MacroGenics 5 deaths seen in ADC trial

 MacroGenics’ safety woes have followed it into phase 2. Having dialed down the dose in response to early-phase data, the biotech saw its stock crater after reporting five deaths alongside an over 50% rate of grade 3 or worse adverse events.

The phase 2 study assessed two doses of MacroGenics’ B7-H3-directed antibody-drug conjugate (ADC) in patients with metastatic castration-resistant prostate cancer who had previously taken Xtandi or Zytiga. MacroGenics used 2 mg/kg and 2.7 mg/kg every four weeks as the phase 2 regimens after seeing high rates of adverse events and dropouts at the higher, more frequent phase 1 dose. 

An early look at the phase 2 safety data on the ADC vobramitamab duocarmazine (vobra duo) triggered a jump in MacroGenics’ share price last month. The biotech gave up the gains—and then some—Friday as traders sent the stock down more than 70% to just $4.37 a share in premarket trading from a Thursday closing price of $14.67.

MacroGenics CEO Scott Koenig, M.D., Ph.D., had a different take on the latest data on the 181 patients enrolled in the trial.

“While the safety data has accumulated more safety side effects, we believe that these are extremely manageable. In discussions with investigators, they are very comfortable with managing these patients and are very encouraged by both the safety and, obviously, the activity data they've seen to date,” the CEO said on a May 9 earnings call.

In the earlier cut of the data, which tracked patients into early January, the rates of treatment-emergent adverse events (TEAEs) in the low- and high-dose arms were 25.3% and 31.4%, respectively. The figures climbed to 54.4% and 51.2% in the latest data set, which covers results through mid-April.

Grade 3 TEAEs is one of several measures that worsened between January and April. Previously, the rates of drug interruption because of adverse events were 11% and 18.6%, respectively, at the low and high dose. MacroGenics’ latest readout shows TEAE-related interruptions were up to 42.2% and 55.8% at the low and high dose, respectively. The discontinuation rates climbed, too, although Koenig said the figures compare well to the results of other studies. 

MacroGenics reported five deaths. Investigators deemed two cardiovascular deaths, one in each arm, to be unrelated to the study drug. Another three deaths, all at the higher dose, are under investigation. Two patients died of pneumonitis, an inflammatory lung condition. 

“One of these cases was very complicated with other confounding matters. It's being further investigated right now, so I don't have a further decision with regard to a cause and effect,” Koenig said. “We have not seen, in the large number of patients here, any association with pneumonitis. That raises questions of what is the ultimate cause of these patients associated with the pneumonitis.”

In terms of efficacy, MacroGenics reported overall response rates of 17.8% and 25.0%, respectively, at the low and high dose. Including patients with unconfirmed responses increased the figures to 24.4% and 43.8%.

One key, outstanding question is how long the responses will last. MacroGenics said 43 patients, split fairly evenly between the two arms, were still on treatment as of the data cutoff. Koenig discussed what the data could mean for radiographic progression-free survival (rPFS), the study’s primary endpoint.

“What we had indicated was an rPFS baseline of 6 [months] or greater and obviously looking for 7, 8, 9, 10 or higher. I think that the data that we show today and the fact that these patients are still on therapy … there is no reason we can't meet some of the longer-lived rPFS values,” Koenig said.

https://www.fiercebiotech.com/biotech/macrogenics-stock-crashes-after-5-deaths-seen-adc-trial