Aventis Pharmaceuticals. Taxotere (docetaxel) Injection Concentrate [Prescribing Information]. 2004. Bridgewater, N.J., Aventis Pharmaceuticals Inc.

8/Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351 (15):1502-1512.

9/Mongiat-Artus P, Teillac P. Abarelix: the first gonadotrophin-releasing hormone antagonist for the treatment of prostate cancer. Expert Opin Pharmacother 2004; 5(10):2171-2179.

10/Praecis Pharmaceuticals Incorporated. Plenaxis (abarelix for injectable suspension) [Prescribing Information]. Waltham, MA: PRAECIS PHARMACEUTICALS INCORPORATED, 2004.

11/Koch M, Steidle C, Brosman S, Centeno A, Gaylis F, Campion M et al. An open-label study of abarelix in men with symptomatic prostate cancer at risk of treatment with LHRH agonists. Urology 2003; 62(5):877-882.

12/McLeod D, Zinner N, Tomera K, Gleason D, Fotheringham N, Campion M et al. A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer. Urology 2001; 58(5):756-761.

13/Trachtenberg J, Gittleman M, Steidle C, Barzell W, Friedel W, Pessis D et al. A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol 2002; 167(4):1670-1674.

14/Schulze H, Senge T. Influence of different types of antiandrogens on luteinizing hormone- releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. J Urol 1990; 144(4):934-941.

15/Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol 1990; 144 (6):1479-1480.

16/Tomera K, Gleason D, Gittelman M, Moseley W, Zinner N, Murdoch M et al. The gonadotropin- releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. J Urol 2001; 165 (5):1585-1589.

17/Whitaker HC, Hanrahan S, Totty N, Gamble SC, Waxman J, Cato AC et al. Androgen receptor is targeted to distinct subcellular compartments in response to different therapeutic antiandrogens. Clin Cancer Res 2004; 10(21):7392-7401.

18/Culig Z, Bartsch G, Hobisch A. Antiandrogens in prostate cancer endocrine therapy. Curr Cancer Drug Targets 2004; 4(5):455-461.

19/Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P et al. Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. J Urol 2004; 172(5 Pt 1):1871-1876.

20/Duff G. Casodex 150 mg (Bicalutamide): no longer indicated for treatment of localised prostate cancer; Broadcast to Directors of Public Health of PCTs. Posted at http://www.info.doh.gov.uk/doh/embroadcast.nsf/. Ref CEM/CMO/2003/15. 10-28-2003. London, England, U.K., Dept of Public Health, Committee on Safety of Medicines.

21/Health Canada MHPD. Accelerated dealths in localized prostate cancer patients: Health Canada has withdrawn its approval for Casodex 150 mg for early (localized) prostate cancer. Available at http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd- dpt/casodex_prof_e.html. 8-26-2003. Ottawa, Ontario, Canada, Health Canada.

22/Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. The Leuprolide Study Group. N Engl J Med 1984; 311(20):1281-1286.

23/Bruchovsky N, Goldenberg SL, Akakura K, Rennie PS. Luteinizing hormone-releasing hormone agonists in prostate cancer. Elimination of flare reaction by pretreatment with cyproterone acetate and low-dose diethylstilbestrol. Cancer 1993; 72 (5):1685-1691.

24/Bubley GJ. Is the flare phenomenon clinically significant? Urology 2001; 58(2 Suppl 1):5-9.

25/Garnick MB. Hormonal treatment of prostate cancer. N Engl J Med 1999; 340(10):812-813.

26/Kuhn JM, Billebaud T, Navratil H, Moulonguet A, Fiet J, Grise P et al. Prevention of the transient adverse effects of a gonadotropin- releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Engl J Med 1989; 321(7):413-418.

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28/Sanofi-Synthelabo. Eligard 7.5mg (leuprolide acetate for injectable suspension) [Prescribing Information]. New York, NY: Sanofi-Synthelabo, 2003.

29/AstraZeneca Pharmaceuticals. Casodex (bicalutamide) tablets. [Presecribing Information]. 2002. Wilmington, DE, AstraZeneca Pharmaceuticals LP.

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Sanofi-Aventisi submits these brief comments in response to the draft national coverage detennination (NCD) for Abarelix (Plenaxistm) for the Treatment of Prostate Cancer. We note that after CMS initially published its acceptance of an NCD request to review Abarelix that came from the drug's manufacturer, CMS received a comment from the Medical Director of COS VI, the Fiscal Intermediary for Puerto Rico and the U.S. Virgin Islands. The commenter specifically asked CMS to consider developing an NCD addressing all drugs classified as Gonadotropin Releasing Hormone (GnRH) Antagonists.

We have reviewed the draft NCD for Abarelix and note that CMS did not include a review of any other GnRH Antagonists in this particular NCD. As this NCD was generated in response to a request from the manufacturer of Abarelix, we support and appreciate CMS' decision to limit this NCD to a coverage review of Abarelix. We trust that if CMS intends to add additional drugs to this particular NCD, or to issue a future draft coverage determination concerning other GnRH Antagonists or other drugs used in the treatment of prostate cancer, CMS will provide public notice prior to doing so. Per CMS practice (see http://www.cms.hhs.gov/coverage/8h), as well as the requirements set forth in Section 701 of the Medicare Modernization Act, we expect that public notice will be provided of both the agency's intent to engage in further national coverage review and of any draft national coverage determination, and that a 30-day public comment period will follow each notice.

We really appreciate the increased efforts that CMS has been making in recent months to reach out to interested stakeholders prior to making decisions that impact Medicare coverage of pharmaceuticals, and we look forward to continuing to work with you on these issues.

1 These comments are submitted on behalf of Sanofi-Synthelabo Inc. and Aventis Pharmaceuticals, both part of the Sanofi-Aventis Group.

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