{"id":7924,"date":"2026-10-05T15:38:27","date_gmt":"2026-10-05T21:38:27","guid":{"rendered":"https:\/\/allphasepharma.com\/dir\/?p=7924"},"modified":"2026-10-06T10:03:25","modified_gmt":"2026-10-06T16:03:25","slug":"vrg50635-lessons-learned-in-als","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2026\/10\/05\/7924\/vrg50635-lessons-learned-in-als\/","title":{"rendered":"VRG50635 – Lessons Learned in ALS"},"content":{"rendered":"
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In a recent blog we took issue with a Nature article about \u2018Lessons learned\u2019 after a TIGIT inhibitor failed in late Phase 3 development.  We felt that the article provided few insights, mainly platitudes.<\/p>\n\n\n\n

This week we saw a different kind of post-mortem.  It was about VRG50635, a PIKfyve inhibitor for ALS which failed in a Phase 1b study earlier this year.  In the world of ALS, few things work.  Let me rephrase: nothing really works.  Even the approved drugs like tofersen, edaravone and riluzole provide very little to no benefit. <\/p>\n\n\n\n

When dealing with a disease like ALS, we can only applaud those who try to tackle it scientifically and those who invest money on a putative new target.  It takes courage to engage in ALS exploratory research.  Failure is the norm at this stage in drug development, and even more so for ALS. <\/a>[1]<\/a><\/p>\n\n\n\n

That said, let\u2019s have a look at VRG50635, a compound from Verge Genomics that came with a good rationale: the science for targeting PIKfyve was compelling, the compound itself was designed for CNS penetration.  The next steps were meant to prove target engagement and proof of clinical efficacy, i.e., clinical improvement of signs & symptoms in ALS patients.<\/p>\n\n\n\n

Sadly, when the company finished the Phase 1b PoC study in 54 ALS patients, there was not a hint of clinical efficacy.  Notwithstanding, VRG50635 had a \u2018biologic effect\u2019 on at least 2 measures considered relevant, NfL and GFAS.  Totally unanticipated and contrary to expectations, treatment with VRG50635 produced a sustained increase in plasma NfL (p<0.001) and GFAP levels.  What are we to make of all this?<\/p>\n\n\n\n

We would have concluded that NfL is not a particularly useful biomarker for ALS disease progression, and that PIKfyve is not central to ALS pathogenesis.  Full stop.<\/p>\n\n\n\n

Verge\u2019s former CEO, a neuroscientist and entrepreneur, begs to differ.   She published an explanation why VRG50635 was doomed.[2]<\/a>  In her words, they were \u2018in the right neighborhood\u2019 but \u2018not the right house\u2019.  While we can agree that they \u2018missed the house\u2019 we stand unconvinced about  \u2018the neighborhood\u2019. <\/p>\n\n\n

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AI generated picture “Scientists looking for the right house in the neighborhood”<\/figcaption><\/figure>\n<\/div>\n\n\n

Admittedly, we are at a disadvantage as full study data have not yet been published; all we have are Top Line results from a short communication.[3]<\/a>  <\/p>\n\n\n\n

Here are Verge\u2019s learnings as proffered (with our comments in BLUE<\/mark>):<\/p>\n\n\n\n

    \n
  1. NfL is one of the field\u2019s most relied-upon efficacy biomarkers<\/strong>
    Accumulating evidence indicates that NfL may be an epiphenomenon.\u00a0 It was an unhelpful and misleading clinical\u00a0 surrogate in the Amplyx and several other ALS trials.1\u00a0 FDA never elevated it to biomarker status, and Ad Board members reviewing ALX0035 were divided in their opinion and quite unsure what to make of it.\u00a0 Everyone agrees that real biomarkers should be tied to clinical outcome.\u00a0 This data does not (yet) exist for NfL or for GPAP.<\/mark><\/li>\n\n\n\n
  2. Severe \/ older \/ more advanced patients don\u2019t respond with plasma NfL changes like early ALS cases<\/strong>
    This statement falls into the bucket of \u2018hypotheses\u2019.\u00a0 It is impossible to conclude this given the small size cohorts in Verge Phase 1b study.\u00a0 A mere conjecture at this time \u2013 to be confirmed!<\/mark><\/li>\n\n\n\n
  3. VRG50538 was conceived by an AI platform predicting PIKfyve as a new target specific for ALS biology<\/strong>
    Using AI for target selection sounds like a great idea but given the results, should we still trust an AI-driven target selection algorithm?\u00a0 There are a few other companies pursuing PIKfyve for ALS.\u00a0 Apilimod clinical data are sparse and hence uninterpretable.    [1]<\/a>\u00a0 Why does Verge Labs (the successor of Verge Genomics) believe that an \u2018improved\u2019 version of their AI approach has a better chance of success?\u00a0 How many times does one have to fail before we acknowledge that AI-based targeting may not a panacea?<\/mark><\/li>\n\n\n\n
  4. Study failure was a result of patient heterogeneity which needs to be controlled better<\/strong>
    Hmm, that sounds like good advice, but very generic if not outright trivial.\u00a0 Why didn\u2019t AI-modelling figure that out upfront?\u00a0 How does Verge Lab plan to address this learning in the next go-around?\u00a0<\/mark><\/li>\n\n\n\n
  5. Study points out difficulty of bridging dead tissue research to living people disease<\/strong>
    Is this is a new learning, really?<\/mark><\/li>\n\n\n\n
  6. Hard to predict how biomarkers relate to intervention and clinical features<\/strong>
    Well, yes, right, of course, good point\u2026<\/mark><\/li>\n<\/ol>\n\n\n\n
    \n\n\n\n

