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I-SPY COVID brings new set of targets to master protocols for acute respiratory distress

COVID R&D Alliance’s adaptive trial launches with therapeutic mechanisms largely untouched in indication

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While most master protocols for COVID-19 have converged on an overlapping set of experimental therapies, the COVID R&D Alliance’s adaptive trial is kicking off with five therapeutic targets largely untouched in the indication.

Three members of the alliance of more 20 companies -- AbbVie Inc. (NYSE:ABBV), Takeda Pharmaceutical Co. Ltd. (Tokyo:4502; NYSE:TAK) and Amgen Inc. (NASDAQ:AMGN) -- announced Monday the enrollment of the first patients in the Phase II I-SPY COVID study to treat severely ill, hospitalized COVID-19 patients who require high-flow oxygen.

The industry consortium, which launched in April to push forward experimental therapies as fast as possible, has partnered with Quantum Health to launch the I-SPY adaptive trial to treat acute respiratory distress syndrome (ARDS) in late-stage COVID-19 patients (see “COVID R&D Consortium Launches I-SPY Adaptive Trial”).

I-SPY COVID is evaluating razuprotafib from Aerpio Pharmaceuticals Inc. (NASDAQ:ARPO), AbbVie’s cenicriviroc, Amgen’s Otezla apremilast and Takeda’s Firazyr icatibant, each in combination with remdesivir from Gilead Sciences Inc. (NASDAQ:GILD). The active comparator is remdesivir plus standard of care.

Enrollment for the first arms of the trial is expected to be completed in two to four months, a Quantum spokesperson told BioCentury, adding that the razuprotafib arm will begin enrolling next week. Quantum, which is sponsoring the trial, plans to add several more arms that will include antivirals and possibly dexamethasone, according to the spokesperson.

The primary endpoint is time to achieve level 4 on the WHO COVID scale -- hospitalized with mild disease and oxygen by mask or nasal prongs -- for at least 48 hours. Secondary endpoints include time on a ventilator and mortality.

While unspecified in ClinicalTrials.gov, SOC likely includes dexamethasone, the only agent so far to have reduced mortality in a randomized, controlled Phase III trial in hospitalized patients requiring oxygen (see “Clinical Scorecard for COVID-19”; Master Protocol Shows Survival Benefit for Steroid”).

The therapies in I-SPY COVID’s arms have a narrower focus than dexamethasone, a broad immunosuppressant, and target different biological mechanisms associated with ARDS.

Cenicriviroc is a dual CCR2/CCR5 antagonist aimed at preventing monocyte recruitment. It is in Phase II and III testing for inflammatory and fibrotic liver indications, diabetes and HIV.

Otezla, a PDE-4 inhibitor, could suppress cyclic AMP-mediated production of inflammatory mediators including cytokines. The drug is approved to treat psoriatic arthritis, plaque psoriasis and oral ulcers associated with Behcet’s disease, a blood vessel inflammation disorder.

Firazyr could reduce pulmonary edema. The BDKRB2 antagonist is approved to treat acute attacks of hereditary angioedema.

Razuprotafib inhibits PTPRB, which negatively regulates the angiogenic receptor Tie2. The trial will assess whether razuprotafib can stabilize the pulmonary vasculature to slow or block COVID-19 progression. Razuprotafib, which was selected for I-SPY COVID in May, is in Phase II trials for macular edema and diabetic retinopathy.

Each I-SPY COVID candidate has a target profile different from other products in trials to treat COVID-19, though Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) plans to test an immune modulator against CCR2/CCR5 in its Phase III ACTIV 1 study to treat hospitalized COVID-19 patients (see “ACTIV Coming into Focus”).

Of the five molecular targets for the four products in I-SPY COVID, only CCR5 is already under clinical evaluation for the infection, according to BioCentury’s COVID-19 Resource Center. Leronlimab, a CCR5 antagonist from CytoDyn Inc. (OTCQX:CYDY), is in Phase II and II/III studies to treat mild to severely ill COVID-19 patients.

Separately, Aerpio said it has agreed with the U.S. Army Medical Research and Development Command’s Medical Technology Enterprise Consortium (MTEC) to evaluate razuprotafib in a randomized Phase II trial to prevent and treat ARDS in adults with moderate to severe COVID-19. MTEC will provide up to $5.1 million in funding, with Aerpio contributing $2.8 million to run the study, which is expected to be completed in 1Q21.

Aerpio shares were up 57% to $2.07 in early after-hours trading. The company ended the regular trading session with a market cap of $54 million.


BDKRB2 (B2R) - Bradykinin B2 receptor

CCR2 (CD192) - CC chemokine receptor 2

CCR5 (CD195) - CC chemokine receptor 5

PDE-4 - Phosphodiesterase-4

PTPRB - Protein tyrosine phosphatase receptor type B

Tie2 - Tyrosine kinase receptor 2

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