“Four million dollars is a significant amount of money, but we believe that this is a cost-effective point,” David Lennon, PhD, president at Novartis-owned AveXis, said in a conference call held on Monday, in which the company presented its R&D and Investor update.
“We’ve shown through other studies we are cost effective in the range of $4 to $5 million, and ultimately, this is an important context as we consider how we are going to evaluate value for AVXS-101,” Lennon said.
Novartis bases its cost-effectiveness model on a 10-year cost of treatment set against quality-adjusted life years (QALY) gained. At a $4 million list price, QALY for AVXS-101 is 13.3, which is within the range for lifelong therapies for rare diseases, including Spinraza (nusinersen, by Biogen), according to Novartis.
Spinraza — the first approved SMA treatment — carries a list price of $750,000 for the first year and about $375,000 for subsequent years, which amounts to around $4.1 million per patient over 10 years. List prices are seldom paid directly by patients or their families. Still, the extent to which this potential therapy’s benefits are sustained over time will dictate its final cost-effectiveness.
Launching AVXS-101 — should it be approved by regulatory authorities — represents a novel challenge for healthcare systems, which are “not designed for introducing one-time, potentially curative therapy,” Lennon said, adding that this is a “entirely new paradigm that we’re introducing with payers, with providers, and with patients.”
Ensuring rapid access is key, he added, which Novartis plans to do through policy support — including newborn screening, inside and outside the U.S. — program support for insurers, and by covering some out-of-pocket costs for eligible patients, as well as helping those in financial hardship with limited or no insurance coverage. A goal is to have these all these programs available “at launch” in “major markets.”
Besides cost-effectiveness, relevant factors in considerations underway at Novartis for commercial pricing of AVXS-101 include payer feedback, exploring payments made over time, and other ways of ensuring that the treatment’s eventual price is sustainable for healthcare systems, said Vasant Narasimhan, MD, the company’s CEO.
The very positive outcomes reported in ongoing clinical trials of AVXS-101 — largely the basis of AveXis’ acquisition by Novartis for $8.7 billion this year — have the company feeling “very confident,” Narasimhan said. “We will find a way to make this medicine broadly available for all SMA patients.”
Approval possible by mid-2019
According to Lennon, AVXS-101 could be approved for SMA type 1 by mid-2019, following the recent regulatory filings in the U.S. and Europe, as well the initiation of a pre-application review period in Japan.
The applications are supported by results from the pivotal, dose-escalation Phase 1 trial (NCT02122952), started in 2014. Two IV doses of AVXS-101 — a higher, proposed therapeutic 2.0E14 vg/kg dose in 12 patients and the lower 6.7E13 vg/kg in three — were given to babies with SMA type 1. This is the most common and most severe disease form, with symptoms appearing at birth or within the first few months of life. Type 1 patients are unable to raise their head, sit upright without support, or to breathe, cough or swallow normally.
AVXS-101 showed a rapid onset of effect, with most approaching maximum CHOP-INTEND scores that assesses movement ability.
While natural history has about 8% of type 1 babies surviving event-free at 20 months, data presented in April showed all 15 toddlers given AVXS-101 with survival and motor function benefits at 24 months post-treatment, including 11 able to control their heads, sit unassisted for 30 seconds or more, and eat by mouth.
Data from the ongoing and long-term START study (NCT03421977), following patients in that Phase 1 trial annually for up to 15 years, show four children are now able stand with assistance, two of whom are walking. One boy, who entered the trial as a 1-month-old headed for “a totally incapacitated life,” is now “preparing to go to preschool,” Lennon said.
Overall, “AVXS-101 has delivered rapid improvement in motor milestone achievements, dramatic survival benefit and a durable response, and favorable safety profile,” said Brian Kaspar, AveXis’ chief scientific officer.
The therapy’s effectiveness and safety is currently being tested in type 1 children younger than 6 months in the STR1VE Phase 3 trial (NCT03306277).
