Biotech Tracker News - Expert Comments on Antegren Potential
April 17, 2003, Two letters published in today’s New England Journal of Medicine comment on the potential clinical applications of Biogen (NASDAQ: BGEN) and Élan’s (NYSE: ELN) Antegren (natalizumab), a monoclonal antibody being developed for the treatment of both multiple sclerosis (MS) and Crohn disease. Both letters comment on phase II data published in the New England Journal on January 2, 2003 and reviewed by BT News (MS, Crohn) on the same day. The letter regarding MS reinforces the shortcomings of a blind reliance on surrogate, as opposed to clinical, outcomes. The letter regarding Crohn disease highlights a potential overestimation of the impact of the drug’s failure to achieve a week 6 remission endpoint. Phase II data in both indications continue to support the ongoing phase III trials, as opposed to providing significant insight regarding enhanced probability for FDA approval or use in the clinical marketplace. The probability of Antegren’s timely approval in both indications remains no greater than average.  Multiple Sclerosis In a letter titled Natalizumab for Relapsing Multiple Sclerosis, Chaudhuri and Behan, University of Glasgow investigators in the original 72-patient Antegren exploratory study, highlight the importance of rigorous scrutiny of Antegren’s effect on clinical endpoints in phase III studies of its efficacy in the management of relapsing-remitting multiple sclerosis (RRMS). We have consistently indicated that the weight that has been accorded earlier achievement of surrogate marker endpoints is too great, and does little to convince us that Antegren will achieve a long-term therapeutic effect of a magnitude large enough to impact the course of disease and its attendant functional decline. Antegren’s ability to delay relapse may provide clinical utility in line with, but not necessarily offer an improvement on, contemporary drugs. These factors limit both its probability of FDA approval and its market potential if approved.  Chaudhuri and Behan “did not find that treatment with [Antegren] was of clinical benefit.” In the January 2 New England Journal study, monthly Antegren significantly reduced relapse rates and enhancing lesions on magnetic resonance imaging (MRI) in the short term. However, Antegren fails to sustain these effects in the six months after treatment. Antegren had no effect on disability scores on the Kurtzke Expanded Disability Status Scale, suggesting that it will not be able to modify the course of RRMS.  Miller and O’Connor, the authors of the January 2 New England Journal study, responded that certainly these are obvious limitations of typical mid-phase investigations relying on surrogate endpoints, so naturally larger trials are needed to more precisely assess Antegren’s clinical and commercial potential. Antegren is currently being tested in phase III trials as monotherapy and in combination with Biogen’s Avonex.  Chaudhuri and Behan cite a translational background featuring “epidemiologic studies (that) have shown a biologic dissociation between relapses and progressive disability once a score of 4 to 4.5 on the Expanded Disability Status Scale is reached,” further citing additional biological evidence that “clearly indicate that the progression of disability is independent of clinical relapses.” They also highlight the dissociation between MRI findings and clinical abilities and disabilities as well as the observation that results of immunotherapy trials in multiple sclerosis suggest that although such treatments may reduce relapse rates, they do not modify progressive loss of function saying, "We are not convinced that the effects of natalizumab on relapsing multiple sclerosis are any exception.”  Miller and O’Connor reply that the focus to date has been on studying surrogate markers, most notably decreases in the number of new gadolinium-enhanced lesions on MRI. Furthermore, they promote an understanding of the limitations of relying on “significant treatment-associated reduction in relapses,” offering that “The mechanisms by which irreversible disability develops in multiple sclerosis are not well understood.” They maintain that since “incomplete recovery from relapses is one mechanism of permanent disability,” Antegren certainly may still yet increase its clinical and commercial potential upon phase III data analysis. They correctly point out that this can only be “addressed…by larger, longer-term, phase III studies.”  Crohn Disease In a letter titled Natalizumab for Active Crohn’s Disease, Dr. Edward A. Lew, a public health specialist from Brigham and Women’s Hospital and Harvard Medical School, and colleague Dr. Elena Martinez Stoffel cautioned that flaws in the design and/or execution of earlier investigation may actually underestimate Antegren’s magnitude of therapeutic effect with regard to sustained remission rates. After a six-month Crohn disease trial, Antegren showed that although it may not provide specific surrogate marker advantages on a test that measures the severity of gut inflammation, it may provide clinical advantages for important endpoints such as self-reported symptom decline for symptoms such as cramps and severe diarrhea. Ongoing phase III trials should reconcile these issues.  A January 2 New England Journal article showed that two infusions of natalizumab 6 mg per kilogram was associated with higher remission rates than placebo at several intervals, but not at week 6, the primary endpoint. However, Lew and Stoffel point out, “the failure to demonstrate a difference may be due in part to chance and to the use of a small study sample.” Whereas randomization should ensure equal distribution of potentially confounding baseline characteristics, in this study randomization assigned 63 patients to placebo and only 51 patients to natalizumab, a substantial 19% difference that may contribute to disconnecting observed from actual outcomes. Lew and Stoffel point out that although the original authors attributed the failure to detect significant differences at week 6 to the unusually high remission rate in the placebo group, the fact that concomitant immunosupression with azathioprine or mercaptopurine was being given to a greater proportion (p=.04) of placebo recipients (35%) than natalizumab recipients (18%) also “may have contributed to the reported null findings with regard to the primary study endpoint in this trial.”
