With hopes for antibodies waning, the NIH will test Novartis partner's novel antiviral in hospitalized Covid-19 patients
After a slew of failures, the NIH’s ACTIV-3 trial for hospitalized Covid-19 patients has earned its reputation as a graveyard for big-name antibodies. Now, with its options running out, the NIH is turning to a Novartis-backed antibody alternative — but is this déjà vu all over again?
Molecular Partners and partner Novartis will try out their “trispecific” DARPin antiviral ensovibep in ACTIV-3, the hospitalized mild-to-moderate patient arm of the NIH’s ACTIV “master protocol” against Covid-19, the pair said Monday.
The molecule is one of a novel class of therapeutics developed by Molecular Partners that aims to perform the same functions as antibodies with far more target specificity and antiviral protection. The drugmaker is perhaps best known for its macular degeneration DARPin pact with AbbVie, which the FDA hit with a CRL back in June.
But now, with Novartis on board to help its pivot toward Covid-19, Molecular Partners thinks it has the winning early-stage data to succeed where big drugmakers haven’t in ACTIV-3, which has proven to be a wasteland for antibodies. Ensovibep, previously known as MP0420, is one of two molecules at the center of a $231 million deal with Novartis signed in October and designed to chart a new path at Covid-19 therapeutics.
“What we know from the preclinical data is we actually get into the lungs very fast, we block the virus very fast so there is no infectivity, no activity, and we don’t clear as fast as the antibodies,” CEO Patrick Amstutz told Endpoints News. Molecular Partners also argues that its high-affinity DARPins bind much better to the SARS-Cov-2 spike protein than antibodies without spurring immune side effects.
But it’s still not a sure thing, Amstutz said.
“If those differences will lead to activity in this setting, we just don’t know,” he said. “I would say the probability of success is higher than an antibody, but it’s still a rough trial. In this situation, we have to try — there is rationale to believe, (but) the bar is very high.”
ACTIV-3 will initially randomize 300 hospitalized patients with mild-to-moderate Covid-19 who have experienced less than 13 days of symptoms on ensovibep and placebo on top of standard of care. Five days after dosing, patients’ condition will be assessed on the need for supplemental oxygen, mechanical ventilation, or other supportive care. If ensovibep shows promise at that early check in, the NIH will enroll an additional 700 patients, who will be followed for 90 days with a primary endpoint of sustained recovery over standard of care 14 days after leaving the hospital.
Earlier this month, GlaxoSmithKline and Vir Biotechnology closed enrollment for their partnered antibody VIR-7831 in ACTIV-3 trial after the drug showed negligible effect in achieving sustained recovery in hospitalized Covid-19 patients. At a predetermined 300-patient interim check-in, an independent data committee “raised concerns about the magnitude of potential benefit” for the antibody and decided to halt enrollment as the data “mature.’
Just days later, the NIH shut down enrollment for Brii Biosciences’ two antibodies in the study. Eli Lilly and its antibody LY-CoV555 were booted from the study way back in October with the drugmaker citing study design issues — including the tall task of proving benefit on top of Gilead’s remdesivir — as a potential barrier to success.
Those failures may have paved the way for the NIH to give ensovibep a try despite its relatively unknown clinical profile. Taking a shot at a high-profile study and succeeding would be a big boost for Molecular Partners’ profile, but Amstutz is still managing expectations.
“For us, we’re bringing the first non-antibody to the trial, and that’s already an achievement for us,” he said. “I know what you know: All antibodies have failed. As a scientist, you can’t run the same experiment in the same setting and expect different results. That’s not what we do so you need to change something.”
Due to the high bar for success, Molecular Partners is holding out more hope for ensovibep in its other clinical trials, which includes a Phase II study focused on infectivity and Phase II/III test, dubbed EMPATHY, for mild-to-moderate patients in the outpatient setting. The partners hope to beginning enrolling that study, which will include 2,400 patients, in early 2021 with eyes on a potential emergency use authorization within the year.
Elsewhere, Molecular Partners is trying intravenous ensovibep in a Phase I safety and dose escalation trial. Early results from that study showed the therapy had a two- to three-week half-life in patients with no serious side effects.
