C5 Inhibitor (Nimble Therapeutics)

It still remains to be seen if Rocket will have enough cash to carry the biotech through the pivotal gene therapy readout. \n The FDA has freed Rocket Pharmaceuticals from a clinical hold, giving the gene therapy developer permission to take flight with its pivotal cardiomyopathy disorder trial.The hold was implemented in late May, around the same time Rocket reported a patient death in its phase 2 study.The lift announcement, occurring at market open today, initially launched Rocket’s stock upwards, though shares have now leveled out a bit to a 10% boost from open, settling at $3.22 per share.The New Jersey-based biotech will now resume its study designed to support accelerated approval of RP-A50, an AAV9 gene therapy made to restore cardiac function by delivering the LAMP2B transgene to heart cells. To date, six patients with Danon disease—a genetic condition known to weaken the heart muscle—have received Rocket’s investigational therapy in the study.Previously, Rocket had stopped dosing and notified the FDA after a patient developed complications linked to capillary leak syndrome, which can cause extremely low blood pressure and organ damage. The patient later developed an acute systemic infection and ultimately died.The federal agency had already imposed a clinical hold before the death to assess the causes of the adverse event. At the time, Rocket identified the addition of a C3 inhibitor to the pretreatment regimen as a potential cause of the capillary leak syndrome. The biotech had incorporated the immunomodulatory agent to counter complement activation by the AAV and prevent thrombotic microangiopathy (TMA).Now, the FDA is allowing the study to continue at a lower dose without the C3 inhibitor, according to Rocket’s release. The mid-stage trial will resume with a new dose of 3.8 x 1013 GC/kg of RP-A501 in three patients, with a minimum of four weeks between dosing. This compares to the first six patients treated at a dose level of 6.7 x 1013 GC/kg.The dose change aligns with the lower range of doses associated with efficacy in Rocket’s phase 1 study, according to the biotech.The company will also use an immunomodulatory regimen similar to that seen in the phase 1 pediatric cohort, while also lowering the threshold for administering C5 inhibitor eculizumab.Rocket has already enrolled the number of patients needed to run the pivotal trial and hasn’t heard of any patients no longer interested in dosing, according to an Evercore ISI analyst note. Dosing is expected to start again in 2026, Rocket told the firm in a call this morning.  After safety data is collected from the next three patients, Rocket will reconvene with the FDA to discuss dosing for the rest of the study, according to Evercore.  However, based on a current cash runway of $271 million that is expected to stretch through the second quarter of 2027, it doesn’t seem likely that Rocket will have enough money to make it all the way through the pivotal readout. Evercore did note that selling off a priority review voucher for another asset called RP-L201 could help. The analyst still predicts a high chance of approval for the therapy in X-linked Danon disease, with the only currently available treatment being a heart transplant. The gene therapy RP-A501 has secured regenerative medicine advanced therapy, fast track, rare pediatric and orphan drug tags from the FDA.  At William Blair, analysts are viewing the lift and discontinuation of the C3 complement inhibitor as positives, though they noted in an Aug. 20 report that the protocol changes come with some separate risk. The analysts questioned whether the C5 inhibitor will be enough to prevent TMA cases and if the recalibrated dose will be capable of providing durable responses for adults.  Editor\'s note: This story was updated at 12:10 p.m. ET to classify Danon disease as a cardiomyopathy disease instead of a metabolic disorder, as it has historically been referred to.