HELIOS-B Shines Bright And Gives Alnylam Pharmaceuticals Another Blockbuster

seekingalpha06-24

HELIOS-B Phase III study of Amvuttra in patients with ATTR-CM succeeded across all metrics, showing significant benefits in both the combined study population and monotherapy groups.Amvuttra showed ...

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Blockbuster\n</h2>\n\n<h4 class=\"meta\">\n\n\n2024-06-24 23:37 GMT+8&nbsp;&nbsp;&nbsp;<a href=https://seekingalpha.com/article/4700725-helios-b-shines-bright-and-gives-alnylam-pharmaceuticals-another-blockbuster><strong>seekingalpha</strong></a>\n\n\n</h4>\n\n</header>\n<article>\n<div>\n<p>HELIOS-B Phase III study of Amvuttra in patients with ATTR-CM succeeded across all metrics, showing significant benefits in both the combined study population and monotherapy groups.Amvuttra showed ...</p>\n\n<a href=\"https://seekingalpha.com/article/4700725-helios-b-shines-bright-and-gives-alnylam-pharmaceuticals-another-blockbuster\">Source 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safety profile.Results support the use of Amvuttra as monotherapy or in combination with stabilizers in people with ATTR-CM, potentially generating billions in incremental revenue for Alnylam.Investors should expect significant debate over when to use stabilizers like Pfizer's tafamidis and silencers like Amvuttra, and HELIOS-B results likely aren't strong enough to force a mass switchover from tafamidis to Amvuttra.The HELIOS-B results significantly upgrade Alnylam's revenue generation opportunities and boost my fair value to over $270/share.   ktsimage/iStock via Getty Images “Hail to you, lord! Freely bestow on me substance that cheers the heart.” Homeric Hymn XXXI (to Helios) Alnylam Pharmaceuticals (NASDAQ:ALNY) investors got about all they could have hoped for, and maybe a little more, with the Monday announcement that the HELIOS-B Phase III study of Amvuttra in people with ATTR amyloidosis with cardiomyopathy (or ATTR-CM) succeeded across all metrics. Not only where the results statistically significant, the drug showed a meaningful benefit in patients across the board, including those on Pfizer’s (PFE) Vyndamax/Vyndaqel (tafamidis). With these results in hand, Alnylam has an excellent chance of generating multiple billions of dollars in revenue with Amvuttra, as the study results not only support the use of the drug in combination with stabilizers like Vyndamax or in patients who do not respond to (or cannot tolerate) stabilizers, but also a front-line monotherapy. With these results, my fair value estimate on Alnylam moves to over $270, though I won’t be shocked if there’s some selling pressure after Monday’s big move and in the weeks to come as analysts debate the real-world impact of this surprisingly positive study. HELIOS-B Hits On All Its Targets The HELIOS-B results were basically in line with the bull/best-case outcome for Alnylam that I laid out earlier this month, or at least in terms of what I’d have considered a realistic best-case. The drug not only showed strong efficacy as a monotherapy, but also in combination with patients taking tafamidis, opening the door to combo therapy despite the high cost. On the study’s primary endpoint, a composite of all-cause mortality and recurrent cardiovascular events, Amvuttra delivered a 28% overall reduction (with a p-value of < 0.0118), and a 33% reduction in the monotherapy group (p < 0.0162). In the arguably equally important secondary endpoint of all-cause mortality, Amvuttra delivered a 36% reduction overall (p < 0.025) and a 35% reduction in the monotherapy group (p < 0.05). Results were positive in all of the major secondary endpoints, including six-minute walk test, Kansas City Cardiomyopathy Questionnaire, and NYHA Class (a measure of heart failure severity). The p-values for all of these secondary endpoints was p < 0.025, but investors will have to wait for the European Society of Cardiology meeting in late August/early September) for more details. Safety and tolerability were also good. There were fewer severe adverse events and fewer SAE-related discontinuations in the Amvuttra group than in the placebo group, and none of the severe adverse events occurred substantially more frequently than in the placebo group. What Now? HELIOS-B results absolutely support approval of Amvuttra for ATTR-CM, and the company will submit a supplemental New Drug Application to the FDA later this year, using a priority review voucher to do so. That will give the company the chance to launch in 2025, and given the existing infrastructure and overlap of ATTR patients, there really isn’t any meaningful incremental marketing work necessary to launch Amvuttra with that ATTR-CM label. What remains to be seen is how this changes clinical practice for ATTR-CM and how it shifts the competitive landscape. Going into this, I thought the standard for establishing Amvuttra’s superiority was a hazard ratio of 0.70 or better in all-cause mortality in the monotherapy group and/or 0.80 or better in the combo group. HELIOS-B surpassed both, and I’d note that the ATTR-ACT study of tafamidis showed a 29.5% reduction in all-cause mortality. Comparing across trials is always problematic, but Pfizer had the advantage of