Leery about signs of liver toxicity among patients taking a B7-H3 × CD3 bispecific under development at MacroGenics $MGNX, the FDA has slapped a partial hold on the early-stage program.
The partial hold — which affects their monotherapy trial as well a combination effort with their own PD-1 checkpoint MGA012, partnered with Incyte — will stop researchers from recruiting new patients, but people who have already signed up can continue treatment.
MacroGenics was quick to downplay the move, noting that signs of elevated transaminases in the single-drug study were quickly resolved. And the biotech got some quick help from analysts, who haven’t been paying all that much attention to this program’s particular potential. CD3, though, plays a prominent role in some leading bispecific efforts, and the analysts would like to know more if the problem here may extend to other developers.
MacroGenics has been testing this bispecific in patients with non-small cell lung, bladder and head and neck cancer, mesothelioma, melanoma, and other B7-H3 positive tumors.
Leerink’s Jonathan Chang passed along management’s confidence that it can get past this hitch in short order and has already pitched a new plan to boost supportive care in the trials.
Overall, management seemed bullish that the partial clinical hold could be lifted as early as January 2019 based on the regulatory discussions so far and the changes being proposed, in our view. Management indicated that liver function test (LFT) elevations were initially observed in the Q2 weekly dosing regimen, which resolved with a reduction in dose. However, LFT elevations were then observed in a couple more patients at a lower dose.
Umer Raffat at Evercore ISI is in the group that wants to learn more ASAP.
We suspect the liver tox in the B7-H3 x CD3 DART may be ON-target tox of this specific combination. Although the company says B7-H3 expression is high in solid tumors and minimal in normal tissues, other sources (see an image from the Human Protein Atlas at bottom) suggest B7-H3 (aka CD276) has medium to high expression in various tissues, including the liver… If normal cells also express B7-H3, then this DART may induce more immune activation than expected, in non-tumor environments like the liver. This is just a hypothesis, and we need to see further clinical data on safety – it’s hard to make a definitive call given the limited detail we’ve seen thus far.
“As we’ve identified to the FDA, we believe that transaminitis observed in patients administered MGD009 was likely a cytokine-mediated event,” noted CEO Scott Koenig in a statement. “We are working with the FDA and will provide an update when we have additional information. This partial clinical hold does not impact ongoing clinical studies for enoblituzumab and MGC018, our other B7-H3-targeted molecules.”
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