    <\/p>\n\n\n\n

    As we have seen, PoC (or lack thereof) can be established early or late for ALS drugs in development.  In the case of VRG50635, a Phase 1b study was sufficient to allow early decision-making.  Good so!  Well done! <\/p>\n\n\n\n

    Let\u2019s keep an eye on Verge Labs.<\/p>\n\n\n\n

    ABBREVIATIONS<\/strong>
    NfL          neurofilament light
    GFAP      glial filament alkaline phosphatase
    PoC         proof-of-concept
    PIKfyve  phosphoinositide kinase with FYVE zinc finger domain<\/p>\n\n\n\n

    <\/p>\n\n\n\n

    \n\n\n\n

    REFERENCES<\/strong>
    [1]<\/a> Huang C.  Innovative therapies under clinical development for ALS treatment. Part 2: biologics and natural Products.  Expert Opinion on Investigational Drugs 2026, DOI: 10.1080\/13543784.2026.2729512
    [2]<\/a> Zhang A.  What We Learned From The Trial of Our First AI-Discovered Drug.  In the right neighborhood, but not yet the right house.  BioPharma May 27, 2026
    [3]<\/a> Cadavid D.  Top Line Results of the Phase 1b, Open-label, Multiple Ascending Dose Proof of Concept Study of the PIKfyve Inhibitor VRG50635 in Familial and Sporadic Amyotrophic Lateral Sclerosis.  (P11-7.013) | Neurology 2026
    [4]<\/a> Babu S.  Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.  Brain 147; 2998, 2024<\/p>\n\n\n\n

    <\/p>\n","protected":false},"excerpt":{"rendered":"

    In a recent blog we took issue with a Nature article about \u2018Lessons learned\u2019 after a TIGIT inhibitor failed in late Phase 3 development.  We felt that the article provided few insights, mainly platitudes. This week we saw a different kind of post-mortem.  It was about VRG50635, a PIKfyve inhibitor Continue reading VRG50635 – Lessons Learned in ALS<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":7925,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"advanced_seo_description":"","jetpack_seo_html_title":"","jetpack_seo_noindex":false,"jetpack_seo_schema_type":"","_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_feature_clip_id":0,"_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},"jetpack_post_was_ever_published":false},"categories":[227,3,18],"tags":[1271,792,2456,2775,2782,2777,2776,2778,1583,2783,2469,2779,2781,2774,2780,2771,2772,2773],"class_list":["post-7924","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-recent_literature","category-the_news","category-the_viewpoint","tag-allphase-pharma-consulting","tag-als","tag-amplyx","tag-amx0035","tag-apilimod","tag-biomarker-for-als","tag-fda-ad-board","tag-gfap","tag-harald-reinhart","tag-lessons-learned","tag-nfl","tag-pikfyve-inhibitors","tag-post-mortem-for-failed-drugs","tag-riluzole","tag-tigit-inhibitor","tag-verge-genomics","tag-verge-labs","tag-vrg50635"],"jetpack_publicize_connections":[],"jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-23O","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":6999,"url":"https:\/\/allphasepharma.com\/dir\/2026\/05\/05\/6999\/the-tiragolumab-saga-tifacogin-flash-backs\/","url_meta":{"origin":7924,"position":0},"title":"The Tiragolumab Saga & Tifacogin Flash-Backs","author":"Harald","date":"May 5, 2026","format":false,"excerpt":"A recent Nature Review Drug Discovery article caught our attention, a review of TIGIT as an IO target and the failed Phase 3 study of tiragolumab which is the TIGIT inhibitor from Roche.[1] \u00a0The science writer interviewed a group of insiders that had a lead role in the development of\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2026\/04\/image-12.png?resize=350%2C200&ssl=1","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2026\/04\/image-12.png?resize=350%2C200&ssl=1 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2026\/04\/image-12.png?resize=525%2C300&ssl=1 1.5x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2026\/04\/image-12.png?resize=700%2C400&ssl=1 2x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2026\/04\/image-12.png?resize=1050%2C600&ssl=1 3x"},"classes":[]},{"id":2911,"url":"https:\/\/allphasepharma.com\/dir\/2016\/11\/25\/2911\/prospecting-antibiotics\/","url_meta":{"origin":7924,"position":1},"title":"Prospecting for New Antibiotics","author":"Harald","date":"November 25, 2016","format":false,"excerpt":"The QIDP designation was introduced in 2012 to incentivize drug development in antiinfectives. 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