Expert insights on tixagevimab/cilgavimab for COVID-19 prevention and treatment

Monoclonal antibodies (mAbs) have emerged as an attractive option for both COVID-19 immunoprophylaxis and treatment, especially since their efficacy vs SARS-CoV-2 is irrespective of patients’ immune system status. MIMS Doctor interviewed Dr Wilson Lam, Specialist in Infectious Disease in private practice in Hong Kong, who shared his experience with tixagevimab/cilgavimab, a combination of two long-acting mAbs, in providing protection against COVID-19 infection as well as evidence supporting its use as early treatment for adolescents and adults with COVID-19 who are at increased risk of progressing to severe disease.

mAbs for COVID-19 immunoprophylaxis and treatment
Global vaccination drive against SARS-CoV-2 has dramatically changed the outlook of the COVID-19 pan­demic, which is no longer considered a public health emergency of inter­national concern by the WHO as of 5 May 2023. [https://www.who.int/news/item/05-05-2023-statement-on-the-fif­teenth-meeting-of-the-internation­al-health-regulations-(2005)-emergen­cy-committee-regarding-the-corona­virus-disease-(covid-19)-pandemic] However, vaccination is contraindicated in a small minority of individuals who are allergic to vaccine components, and it may be of moderate efficacy in im­munocompromised patients. [MMWR Morb Mortal Wkly Rep 2022;71:1335-1342] Tixagevimab/cilgavimab, which became available in Hong Kong in May 2022, may provide additional protection against SARS-CoV-2 for these individu­als. [Evusheld Hong Kong Prescribing Information]

“Tixagevimab/cilgavimab was initially approved to help prevent SARS-CoV-2 infections in immuno­compromised individuals [ICIs] and those ineligible for vaccination,” said Lam. “This combination of two long-acting mAbs is indicated for COVID-19 pre-exposure prophylaxis [PrEP] in adults and adolescents ≥12 years of age weighing ≥40 kg.” [Evusheld Hong Kong Prescribing Information]

For PrEP, the recommended dose of tixagevimab and cilgavimab is 300 mg each, administered as two separate sequential intramuscular (IM) injections that may be repeated every 6 months if continued protection is needed (eg, continued risk of exposure to COVID-19). [Evusheld Hong Kong Prescribing Information] This extended dosing interval is due to the modified fragment crystallizable (Fc) receptor in both mAbs, which extends their half-life to approximately 90 days. [Viruses 2022;14:2278]

“COVID-19 PrEP mAbs may be appropriate for individuals at in­creased risk of SARS-CoV-2 infection and severe disease, namely, those who may have insufficient immune re­sponse to vaccination [eg, ICIs, elderly, organ-transplant patients on immuno­suppressants, cancer patients], those with contraindications to COVID-19 vaccines, and those with multimorbid­ity, which is an independent predictor of worse outcomes,” Lam explained. [Lancet 2022;400:1305-1320; Clinic Microbiol Infect 2022;28:163-177; Lancet Reg Health Eur 2022;19:100441]

“Tixagevimab/cilgavimab is also approved for treatment of COVID-19 in patients ≥12 years of age weighing ≥40 kg who do not require supplemen­tal oxygen and who are at increased risk of progressing to severe COVID-19,” he added. As COVID-19 treatment, the recommended dose is 300 mg each of tixagevimab and cilgavimab admin­istered as two separate IM injections, to be given as soon as possible after a positive SARS-CoV-2 test and within 7 days of COVID-19 symptom onset to eligible patients. [Evusheld Hong Kong Prescribing Information]

Use of mAbs as PrEP and treat­ment of COVID-19 offers protec­tion irrespective of patients’ immune system status. [Nat Rev Immunol 2021;21:382-393; Clin Microbiol In­fect 2019;25:60-64] It should be noted, however, that PrEP with tixa­gevimab/cilgavimab is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommend­ed. [Evusheld Hong Kong Prescribing Information]

Tixagevimab/cilgavimab as PrEP
In PROVENT, a phase III, multi­centre, double-blind, parallel-group trial, participants at increased risk of inadequate response to COVID-19 vaccination, increased risk of expo­sure to SARS-CoV-2, or both, were randomized to receive either a combi­nation of consecutive IM injections of tixagevimab 150 mg and cilgavimab 150 mg or saline placebo. Study par­ticipants included those who were ≥60 years of age, obese (body mass index ≥30 kg/m²), immunocompromised, with contraindications to COVID-19 vaccination, or had congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, or chronic liver disease. Randomization took place between November 2020 and March 2021 in a 2:1 ratio. [N Engl J Med 2022;386:2188-2200]

After approximately 3 months of follow-up, primary analysis results showed that symptomatic COVID-19 occurred in 8 of 3,441 participants (0.2 percent) in the tixagevimab/cilgavimab group vs 17 of 1,731 participants (1.0 percent) in the placebo group (relative risk reduction [RRR], 76.7 percent; 95 percent confidence interval [CI], 46.0–90.0; p<0.001). After a median follow-up of 6 months, RRR further improved to 82.8 percent (95 percent CI, 65.8–91.4) with tixagevimab/cil­gavimab vs placebo.

Tixagevimab/cilgavimab was gen­erally well tolerated with no evident safety concerns. Most adverse events (AEs) were mild or moderate in se­verity. Five cases of severe or critical COVID-19 and two COVID-19–related deaths occurred in the placebo group; no such cases were recorded among tixagevimab/cilgavimab recipients.

