“With genetic testing in hand and presymptomatic treatment, we can look forward to a future in which age-appropriate motor milestone development is a reality,” Olga Santiago, MD, chief medical officer at Novartis-owned AveXis — the company that develops Zolgensma — said in a recent media briefing.
Besides the SPR1NT study in presymptomatic babies (NCT03505099, still recruiting), Santiago and Dave Lennon, PhD, AveXis’ president, also discussed the latest findings of a Phase 3 program in SMA type 1 and long-term data of the START trial (NCT03421977) at the 13th European Paediatric Neurology Society (EPNS) Congress in Athens, Greece.
Altogether, these studies demonstrate that treatment with Zolgensma preserves respiratory function and enables the continued achievement of developmental milestones.
As of May 31, 23 babies with two to four copies of the SMN2 gene had been treated in SPR1NT, which assesses intravenous infusion of Zolgensma in presymptomatic babies age 6 weeks or younger. Of note, a higher number of copies of SMN2 — a gene that creates a shorter and unstable version of the SMN protein — correlates with reduced disease severity. Defects in SMN1, the gene coding for full-length protein, underlie the development of SMA.
At follow-up, patients’ mean age was 6.6 months among the 10 infants with two SMN2 copies — most likely to have type 1, the most severe form of SMA — and 4.6 months in the 12 with three SMN2 copies, expected to develop type 2.
Treatment with Zolgensma, which uses an AAV9 viral vector to deliver a normal SMN1 gene to motor nerve cells, prolonged event-free survival — meaning no death or permanent respiratory support. All the patients who underwent the six-month evaluation did not need permanent ventilation, had no swallowing problems and were fed exclusively by mouth.
As for motor function, all infants with two SMN2 copies achieved or maintained a CHOP-INTEND score greater than 50, with five patients reaching the maximum score of 64 seen in healthy infants. Defying the course of SMA in untreated children, six patients (60%) were able to sit without support for at least 30 seconds at an average age of 7.6 months, three of whom (30%) could stand with assistance at 10.1 months post-treatment.
Thirteen patients experienced at least one treatment-emergent adverse event (TEAE). In seven cases, these adverse reactions were deemed treatment-related. Three TEAEs (in one patient each) were serious — croup, lethargy, and hypercalcemia — but all were resolved and considered unrelated to Zolgensma. Four patients had TEAEs of special interest, which included increased levels of liver enzymes.
“For families who never expected their children to reach meaningful motor milestones, the results we’re presenting at EPNS demonstrate the life-changing impact Zolgensma can have on children with SMA Type 1,” Santiago said in a press release. “It is critical to diagnose SMA and begin treatment as early as possible in order to stop irreversible motor neuron loss and make the achievement of major motor milestones such as crawling, sitting, and walking a possibility.”
Altering the course of SMA
Zolgensma is also being tested in three multi-center Phase 3 trials with type 1 patients up to 6 months old when receiving the gene therapy. Overall, similar to SPR1NT, these studies show extended survival, prolonged time without permanent ventilation and achievement of motor milestones.
In STR1VE, 20 (89.5%) of the 22 patients enrolled were alive and did not need permanent ventilation as of May 31. Seventeen of the 19 (89.5%) who had either experienced an event or reached 13.6 months of age — when only 25% of children with SMA are event-free if untreated — did not require permanent ventilation.
Eleven patients (50%) were able to sit unassisted for at least 30 seconds, five of whom were able to do so at 18 months of age (study completion). One patient, who initially revealed low muscle tone became able to walk with assistance. The CHOP-INTEND score increased by an average of 6.9 points at one month and by 11.7 points at three months.
The mean age at the most recent visit was 15.8 months, at an average follow-up period of 12.1 months. One patient died from respiratory failure deemed unrelated to treatment. Another participant required permanent respiratory support when withdrawing from the study.
As for STR1VE-EU, nine of the 10 patients (90%) who had reached 10.5 months of age or experienced an event did not require permanent ventilation. Two patients (6%) were able to sit without support for 30 seconds or longer. The average age at the most recent visit was 8.2 months and follow-up duration was 4.2 months.
CHOP-INTEND score increased by an average of 6.4 points at one month and by 10.6 points at three months after treatment.
One patient died prior to the March 8 cutoff date because of hypoxic-ischemic brain damage with respiratory tract infection. SMA type 1 was deemed as the cause of the respiratory tract infection. Following autopsy, the patient’s respiratory distress was considered unrelated to treatment, though Zolgensma may have contributed to increased levels of liver enzymes, low platelet counts, and low blood pressure. These adverse events will be submitted to health authorities, AveXis said.
According to the company, it is important to note that the two trials partially differed in the baseline characteristics of their participants. Mean age at dosing was 3.7 months in STR1VE and 4.1 months in the European counterpart. Mean CHOP-INTEND score was 32 in the U.S. trial and 28 in STR1VE-EU.
Also, in STR1VE-EU, nine patients required nutritional support, seven ventilatory assistance and five were excluded at screening due to elevated anti-AAV9 antibodies. In contrast, no patient in STR1VE needed such types of support at study start, nor was excluded due to anti-AAV9 antibody levels.
These differences at baseline make the largely similar results of these two STR1VE studies “striking,” Santiago commented during the media briefing.
“These updated data reinforce what we have seen in other Zolgensma studies, including survival of children with SMA Type 1 who would have in the past died or required permanent ventilation before the age of 2,” said Eugenio Mercuri, MD, PhD, a pediatric neurologist from the Università Cattolica del Sacro Cuore, in Italy. “We are seeing further robust evidence of the potential of gene therapy to effectively halt motor neuron loss, help patients achieve motor milestones and alter the course of SMA with a one-time treatment.”
Sustained motor development years into treatment
AveXis also presented updated results of START, a long-term extension study in infants who took part in the company’s pivotal Phase 1 study. Thirteen patients had joined by the end of 2018, 10 of whom took the therapeutic dose (1.1E14 vg/kg).
All patients continued maintaining developmental milestones as of May 31. Two reached the ability to stand with assistance, adding to two others able to walk independently. Among the remaining patients, three have been started on Spinraza (nusinersen, by Biogen). None of these has gained the ability to stand with assistance.
All maintained or improved their respiratory function status, with six not requiring daily respiratory support.
Patients’ mean age was 4.2 years, with one child already age 5. Mean time since gene therapy treatment was 3.9 years (maximum of 4.6 years).
No treatment-related serious adverse effects occurred, nor any of special interest. Serious TEAEs in more than one patient included pneumonia (in three), dehydration (two), acute respiratory failure (two), and respiratory distress, also in two patients. No serious TEAE led to death in both START and its parent study.
At the EPNS Congress, AveXis also presented data on the levels of anti-AAV9 antibodies in participants of SPR1NT, STR1VE, STR1VE-EU, the pivotal Phase 1 trial, and the STRONG study (NCT03381729). STRONG is a Phase 1 trial assessing intrathecal (spinal canal) delivery of Zolgensma in patients ages 6 months to 5 years with SMA type 2. It is still enrolling in the higher- dose group (C).
The research, “Adeno-Associated Virus Serotype 9 (AAV9) antibodies in patients with Spinal Muscular Atrophy Screened for treatment with Onasemnogene Abeparvovec,” showed that, similar to Zolgensma’s managed access program in the U.S., no baby enrolling in SPR1NT was excluded due to high antibody levels (titers greater than 1:50). In contrast, one participant in the pivotal trial and four in STRONG were excluded at screening for this reason.
“Elevated AAV9 antibody titers should not impact the vast majority of SMA patients from receiving [Zolgensma],” the scientists said.