by Manasi Vaidya in New York.
Hyperimmune intravenous immunoglobulin’s (hIVIG’s) clinical development in Covid-19 may be hampered by competition with authorised convalescent plasma and the reliance on convalescent plasma supplies. Since convalescent plasma is already an authorised Covid-19 treatment, hIVIG, which is derived from convalescent plasma, may be a tough sell to recruit patients into hIVIG investigational studies, but physician enthusiasm to conduct the studies may help enrollment.
The largest trial evaluating hIVIG is the 500-patient Phase III ITAC study (NCT04546581) led by the National Institutes of Health (NIH). Takeda Pharmaceuticals, Emergent BioSolutions, Grifols and CSL Behring are providing the hIVIG for the trial, as per an Emergent press release on 8 October. The ITAC study is scheduled to complete in July 2021. Kamada is also testing its hyperimmune immunoglobulin (IgG) in a 12-patient Phase I/II trial (NCT04550325). Topline results are expected by January 2021, as per an 8 September press release.
Given the dependence on the supply of convalescent plasma and supply constraints, hIVIG may not be a therapy for all Covid-19 patients but may be used as an adjunct for some. This stands in contrast to monoclonal antibodies (mAb), which do not have the same constraints and can be manufactured on a larger scale. Nonetheless, as Covid-19 cases continue to rise, the field may be able to adapt to provide the required plasma supplies.
Takeda and CSL Behring are part of the CoVIg alliance, which was announced in May 2020 and is comprised of several companies collaborating to begin the clinical production of hIVIG. Takeda referred to public releases made by the CoVIg alliance when asked to comment for this story, while CSL Behring and Grifols did not respond to a request for comment. Kamada declined to comment.
Competition with convalescent plasma
Patient recruitment can be challenging for hIVIG studies as potential patients recognise they could get convalescent plasma under an Emergency Use Authorization (EUA) without being in a trial, said Dr Nasia Safdar, professor, Division of Infectious Disease, University of Wisconsin School of Medicine and Public Health, Madison. Being able to access medicines through an EUA is affecting patient enrollment in all major trials since hospitals provide these therapies as standard of care (SOC), said Dr Richard Davey, chief, Clinical Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. Patients on ITAC will be randomised to receive hIVIG or placebo in addition to background treatment with Gilead Sciences’ Veklury (remdesivir).
hIVIG is processed from convalescent patients and contains a higher titer of antibodies against SARS-CoV-2. On 27 October, this news service reported hIVIG will likely be more effective than convalescent plasma since it contains a higher antibody titer. The FDA awarded an EUA for convalescent plasma on 23 August, based on data in 35,322 Covid-19 patients in an expanded access program at Mayo Clinic (Joyner, M. J., et al.  ‘Effect of Convalescent Plasma on Mortality among Hospitalized Patients with Covid-19: Initial Three-Month Experience’, medRxiv preprint).
The value of using hIVIG is balanced by the expectation investigators will support the notion of a randomised trial, said Davey. Even though not everyone in the study will receive hIVIG, the medical community understands the necessity of getting these studies done, said Dr Jens Lundgren, professor of Infectious Diseases, University of Copenhagen, Denmark, adding he did not have concerns about the ability to recruit patients.
It may be difficult to conduct a hIVIG study while there is an EUA for convalescent plasma, but even with an EUA, there is no clear clinical data showing convalescent plasma is beneficial, said Dr Mamta Jain, professor, Internal Medicine, University of Texas, Southwestern Medical Center, Dallas. Despite the EUA, there are enough ongoing convalescent plasma trials to establish efficacy because physician societies say there is insufficient conclusive data to make it the SOC, said Safdar. The Mayo Clinic data was created from an expanded access program, and was neither randomised nor placebo-controlled. It is important to explain to patients why enrolling in a trial may be beneficial versus getting available authorised drugs, said Jain.
It was generally challenging to get people to donate plasma during the early days of the outbreak, said Laura Saward, PhD, SVP and Therapeutics Business Unit Head at Emergent. Nonetheless, the company has a sufficient supply to align with its hIVIG clinical programs including the ITAC trial, said Saward. Moreover, since the number of individuals with Covid-19 is increasing, the pool of plasma donors is not finite, she added.
Logistics involve more complexity than mAbs
The logistics of manufacturing and administering hIVIG are challenging as there is a limited number of doses for whom eligible patients will have to be identified, said Dr Stuart Adler, professor emeritus, Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond.
There is always a lag in the time between someone donating plasma and its available use for therapeutic purposes, said Dr Elena Perez, physician, Allergy Associates of The Palm Beaches, Florida. With gamma globulin, another plasma product, used to treat neurological disorders, the lag is 6–9 months between donation and therapeutic use, she added.
The sourcing of plasma is ahead of the hIVIG manufacturing schedule, but coordinating the supply chain and manufacturing schedule is a normal course of business for Emergent, said Saward, citing experience with other plasma-derived products. There are multiple manufacturers supplying the hIVIG product for ITAC and while it has taken some time to start the study, it will likely be enough to fuel its continuation, said Davey. If proven effective, the availability of plasma to produce hIVIG could be an issue, but since there are thousands of Covid-19 cases, plasma donation should get easier over time, said Davey. The machinery to ramp up production exists, if the efficacy is backed up scientifically, he added.
Emergent has also set up additional partnerships to source convalescent plasma and programs to screen plasma donated under other programs for neutralising antibodies, Saward said.
Nonetheless, while hIVIG is a promising intervention, its clinical utility outside of a trial is not clear, said Lundgren, adding the same is true for convalescent plasma due to the nonrandomised nature of clinical data. Whether hIVIG can be used to stall hospitalisations or reduce morbidity among hospitalised patients will have to be seen, said Davey. While ITAC is focused on hospitalised patients, Emergent has announced plans to study hIVIG in other settings, including as a postexposure prophylaxis option. It is difficult to envision how hIVIG can be used on a large scale as a prophylactic the way mAbs are being studied. Also, unlike hIVIG, mAbs can be produced on a large scale and are not dependent on donors, said Lundgren. However, hIVIG could still be an option for those at risk of exposure, like nursing home residents, said Adler.
Manasi Vaidya is an Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.