“The current recommended dose of tixagevimab/cilgavimab is 600 mg [300 mg each], which was increased from the original 300 mg dose in Feb­ruary 2022 due to the emergence of the BA.2, BA.4 and BA.5 Omicron SARS-CoV-2 subvariants,” noted Lam. [N Engl J Med 2022;386:2188-2200; Evusheld Hong Kong Prescrib­ing Information]

Clinical experience with tixagevimab/cilgavimab for PrEP
“In Hong Kong, tixagevimab/cil­gavimab for COVID-19 PrEP is easily administered to patients requiring ad­ditional protection against COVID-19 in an outpatient setting by a doctor or a nurse,” explained Lam.

“In my experience, none of the pa­tients given tixagevimab/cilgavimab as PrEP contracted COVID-19. In fact, I have one patient with HIV who received PrEP with tixagevimab/cilgavimab. This patient did not contract COVID-19 de­spite living with a household member who tested positive for the infection,” he shared.

“Measuring SARS-CoV-2 neu­tralizing antibody [nAb] titres may be used to determine patients’ response to COVID-19 immunization, especially those at increased risk of severe dis­ease due to comorbidities; however, it has limited utility in determining patients’ eligibility for COVID-19 PrEP, as there is no standardized cut-off for nAb levels,” Lam noted. “Instead, the clinical de­cision to use PrEP should be primarily based on patients’ characteristics [ie, immune status and risk of severe dis­ease], especially since nAb testing may not be easily accessible and may thus delay the timely identification of patients likely to benefit from PrEP the most.” [Nat Rev Immunol 2021;21:382-393; https://www.fda.gov/medical-devices/safety-communications/antibody-test­ing-not-currently-recommended-as­sess-immunity-after-covid-19-vaccina­tion-fda-safety]

“However, nAb testing can be used to describe patients’ response to PrEP,” Lam remarked. “For example, we had a patient with vasculitis who was on im­munosuppressive therapy and had a very low level of SARS-CoV-2 nAbs fol­lowing vaccination. Their titres markedly increased after receiving tixagevimab/cilgavimab and to date, the patient has not been infected with SARS-CoV-2.”

“I started prescribing tixagevimab/cilgavimab for PrEP to eligible patients in the second half of 2022, and my pa­tients have received only one dose of the mAb combination to date,” he not­ed. “The duration of protection follow­ing administration of a single dose of tixagevimab/cilgavimab is estimated to be ≥6 months. If needed, patients may receive another dose after 6 months.” [Evusheld Hong Kong Prescribing Infor­mation]

Tixagevimab/cilgavimab is a relative­ly safe combination that is only contra­indicated in patients with a history of hypersensitivity to the active substanc­es or to any of the excipients in its for­mulation. No dose adjustments are need­ ed in most patients, including elderly and those with hepatic or renal impairment, although special precautions should be taken for those at high risk of cardio­vascular or thromboembolic events.

“Aside from a few mild injection-site reactions, PrEP with tixagevimab/ cilgavimab has been well tolerated by my patients, with no notable side ef­fects,” reported Lam.

Tixagevimab/cilgavimab as treatment
“Although tixagevimab/cilgavimab is primarily used for PrEP in Hong Kong, it is also approved for COVID-19 treatment and may be added to pa­tients’ standard-of-care antibody cocktail and antiviral therapies,” said Lam. “It should be administered early [ie, within 7 days of COVID-19 symp­tom onset] and is usually included as part of the treatment regimen for hos­pitalized patients at high risk of severe disease, especially those who have not been vaccinated vs COVID-19 and in those we anticipate to have poor re­sponse to standard-of-care antivirals.”

Tixagevimab/cilgavimab’s approval for COVID-19 treatment is based on results of TACKLE, an ongoing phase III, randomized, double-blind, place­bo-controlled trial, which investigat­ed the efficacy and safety of a single 600 mg IM dose of tixagevimab (300 mg) and cilgavimab (300 mg) for treat­ment of COVID-19 in nonhospitalized adults with mild-to-moderate disease who had not received any COVID-19 vaccines. A total of 910 patients with WHO Clinical Progression Scale score >1 to <4 received either tixagevimab/cilgavimab or placebo ≤7 days from self-reported onset of mild-to-mod­erate COVID-19 symptoms or mea­sured fever. [Lancet Respir Med 2022;10:985-996]

Primary efficacy results showed that severe COVID-19 or death occurred in 18 (4 percent) of 407 evaluable partic­ipants in the tixagevimab/cilgavimab group vs 37 (9 percent) of 415 partic­ipants in the placebo group (RRR, 50.5 percent; 95 percent CI, 14.6–71.3; p=0.0096). (Figure) The absolute risk reduction was 4.5 percent (95 percent CI, 1.1–8.0; p<0.0001).

AEs, which were mostly mild or moderate in severity, occurred in 29 percent of patients in the tixagevimab/cilgavimab group vs 36 percent in the placebo group.

These results demonstrated that early administration of a single IM dose of tixagevimab/cilgavimab is safe and effective in providing statistically and clinically significant protection against progression to severe COVID-19 or death vs placebo in unvaccinated indi­viduals.

Future outlook
“The evolving nature of SARS-CoV-2 warrants continuing real-time molecular surveillance and assess­ment of in vitro activity of mAbs used in COVID-19 PrEP and treatment, as is be­ing done for tixagevimab/cilgavimab,” said Lam. “As new SARS-CoV-2 variants continue to emerge, current­ly available mAbs will require regular molecular updates to remain effective and offer extra protection in addition to COVID-19 vaccination in individuals at increased risk of SARS-CoV-2 infection and severe disease or in individuals for whom vaccination is not suitable.” [Micro­biol Spectr 2023;11:e0033323; N Engl J Med 2022;386:2236-2238]