DISCLAIMER The above information transmitted via BioPortfolio has been provided by the original publishers BiotechTracker ("BT") a financial information, news, and software service focusing on event-driven biotechnology and pharmaceutical research. The Service is provided by DPBT, LLC ("DPBT"). a joint venture formed between BT Investor, Inc. and PCS Research Technology, Inc. It is not guaranteed as to completeness or accuracy by BioPortfolio, the BT publishers, or any person. Such Information is neither an offer to sell nor a solicitation to buy the securities of any company. Opinions expressed are subject to change without notice. The Information and views provided by BT are prepared by BT employees and in no way reflect the views or efforts of BioPortfolio Limited., any of BioPortfolio's employees or officers. BioPortfolio, and BioPortfolio's employees and officers, as well as BT’s employees and officers, in no way accept responsibility for any of the BT content published on www.bioportfolio.com/.  While all reasonable care has been taken to ensure that the Information contained herein is presented in good faith, and is not untrue or misleading at the time of publication, BioPortfolio, and BT make no representation as to its accuracy or completeness and it should not be relied upon as such. The Information is supplied on the condition that the reader or any other person receiving the Information will make his or her own determination as to its suitability for any purpose prior to any use of the Information. From time to time, BioPortfolio and any officers or employees of BioPortfolio, as well as BT, and any officers or employees of BT, may, to the extent permitted by law, have a position or otherwise be interested in any transactions, in any investments (including derivatives) directly or indirectly the subject of this report. Also BioPortfolio and BT may, from time to time solicit business from any company mentioned in this report. This report is provided solely for the information of viewers of BioPortfolio and/or viewers and subscribers of BT and BioPortfolio information services, who are expected to make their own investment decisions without reliance on this report. Neither BioPortfolio nor any officer or employee of BioPortfolio, nor BT, or any officer or employee of BT, accepts any liability whatsoever for any direct, indirect, special or consequential damages or loss arising from any use of this report or their contents. This report may not be reproduced, distributed or published by any recipient for any purpose without the prior express consent of the publishers. Nothing contained herein shall be construed as conferring by implication, estoppel or otherwise any license or right under any patent, trademark or copyright of BioPortfolio, BT or any third party.  The value of the investment(s) to which this report relates and their income yield(s) may go up or down. The investment(s) referred to in this report may not be suitable for private investors: if you are in any doubt you should seek advice from your investment advisor. Changes in rates of currency exchange may have an adverse effect on the value, price or income of investments. Statements as to past performance of any investment are not a guide to future performance. The levels and bases of taxation can change, and if you are in doubt you should seek independent professional advice. In some cases it may be difficult for you to sell or realize your investment or to obtain reliable information about its value or the extent of the risks to which you are exposed.  THIS INFORMATION IS PROVIDED "AS IS" AND NO REPRESENTATIONS OR WARRANTIES, EITHER EXPRESS OR IMPLIED OF ACCURACY, MERCHANTIBILITY FITNESS FOR A PARTICULAR PURPOSE OR OF ANY OTHER NATURE ARE MADE WITH RESPECT TO THIS INFORMATION OR TO ANY EXPRESSED VIEWS PRESENTED IN THIS INFORMATION.