Early interim data from a Phase 2 clinical trial evaluating varying doses of a potential oral therapy, RG7916, in infants with type 1 spinal muscular atrophy (SMA) is showing good safety and tolerability, researchers said in a recent scientific presentation.
Preliminary findings of 13 babies enrolled — extending to week 35 of treatment in three of them — also show that none have lost the ability to swallow or required ventilation in order to breathe, and eight of nine infants evaluated at week eight also were swallowing and breathing on their own.
One infant entered the study unable to swallow, and had not regained that ability after eight weeks of treatment, though no others had lost it.
The data was presented by Giovanni Baranello, MD, PhD, a neurologist with the Carlo Besta Neurological Research Institute Foundation in Milan, Italy, and a study lead researcher, at the first International Scientific Congress on Spinal Muscular Atrophy that took place in Krakow, Poland, Jan 25–27.
“Even at this early interim look, investigators felt that it was important to start sharing with the community what we observe,” Nikolai Naryshkin, PhD, vice president of biology at PTC Therapeutics and head of its SMA program, said in an interview with SMA News Today.
Oral therapy with potential wide-ranging effect
RG7916 — developed initially by PTC Therapeutics and the SMA Foundation, and led by Roche since 2011 — is an oral therapy, swallowed or delivered through a feeding tube. That alone could be a distinct advantage over the only other approved therapy for SMA, Spinraza, which requires spinal injections.
“We feel that the ability to provide the therapy as a simple oral delivery is something the community does appreciate,” Naryshkin said.
That the therapy is ingested does not create any new safety concerns, he added, noting “There is nothing more toxic about oral compounds versus any other mode, it’s compound-specific.”
Creating an orally delivered drug that is able to bypass the blood-brain barrier and enter the central nervous system (CNS) is complex. That’s one reason for using spinal injection — it is a more direct route to the CNS, which is the major source of issues in SMA. RG7916 is a small molecule, and was designed to be able to bypass the blood-brain barrier when ingested; it enters the central nervous system from the bloodstream by avoiding interaction with one of the transporter proteins that keep foreign substances out of the brain, called MDR1.
Specifically, RG7916 works by interacting with the SMN2 gene in cells to increase production of the survival motor neuron, or SMN, protein, which is critical for the proper function of motor neurons — nerve cells that control muscles and their movement. The genetic mutation responsible for SMA leads to an insufficient production of this protein, leaving patients with limited mobility. In severe cases like type 1, babies are unable to raise their heads or sit unsupported, and progressively lose the ability to swallow and breathe without aid.
The compound also was designed to be able to distribute throughout tissues of the body, not just the central nervous system.
That’s important, Baranello said in an email response, because “increasing evidence suggests that SMA is a multi-system disease, in which different cells, tissues and organs or systems, including muscle, liver, heart, vascular system, bones, can be differentially involved by low levels of SMN protein.
“The possibility to have an orally administered medicine, which is able to increase systemically the levels of SMN may have potential benefits, not only on motor neurons, but also on these organs and tissues, thus enhancing the beneficial effects for patients,” he said.
Added Naryshkin: “SMN is in every cell in the body. If you want the most comprehensive approach, you want to have the therapy addressing all the cells in the body. That’s exactly what our molecule does.”
In Krakow, investigators also presented results from preclinical studies in mice, rats and monkeys, which show that RG7916 distributes to all types of tissues. Their analysis showed that levels of RG7916 measured in the blood matched the levels that were found in the other tissues, which indicates that blood sample measurements were a good way to track drug levels across the body.
Clinical trials underway
The trial in type 1 infants, FIREFISH (NCT02913482), opened in December 2016 and has two parts. Part one is an exploratory study to identify an optimal dose for its second part, set to begin soon. That dose has not yet been identified, Naryshkin said.
Data on the first 13 of 16 treated infants were presented in Krakow, and showed no serious safety issues that led to study withdrawal.
Ten infants did have adverse events, including fever, upper respiratory tract infections, and diarrhea, but most were mild and resolved, the presentation showed. Two died, but their deaths were attributed by independent evaluators to the disease, and not to treatment.
The remaining 14 infants — between 1 and 7 months old at the study’s start — are expected to continue treatment in an open-label extension.
In part two, investigators will treat up to 40 babies with RG7916 for two years to determine both its continued safety and whether it works, partly by looking after 12 months at the number able to sit unsupported for five seconds.
RG7916’s effectiveness also will be measured by comparing treated infants with the natural history — or normal progression — seen in type 1 SMA patients of equivalent age. Such measures allow researchers to evaluate effectiveness without requiring a portion of the patients to take a sham treatment as a control group, Naryshkin said.
“Clinical trial design with a placebo arm in a rapidly progressing terminal disease is always a challenge,” Naryshkin said. “In discussions with the SMA community, patients, caregivers and advocacy groups, as well as health authorities in different countries, it was decided that the best path forward was an open-label study design.”
Throughout the dose-finding phase, investigators are taking blood samples to measure changes in patients’ SMN protein levels in response to treatment. Analysis of patients in previous trials showed improvement in these levels was the best indicator of clinical response. For a type 1 SMA patient, for example, a two-fold increase in SMN protein levels might bump them into type 2, Naryshkin said.
Preliminary data announced in October from part one of an ongoing Phase 2 study in later-onset SMA patients, called SUNFISH (NCT02908685), showed that RG7916 given for at least 28 days caused a median 2.5-fold increase in SMN levels compared to levels at the study’s start. SUNFISH is evaluating the treatment’s safety and effectiveness in type 2 and 3 patients who are 2 to 25 years old.
In addition to FIREFISH and SUNFISH, a third clinical trial of RG7916, JEWELFISH (NCT03032172), is an open-label study for patients who participated in study of an SMN2-targeting therapy other than RG7916.
All three are recruiting eligible SMA patients — types 1, 2 and 3 — at sites across the U.S. and Europe. SUNFISH also is enrolling patients in Japan. More information is available by clicking on each trial’s identification number.
“We feel that it’s a very nice cross section of clinical programs that touch upon many different types of SMA,” Naryshkin said. “We have very deep connections to the SMA community, and we’re excited about all of these options coming online for SMA patients. It’s really rewarding that scientific discoveries … really can yield drug discovery and result in active and efficacious therapies.”