running that test with generally sicker patients that were expected to show more benefit to medical intervention. I don’t expect these results to destroy the market opportunity for tafamidis. In fact, I expect that there will be spirited debates in the clinical community over when and why to use stabilizers over silencers - drugs like tafamidis and BridgeBio’s (BBIO) acoramidis attach to the TTR protein and keep it from degrading into monomers that aggregate into amyloid fibrils that cause the toxic effects of the disease, while drugs like Amvuttra stop TTR proteins from being made in the first place by interfering with TTR messenger RNA. Even so, I would argue that this supports (and arguably restores) the basic hypothesis that silencing TTR production should be more effective over time than simply stabilizing TTR proteins. I do expect to see more use of tafamidis and Amvuttra together in combo therapy, and I believe the monotherapy results from HELIOS-B do argue for the use of Amvuttra as front-line monotherapy. Again, I expect a lot of debate over this in the clinical community (particularly after full HELIOS-B results are available), and some of this may come down to patient preferences and economics (tafamidis is oral, but some amyloidosis patients have difficulty swallowing, and as a Part B drug, Amvuttra will be cheaper for many patients). These results should make life interesting for BridgeBio when it launches acoramidis, as I do think it has the risk of shrinking the market for new patients going on stabilizers – I can certainly understand clinicians who elect to keep patients on tafamidis for now if it’s working for them, but it may well shrink new prescriptions, as I expect Amvuttra to gain front-line share. It’s harder to assess the impact on Ionis (IONS) and its drug Wainua (eplontersen), co-marketed with AstraZeneca (AZN). The success of Amvuttra can be seen as supportive for silencers (eplontersen works differently, but both reduce TTR production “at the source”), but the HELIOS-B results also establish a very high bar for future therapies. The Outlook As I’ve said in earlier articles on Alnylam, I believe the addressable market for ATTR-CM may well be in excess of 150,000 people just in the U.S., supporting over $10B in annual revenue opportunities. That said, patient identification remains a gating factor, as many people are not screened for the disease until they start to show symptoms. Whether or not medical practice shifts towards general screening for all adults remains to be seen, but I do believe Amvuttra can get a solid 30% to 40% share of the market (sharing the market with stabilizers, other silencers, and acknowledging that not all patients will seek or receive treatment). I also note that, over time, gene therapy could be an emerging threat to the market, though I think there will be coexistence between more conventional therapies and gene therapies for some time, even if candidates like Intellia’s (NTLA) NTLA-2001 gene therapy produce good Phase III data. With HELIOS-B de-risking the ATTR-CM opportunity, I believe the value of Alnylam’s ATTR program is now closer to $175 per share (from around $116), and I’d note the company continues to innovate here (TTRsc04 is a new compound that could offer even more convenient dosing without compromising efficacy). Adding in other commercialized and pipeline compounds (which I discussed in that prior article linked to earlier in this article), my fair value estimate moves to just over $277/share. The Bottom Line As of this writing, Alnylam shares are trading at around $220, suggesting meaningful upside is still in play even after this positive trial readout. I do expect plenty of debate over just how good the HELIOS-B results really were and how it will (or won’t) change clinical practice for ATTR-CM, but I believe it solidifies the case for Alnylam getting at least a third of a market that I believe is worth over $15B worldwide today and likely to grow as more asymptomatic adults are identified and started on therapy.  With the success of HELIOS-B de-risking the ATTR franchise and other attractive opportunities still in the pipeline (including treatments for hypertension, Alzheimer’s, and diabetes), I believe Alnylam shares are worth owning.","kind":null,"is_publish_news":true,"is_publish_highlight":false,"is_publish_live":null,"is_publish_wemedia":null,"editions":null,"column":"","sentiment":"","news_tag":"","news_rank":0,"symbols":[],"gpt_button":1},"commentList":[],"isCommentEnd":true,"newsSizeData":{"likeSize":0,"commentSize":0,"repostSize":0,"favoriteSize":0,"likeStatus":false,"favoriteStatus":false},"APP":{"userAgent":"Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)","isDev":false,"isTTM":true,"deviceId":"web-server-community-laohu8-v3","version":"4.24.2","shortVersion":"4.24.2","platform":"web","vendor":"web","appName":"ttm","isIOS":false,"isAndroid":false,"isTiger":false,"isTHS":false,"isWeiXin":false,"isWeiXinMini":false,"isWeiBo":false,"isQQ":false,"isBaiduSwan":false,"isBaiduBox":false,"isDingTalk":false,"isToutiao":false,"isOnePlus":false,"isHuaWei":false,"isXiaomi":false,"isXiaomiWebView":false,"isOppo":false,"isVivo":false,"isSamsung":false,"isMobile":false},"href":"/m/news/2445006620"}