Preliminary results showed that, in three of six treated babies given AVXS-101, mean CHOP-INTEND scores rose by an average of 7.8 at one month and by 17.3 at three months. None required respiratory or nutritional support.
No need for combination therapy
AVXS-101 is designed to restore production of working SMN protein in motor neurons, which control muscle contraction. The therapy contains a functional copy of the SMN1 gene that is defective in SMA patients. This mutation leads to substantially lower levels of a working protein, with subsequent loss of motor nerve cells, progressive muscle weakness, and atrophy (shrinkage).
“AVXS-101 has the ability to produce either normal or even greater than normal levels of the SMN1 gene that is so required for all of these patients” Kaspar said. Importantly, the treatment is designed to start producing protein “immediately and continuously,” he added for “rapid, transformational and durable benefit.”
The therapy uses a modified, and harmless adeno-associated virus (AAV) known for its ability to cross blood vessels and get into muscles. This viral “capsule” works as a delivering vehicle. In preclinical work, AAV9, the specific AAV subtype in AVXS-101, could target cells in the brain and spinal cord “at unprecedented levels, in ways we had never seen before,” Kaspar said in a February interview with SMA News Today.
Spinraza uses a different strategy. It raises SMN protein levels by increasing the ability of the SMN2 gene to produce a full-length SMN protein. SMN2 normally produces a shorter-than-normal version of SMN that is destroyed by the cells. One might think that using an additional treatment to boost protein production beyond what is possible with gene therapy could be beneficial, but scientists at Novartis have seen otherwise.
“In essence, SMN is probably a threshold effect and we believe that AVXS-101 delivers above that threshold, so there’s no added [clinical] benefit,” said Kaspar.
“We really do not believe combination [disease-modifying treatment] is going to be the answer. We believe it’s going to be the one-time gene therapy across all these SMA types that’s ultimately gonna carry the day,” Narasimhan added. “As you see the data come forward, patients are going to want the transformational therapy.”
For type 1 patients who cannot use this therapy — a few may show an immune reaction to its transport virus or viral vector — Novartis is developing branaplam (LMI070), which like Spinraza intends to raise functional SMN protein levels derived from SMN2. Data from a Phase 1 proof of concept study (NCT02268552) pointed to both motor benefits and good tolerability. This trial is still enrolling babies and toddlers at sites in Europe; more information can be found here.
A commitment to treat all types of SMA
To date, a total of 86 patients have been treated with AVXS-101 across all types of SMA. According to Lennon, this is the “largest single treatment population for any gene therapy that’s been investigated so far in the world.”
Besides IV infusion, treatment with AVXS-101 is also being tested via intrathecal delivery (through the spinal canal). This IT approach enables CNS-targeted delivery and a lower AVXS-101 dose (anywhere from one-third to one-tenth) in comparison to IV infusion.
The ongoing STRONG Phase 1 trial (NCT03381729), the first of the IT formulation, is testing the therapy’s safety and tolerability in patients up to 60 months (5 years) of age who are able to sit but not stand or walk. Patient enrollment for the low and medium doses is now complete, with recruitment for the high dose expected to start in December, Lennon said.
Results from STRONG will inform the final design of a trial named REACH, set to begin in 2019. It will include children up to 18 years of age with SMA types 1–3 and patients ineligible for the company’s other studies. AveXis expects to present major clinical data on the AVXS-101 program at the AAN meeting set for May.
The companies are taking steps in anticipation of AVXS-101’s approval. To enable sufficient supply for the launch markets, AveXis tripled its capacity with its new manufacturing site in Durham County, North Carolina, expected to be operational by 2020.
Overall, the broad clinical program of AVXS-101 reflects a grand goal. “We are committed, at AveXis, to treating all types of SMA” Kaspar said.
With the recent addition of SMA to the U.S. list of diseases recommended for universal screening, AVXS-101 could treat the entire yearly incidence for SMA types 1-3, now estimated at around 1,150 people in the U.S., Europe and Japan, he added.