{"id":2328,"date":"2016-02-26T14:01:32","date_gmt":"2016-02-26T19:01:32","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=2328"},"modified":"2016-05-19T21:30:36","modified_gmt":"2016-05-20T01:30:36","slug":"brincidofovir-another-drug-fails-in-phase-3","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2016\/02\/26\/2328\/brincidofovir-another-drug-fails-in-phase-3\/","title":{"rendered":"Brincidofovir \u2013 Another Drug Fails in Phase 3"},"content":{"rendered":"

\"Chimerix<\/a><\/p>\n

It is sad to see a pivotal trial fail, and you have to wonder why we recently had several such late-stage \u2018mishaps\u2019. Take Tetraphase\u2019s eravacycline which failed in a Phase 3 cUTI trial. We have analyzed this drug’s failure in\u00a0earlier blogs<\/a>; there is reason to believe that inadequate dosing was the reason for the poor efficacy results. Now we hear\u00a0that Chimerix has\u00a0a similar disaster with brincidofovir\/CMX001, its long-acting, kidney-sparing anti-CMV nucleoside: no difference over placebo was seen in the SUPPRESS trial which was conducted in HSCT patients at high risk of CMV reactivation in the post-transplant phase [1]<\/a>.<\/p>\n

How can it be that in both instances earlier data suggested efficacy which could not be confirmed in a subsequent larger trial? Not surprisingly, explanations provided by the\u00a0companies in press releases and at investor conference calls are often unrevealing.<\/p>\n

In the case of brincidofovir\/CMX001, a previous Phase 2 trial supposedly showed efficacy for the 100mg BIW regimen\u00a0[2]<\/a>. In light of the failed successor trial it is worth reviewing these data again. Table 1 shows the primary efficacy results from this study, a 230 patients, 5 dosing cohort trial.\u00a0 Note that only in the 100 mg twice weekly\u00a0group a significant treatment benefit was observed but not in any other cohort (Figure 1). There is also no evidence of a dose response as the 2x\u00a0greater\u00a0dose of 200 mg twice weekly\u00a0had no demonstrable efficacy (P=0.24).<\/p>\n

\"CMX<\/a>
CMX001 Results from Phase 2 Trial (from: Marty, see NEJM ref below)<\/figcaption><\/figure>\n

Had we seen activity in more than 1 cohort, we would have been more convinced that brincidofovir is truly efficacious, even in the absence of a dose-response. In summary, the claim to efficacy rested on data from a single cohort, at best a weak indicator of potency as the higher dose group failed to show a similar benefit. Given this situation, Chimerix took a big risk by proceeding to a full-fledged Phase 3 trial without further corroboration of what could be a spurious result.<\/p>\n

\"CMX<\/a>
Brincidofovir 100 mg Twice Weekly cohort – the only dosing group with demonstrable efficacy (modified from: Marty – NEJM)<\/figcaption><\/figure>\n

In addition, significant GI side effects (diarrhea) occurred already in the Phase 2 study with alarming frequency, raising concerns that this brincidofovir AE may be misinterpreted as a sign of early GVHD and trigger treatment with steroids which \u2013 in its wake \u2013 may lead to CMV reactivation and blunt any benefit that the antiviral may have.<\/p>\n

The team realized this dilemma and developed a patient management plan recommending discontinuation of CMX001 in such cases before starting immunosuppressive anti-GVHD therapy. Still, in the Phase 3 trial, investigators were unable to clinically differentiate GI toxicity due to CMX001 from early GVHD and treated with steroids if in doubt.<\/p>\n

Then there is the issue of timing of the primary efficacy endpoint. In the Phase 2 study this was within a week of ending prophylaxis, in the Phase 3 trial it was 10 weeks after ending prophylaxis. During this long drug-free follow-up period the prophylactic benefit of brincidofovir evaporated. Was it the FDA which insisted on this delayed efficacy timepoint? It strikes us as strange that the company would make such a dramatic change from the successful Phase 2 protocol knowing that recrudescence is likely to catch up in the CMX001 arm once suppressive antiviral prophylaxis has ended.<\/p>\n

A strange dynamic is often created within teams at the end of Phase 2: the drive to move swiftly to the \u201cpot of gold at the end of the rainbow\u201d clouds sound analysis and \u201cgroup-think\u201d takes over. Call it a case of \u2018irrational exuberance\u2019, call it \u2018wishful thinking\u2019, the example of CMX001 should give pause for reflection.<\/p>\n

CMV has already created a small graveyard for drug candidates out there: ViroPharma\u2019s maribavir also failed in this indication (prevention of CMV recurrence post-HCT), and it so happened in a large Phase 3 trial. In that case suboptimal dosing was possibly the culprit.<\/p>\n

 <\/p>\n

 <\/p>\n

References:
\n<\/strong>[1]<\/a> http:\/\/files.shareholder.com\/downloads\/AMDA-1QNA05\/1552591840x0x876376\/47AE0320-F2E5-4F84-960B-3081B69DEB39\/CMRX_Corporate_Update_Call_February_22_2016.pdf
\n[2]<\/a> F Marty. CMX001 to Prevent Cytomegalovirus Disease in Hematopoietic-Cell Transplantation. N Engl J Med 2013;369:1227-36<\/p>\n","protected":false},"excerpt":{"rendered":"

It is sad to see a pivotal trial fail, and you have to wonder why we recently had several such late-stage \u2018mishaps\u2019. Take Tetraphase\u2019s eravacycline which failed in a Phase 3 cUTI trial. We have analyzed this drug’s failure in\u00a0earlier blogs; there is reason to believe that inadequate dosing was Continue reading Brincidofovir \u2013 Another Drug Fails in Phase 3<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":2329,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[3],"tags":[1271,403,1546,1543,31,1545,1544,1583,1550,1549,1547,1551,1548],"class_list":["post-2328","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-the_news","tag-allphase-pharma-consulting","tag-antibiotic-blog","tag-brincidofovir","tag-chimerix","tag-cmv","tag-cmx-001","tag-failed-phase-3-trials","tag-harald-reinhart","tag-hsct-trial","tag-maribavir","tag-prevention-of-cmv-disease","tag-suppress-trial","tag-viropharma"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/02\/Chimerix-slider-copy.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-By","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":3131,"url":"https:\/\/allphasepharma.com\/dir\/2017\/02\/02\/3131\/monoclonal-pursuit-cmv-therapeutic\/","url_meta":{"origin":2328,"position":0},"title":"The Monoclonal Pursuit of the Next CMV Therapeutic","author":"Harald","date":"February 2, 2017","format":false,"excerpt":"There is no doubt that immunity to human cytomegalovirus (CMV) is both cell-and antibody-mediated. 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