{"id":41003,"date":"2021-08-01T06:48:43","date_gmt":"2021-08-01T06:48:43","guid":{"rendered":"https:\/\/i-base.info\/htb\/?p=41003"},"modified":"2021-08-01T10:14:53","modified_gmt":"2021-08-01T10:14:53","slug":"ias-2021-lenacapavir-studies-show-impressive-results-in-naive-extensive-drug-resistance-and-potential-as-prep","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/41003","title":{"rendered":"IAS 2021: lenacapavir studies show impressive results in naive, extensive drug resistance and potential as PrEP"},"content":{"rendered":"
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S\"\"imon Collins, HIV i-Base<\/span><\/strong><\/p>\n<\/div>\n

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Three studies at IAS 2021 included new data on the long-acting capsid inihibitor lenacapavir that only requires 6-monthly dosing.<\/span><\/strong><\/p>\n<\/div>\n

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This included two late-breaking abstracts reporting clinical results from the phase 2 CALIBRATE induction\/maintenance study in treatment na\u00efve participants and the phase 3 CAPELLA study in treatment experienced participants. [1, 2]<\/span><\/p>\n

Lenacapavir results in treatment naive<\/h2>\n<\/div>\n
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CALIBRATE randomised 182 participants (2:2:2:1) to one of three lenacapavir arms with F\/TAF (two using injections with later reduction to two-drug ART at week 28, one using oral lenacavir plus F\/TAF throughout) or to a control arm of bictegravir\/F\/TAF. [1]<\/p>\n<\/div>\n

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Interim pre-specified 16-week results for achieving viral load <50 copies\/mL included <\/span>92% (48\/52), 94% (50\/53), 94% (49\/52), and 100% (25\/25) in the three lenacapavir and control groups respectively.<\/p>\n<\/div>\n

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Baseline characteristics included median age 29 years (range: 19 to 72), 7% women (yes, 7%), 52% black, 45% Hispanic\/Latinx,<\/p>\n<\/div>\n

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Median viral load and CD4 count at baseline were 4.3 log copies\/mL (IQR: 3.8 to 4.7) with 15% >100,000 c\/mL and 437 cells\/mm3<\/sup>(IQR: 332 to 599), with only two participants <200 cells\/mm3<\/sup>.<\/p>\n<\/div>\n

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At week 16 by ITT analysis, viral load was <50 copies\/mL in 94% (147\/157) vs 100% (25\/25) in the pooled lenacapavir vs control groups respectively. The two cases of virological failure included one participant who did not reach <50 copies\/mL at week 28 and one who discontinued the study after two days. Early response rates at week 4 were similar in all groups. The primary endpoint is at week 54.<\/p>\n<\/div>\n

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One participant who had an early viral response at week 2 that rebounded close to 100,000 copies\/mL baseline by week 10, developed lenacapavir emergent mutations (capsid Q67H + K70R) associated with a 20-fold loss of sensitivity, together with M184V in RT. Lenacapavir drug levels were consistently within the target range and although viral load was dropping again, treatment was changed to AZT\/3TC\/TDF plus dolutegravir (an unusual choice) and then became undetectable.<\/p>\n<\/div>\n

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Adverse events were similar across groups (including 11 cases of COVID-19 and 17 cases of syphilis overall) with no drug-related discontinuations or grade 4 side effects.<\/p>\n<\/div>\n

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Injection site reactions (ISRs) were common (40\/183) but mostly grade 1 (33\/40), with only 1 grade 3 and no grade 4. However, the study reported some nodules lasting for several months that were \u201cpalpable but not visible\u201d and these extended from 1 to 4 cms. Two participants discontinued due to grade 1 ISRs with local hardening of the skin.<\/p>\n<\/div>\n

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Laboratory abnormalities included high creatine kinase (n=5 vs 0), mainly explained by recent exercise with no grade 3\/4 results judged clinically relevant or leading to discontinuations.<\/p>\n<\/div>\n

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These results support continuing to the dual therapy maintenance therapy switches with extended follow-up to week 80.<\/p>\n

Lenacapavir with extensive drug resistance<\/h2>\n<\/div>\n
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Clinical results were also presented at IAS 2021 from the phase 2\/3 CAPELLA study in 72 highly treatment experienced participants who had HIV multidrug resistance (MDR) to at least three drug classes. [2]<\/span><\/p>\n<\/div>\n

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Half the participants were randomised to lenacapavir or placebo for 14 days (before optimising treatment) and half used open label lenacapavir. <\/span><\/p>\n<\/div>\n

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The results at IAS 2021 were week 26 from the 36 participants in the randomised section of this study.<\/p>\n<\/div>\n

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Median age was 52 years (range: 23 to 78), 25% were women, 38% were back and 28% Hispanic\/Lantinx. Participants had been living with HIV for an estimated median or 24 years (range: 9 to 44 years).<\/span>Extensive drug resistance to >2 <\/span>drugsin each class was 99% (NRTIs), 97% (NNRTIs), 81% (PIs) and 69% (INSTIs) at baseline. <\/span><\/p>\n<\/div>\n

