A few weeks after the FDA slapped a clinical hold on GlaxoSmithKline’s late-stage work on an experimental drug for a rare cardiac condition, the pharma giant has decided to put its plans for a Phase III on a back burner. And in a call with analysts, its development partners at Ionis Pharmaceuticals say those safety issues are related to severe declines in platelets--thrombocytopenia--which also recently appeared unexpectedly among some of the patients enrolled in a separate, ApoCIII trial for another drug called volanesorsen.
“While I don’t want to speculate,” said CEO Stanley Crooke, there appears to be a link between the top doses used in the studies and the platelet decline.
“We were very surprised by these events," Crooke told analysts, some of whom were clearly alarmed by the prospect that the safety problem could extend to the whole platform at Ionis. "We’ve never seen platelet declines” before this recently appeared. Crooke declined to say if any of the patients suffering from a severe platelet decline had died.
The problems immediately raised red flags with investors. Ionis' shares ($IONS) plunged 40% by the middle of the day.
Particularly perplexing, Crooke said, is that the platelet declines appear just three to four months after dosing begins, rather than after a lengthy treatment regimen. And Crooke made it clear that the company still has no clear idea of what is causing the safety issue among the patients.
"I know it's frustrating, but you're just going to have to give us time to explain this," the CEO told analysts, who had more questions than the company had answers for this morning. "I'm not getting into numbers, because whatever I say will be wrong." More time will be needed to explore what is happening and why this is happening.
"Regardless of the specific mechanism, we believe these observations clearly increase the risk around IONS platform, especially with respect to systemically administered antisense-oligonucleotides (ASOs)," noted Leerink's Michael Schmidt.
GSK ($GSK) was in the final stages of putting the finishing touches to its Phase III study of IONIS-TTRrx among patients suffering from transthyretin (TTR) amyloid cardiomyopathy, a rare disease involving misfolded proteins that build up in heart muscles, which kills its victims in about 7 years. But the safety issues that appeared in a separate Phase III study, NEURO-TTR, prompted regulators to apply the brakes on GSK’s effort, according to its partner Ionis.
The news marks a fresh setback for GSK, which has been struggling to overcome a lackluster R&D effort. Despite some high hopes and a new R&D strategy that dates back several years now, GSK has failed to come up with the kind of blockbuster drugs needed to offset the impact of generic competition and excite investors about its future. The pharma giant racked up a string of high-profile failures in Phase III, including drugs for Duchenne muscular dystrophy and heart disease.
Antisense specialist Ionis (formerly Isis) has a pact with the pharma company that dates back to 2010. GSK has an option on an exclusive license on the drug.
“GSK will consider options for TTR amyloid cardiomyopathy once additional clinical data are available from the ongoing studies,” Ionis said in its statement.
Some answers on that may come from two ongoing studies: a Phase II open-label study for amyloid cardiomyopathy and the ongoing NEURO study, focused on TTR familial amyloid polyneuropathy, which includes a subset of patients with cardio issues. The NEURO data will be updated this summer as Ionis and GSK say they’re prepping an NDA.
During the call, though, Crooke also revealed that the Phase II study had been briefly put on hold by the FDA, but got back on track soon after investigators amped up its patient monitoring.
Ionis’ two Phase III studies with GSK are part of a slate of 6 late-stage trials, including a pair of nusinersen studies with Biogen ($BIIB) on spinal muscular atrophy.
The biotech's setbacks this morning are Alnylam's gains. Barclays' Geoffrey Meacham noted that GSK's option to not start the Phase III Ionis program now offers a distinct advantage to the Cambridge, MA-based rival, which saw its shares surge 8% as news about the adverse events spread.
"We continue to believe that the issues related to the Ionis program both (1) do not affect Alnylam’s competing programs in FAP and FAC, and (2) strengthen Alnylam’s competitive position in both indications," noted Meacham. "In particular, we note mechanistic differences between the two companies (anti-sense vs. RNAi), and differences in enrollment (wtTTR and mutant TTR patient vs. Alnylam enrolling just mTTR patients)."
- here's the release