By Frances Bishopp
Hybridon Inc.'s stock plummeted 34 percent after the company reported Friday it has stopped further development of its lead product, GEM91, based on data from a Phase II clinical trial of patients with advanced HIV infection.
Hybridon's stock (NASDAQ:HYBN) closed Friday at $3.125 down $1.625.
GEM91 (gene expression modulator) is a first-generation (phosphorothioate) antisense oligonucleotide that targets the gag (group-specific antigen) site in the HIV genome.
Hybridon develops drugs based on antisense technology, which involves using synthetic segments of DNA and RNA to stop the production of disease-associated proteins by interacting at the genetic level with target strands of messenger DNA.
In the confirmatory, open-label Phase II trial in the U.S. and Puerto Rico, three of nine subjects tested experienced decreases in platelet counts that required dose interruption, Robin Hogen, vice president of corporate communications and public affairs at the Cambridge, Mass., company, told BioWorld Today.
The drop in platelet counts happened after 10 days, Hogen said. In addition, a review of the data showed inconsistent responses to the treatment and failed to confirm the decrease in cellular viremia (level of virus in the blood) observed in an earlier trial, he said.
Hybridon proceeded with the trial based on earlier clinical trials that demonstrated GEM91, administered to more than 250 subjects, had been well tolerated as a monotherapy at doses of up to 4.4 mg/kg/day for eight days. "We had no dose-limiting side effects in this trial of over 200 patients," Hogen said, "but the trials were of shorter duration."
High GEM91 Levels Linked To Low Platelets
In the 14-day Phase II clinical trial, a decrease in platelet levels was seen in three patients after 10 days on GEM91, administered at the 3.2 mg/kg/day level. "We believe what was happening was we were getting fairly high concentrations of GEM91 in the plasma and that caused this drop in platelets," Hogen said. "The longer dosing seemed to bring on this effect," he added.
Russell Martin, Hybridon's vice president for drug development, said platelet effects had been recorded for some time in some patients but not in other patients, which is what had been seen in the current trial. "We have seen this [platelet effects] at doses of 2 mg/kg and above in some individuals, but we don't know exactly what the risk factors are. Some are susceptible and others are not," Martin said.
"At least one-third of our patients and sometimes half at any given dose would have some platelet lowering. We never, though, had to stop anyone at eight days. We have done safety escalation in slightly less-advanced patients than were enrolled in the current trial to see if 14 days of treatment could be tolerated and we had platelet effects in some of those individuals, but again did not go below the limit to continue treatment for the full 14 days," Martin explained.
Martin said the Phase II trial enrolled patients with slightly lower platelet counts, which is characteristic of advanced HIV infection. These patients also had high levels of virus, he said. Additionally, the enrolled patients could come into trials without requiring they be washed out for any retroviral therapy.
"If they were breaking through two-drug and three-drug therapy, they were allowed to continue on that," Martin said. "In our prior trials we have always required that other therapy be stopped in order to get a stable virus load."
The FDA stipulated that Hybridon not go beyond 14 days of treatment until the safety of that duration was established, Martin said. "Discontinuations in the second week of therapy has impacted our feelings about GEM91 for long-term therapy," Martin said. "We have realized with GEM91 that the critical thing will be to be able to administer antisense for HIV for a longer period of time than two weeks to make a difference."
E. Andrews Grinstead, Hybridon's chairman and CEO, said the company will focus its resources on four second-generation compounds: GEM132 for systemic CMV infections and retinitis, now in Phase II clinical trials; GEM92 for HIV and AIDS, which the company expects to enter clinical trials in October; GEM231, initially for colon cancer (target is protein kinase A), which likely will enter clinical trials in the fourth quarter of 1997; and GEM220 for retinopathies, psoriases and solid tumors, which should begin clinical trials for one of these indications in the first quarter of 1998.
"We think everyone will go to second-generation compounds [mixed backbone oligonucleotides]," Grinstead said. "We have, with our second-generation compounds, shown in animals that we can get four times the therapeutic window on platelets," he said.
Analyst Anthony Butler, of Lehman Brothers, of New York, agreed with Grinstead. "GEM91 clearly had some side-effect profiles, but I wouldn't necessarily call it a failure," Butler said.
"Hybridon's second-generation compounds are much better than the first-generation phosphorothioates," Butler said. "The important thing to remember is that is not conducive to all antisense molecules. None of Hybridon's other compounds have exhibited this kind of toxicity."
Hybridon has corporate collaborations with Roche Holdings Ltd., of Basel, Switzerland, Metronic Inc., of Minneapolis, and G.D. Searle & Co., of Skokie, Ill. Hybridon has no collaborators for GEM91.
Hybridon's cash on hand, as of March 31, 1997, was $49.5 million. *