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Virological results included 81% (n=29\/36) of participants reaching an undetectable viral load (<50 copies\/mL) and 89% (32\/36) <200 copies\/mL. There were no missing data, with 7 and 4 participants having viral load >50 and >200 copies\/mL, respectively. Although numbers are small, 4\/6 participants with no active background drugs also reached <50 copies\/mL.<\/span><\/p>\n<\/div>\n

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The<\/span>mean CD4 count increased to 81 cells\/mm3<\/sup>included increases to >50 cells\/mm3<\/sup>in the 8\/36 participants who had CD4 counts <50 cells\/mm3<\/sup>at baseline.<\/p>\n<\/div>\n

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Limited data were available for the 11 participants who met criteria for resistance testing. Of these, 4\/11 developed emerging mutations associated with drug resistance to lenacapavir: M66I (4), Q67H (1), K70N\/R\/S (1) and N74D (1) although related phenotypic impact was not discussed. Of these, 3\/4 later suppressed, one with OBR change and two without.<\/span>One person without other sensitive drugs who did not become undetectable reported a \u20131.7 log reduction in viral load.\u00a0Although no new resistant mutations were reported for other ART, this is likely related to the relatively short follow-up.<\/p>\n<\/div>\n

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Tolerability was good with no study discontinuations and no serious drug-related side effects. Injection site reactions (ISRs) were common (56%; 40\/72) but mainly grade 1 (28\/40) that resolved in a few days. None were grade 4 and the two grade 3 reactions resolved by days 4 and 8.<\/p>\n<\/div>\n

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All participants have since received a second 6-monthly injection.<\/p>\n

Lenacapavir as PrEP<\/h2>\n<\/div>\n
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Finally, further results were presented on the potential of lenacapavir as PrEP. [3]<\/p>\n<\/div>\n

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This was a study in 24 female macaques, randomised to one of two doses of a single lanacapavir injection or placebo followed by ten vaginal weekly challenges with SHIV.<\/p>\n<\/div>\n

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The single administration of <\/span>lenacapavirexceeded the protein adjusted EC95 value (30.2 nM) for at least 10 and 16 weeks (in the 150 mg\/kg and 300 mg\/kg groups, respectively). <\/span><\/p>\n<\/div>\n

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All 8\/8 control animals all became infected by week 8 (median of 4 weeks). In contrast, 6\/8 animals became viraemic in the 150mg\/kg at a median of 14 weeks (p<0.0001). However, there were no infections (100% protection) in the 8\/8 animals in the 300 mg\/kg group, (p<0.0001).<\/span><\/p>\n<\/div>\n

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This showed similar efficacy to a rectal challenge macaque study reported at CROI 2021. [4]<\/span><\/p>\n<\/div>\n

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comment<\/span><\/h3>\n<\/div>\n
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These combined results show exciting potential of very long-acting drugs.<\/span><\/strong><\/p>\n<\/div>\n

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Phase 3 studies are already ongoing for both treatment and PrEP.<\/span><\/strong><\/p>\n<\/div>\n

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References<\/span><\/p>\n<\/div>\n

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  1. Gupta S et al. Long-acting subcutaneous lenacapavir dosed every 6 months as part of a combination regimen in treatment-na\u00efve people with HIV: interim 16-week results of a randomized, open-label, phase 2 induction-maintenance study (CALIBRATE). IAS 2021. Oral abstract OALB0302.
    \n<\/span>https:\/\/theprogramme.ias2021.org\/Abstract\/Abstract\/2211<\/a> (abstract)
    \n    https:\/\/conference.ias2021.org\/media-1057-oalb03—modern-art-and-covid-19-in-plhiv-cme-accredited<\/a> (webcast)<\/li>\n
  2. Molina J-M et al. Efficacy and safety of long-acting subcutaneous lenacapavir in phase 2\/3 in heavily treatment-experienced people with HIV: week 26 results (Capella study). Oral abstract <\/span>OALX01LB02.
    \n    https:\/\/theprogramme.ias2021.org\/Abstract\/Abstract\/2605<\/a><\/li>\n
  3. Bekerman E et al. Long-acting capsid inhibitor effective as PrEP against vaginal SHIV transmission in macaques. IAS 2021. Poster abstract PECLB24.
    \n    https:\/\/theprogramme.ias2021.org\/Abstract\/Abstract\/2474<\/a> (abstract)
    \n    https:\/\/conference.ias2021.org\/media-537-long-acting-capsid-inhibitor-effective-as-prep-against-vaginal-shiv-transmission-in-macaqu<\/a> (webcast)<\/li>\n
  4. CROI 2021: First results using capsid inhibitor lenacapavir against MDR HIV: potential for six-monthly ART and PrEP. HTB (1 April 2021).
    \n    https:\/\/i-base.info\/htb\/40290<\/a><\/li>\n<\/ol>\n

    This report was was posted on 20 July 2021.<\/em><\/p>\n<\/div>\n

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    \u00a0<\/span><\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

    Simon Collins, HIV i-Base Three studies at IAS 2021 included new data on the long-acting capsid inihibitor lenacapavir that only requires 6-monthly dosing. This included two late-breaking abstracts reporting clinical results from the phase 2 CALIBRATE induction\/maintenance study in treatment …<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,3],"tags":[],"class_list":["post-41003","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-antiretrovirals"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/41003","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=41003"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/41003\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=41003"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=41003"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=41003"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}