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Clinical Trials

Date: 2017-07-01

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the 23rd International Annual Congress of the World Muscle Society

Company: PTC Therapeutics (USA - NJ) Roche (Switzerland)

Product: risdiplam - RO7034067/RG7916

Action mechanism:

  • splicing modifier. RG7916 directly targets the underlying molecular deficiency of SMA by modulating SMN2 splicing to increase expression of stable full-length SMN2 mRNA from the SMN2 gene. A healthy volunteer study was recently completed and the preliminary results demonstrate that RG7916 increased the production of full-length SMN2 mRNA further demonstrating proof of mechanism for oral small molecule SMN2 splicing modifiers. RG7916 was also well tolerated.
 

Disease: type 2 and type 3 spinal muscular atrophy (SMA)

Therapeutic area: Rare diseases - Genetic diseases - Neuromuscular diseases

Country: Australia, Canada, Germany, Spain, Sweden, Switzerland, UK, USA

Trial details:

  • SUNFISH is a two-part phase 2 clinical study. Part 1 is a double-blind, placebo-controlled, randomized, exploratory dose-finding study in Type 2/3 pediatric and adult SMA patients. The primary objective of the first part of the study is to evaluate the safety, pharmacokinetics, and pharmacodynamics of RG7916 in patients, and to select the dose for the second part of the study. The pivotal second part is a double-blind, placebo-controlled, randomized, confirmatory study in Type 2/3 SMA patients followed by an open-label extension. The primary objective of the pivotal second part of the study is to evaluate the safety and efficacy of RG7916 compared to placebo. SUNFISH is one of three ongoing clinical trials of RG7916, along with FIREFISH and JEWELFISH. (NCT02908685 )

Latest news:

  • • On October 3, 2018, Roche announced  interim clinical data from the dose-finding parts of the pivotal FIREFISH and SUNFISH studies investigating risdiplam (RG7916) in spinal muscular atrophy (SMA) at the 23rd International Annual Congress of the World Muscle Society in Mendoza, Argentina. In the FIREFISH study in Type 1 SMA, six out of 14 infants (43 percent) were able to sit (with or without support), including three (21 percent) who achieved unassisted stable sitting after eight months of treatment. In addition, four infants (29 percent) demonstrated rolling to the side; seven (50 percent) kicking and six (43 percent) achieved upright head control. These milestones were assessed according to the Hammersmith Infant Neurological Examination (HINE) Module 2 and are key secondary endpoints in the confirmatory part of FIREFISH.
  • Updated analyses of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), a scale developed to assess motor function in infants with Type 1 SMA, demonstrated that eight out of 14 infants in FIREFISH (57 percent) achieved a score of 40 or above at their eight-month visit. Typically, an infant with Type 1 SMA does not demonstrate any motor improvement and can decline during this time period. The median CHOP-INTEND scores increased over time (37.5 at 6 months [n=20] compared to 41.5 at eight months [n=14]). The median age at first dose in FIREFISH was 6.7 months and median treatment duration was 9.5 months. Nineteen out of 21 infants enrolled (90 percent) remain alive with two having discontinued due to the fatal progression of their disease. Three patients are now over 24 months old. No infant has required a tracheostomy or permanent ventilation since study initiation, and no infant has lost the ability to swallow. The most common adverse events were fever (pyrexia; 52.4 percent), diarrhea (26.8 percent), upper respiratory tract infections (19 percent), ear infections (14.3 percent), pneumonia (14.3 percent), constipation (14.3 percent), vomiting (14.3 percent), cough (14.3 percent) and upper respiratory tract inflammation (14.3 percent).
  • In Part 1 of the SUNFISH study in Type 2 and 3 SMA, SMN protein median increases of greater than two-fold, as measured in blood, were seen after 12 months. A very broad patient population aged between two to 24 years was included, ranging in functional status from weak non-ambulant to strong ambulant, and with varying degrees of scoliosis from none to severe. Twenty-one patients initially received lower doses of risdiplam for at least 12 weeks. Of the patients treated with risdiplam for at least one year (n=30), the median change from baseline in Motor Function Measure (MFM), the primary endpoint in the confirmatory part of SUNFISH and a scale used to assess motor function in neuromuscular diseases, was a 3.1-point improvement. Sixty-three percent of patients experienced an improvement in MFM over baseline of three points or more after one year. Such improvements were seen both in patients under 12 years old (76 percent; n=17) and over 12 years old (46 percent; n=13). When considering patients who experienced any amount of improvement over baseline, the percentages were 70 percent overall, 76 percent for the younger age group, and 62 percent for the older patients. Serious adverse events that occurred in two or more of the 51 patients exposed to risdiplam were nausea (4 percent), upper respiratory tract infection (4 percent) and vomiting (4 percent). To date there have been no drug-related safety findings leading to withdrawal from any study.
  • Follow-up is ongoing for the confirmatory Part 2 portions of both the FIREFISH and SUNFISH studies. • On July 1, 2017, PTC Therapeutics announced the presentation of preliminary clinical data from the company's joint development program with Roche and the SMA Foundation in spinal muscular atrophy (SMA) at the Cure SMA Meeting in Orlando. Preliminary results from an early analysis of Part 1 of the Phase 2 SUNFISH trial evaluating oral RG7916, a small molecule modifier of Survival Mo tor Neuron 2 (SMN2) splicing, were highlighted in an oral presentation titled "Clinical Studies of RG7916 in Patients with Spinal Muscular Atrophy: Study Update."
  • Preliminary results from an early analysis from the ongoing Part 1 of the RG7916 SUNFISH study in Type 2/3 SMA patients demonstrated a dose-dependent increase in SMN2 full length/?7 mRNA ratio of ~ 400% versus baseline, as measured in whole blood. These results provided proof of mechanism for oral small molecule SMN2 splicing modifiers. No drug-related adverse events leading to withdrawal have been observed to date for RG7916.
  • • On October 20, 2016, PTC Therapeutics announced that its joint development program in Spinal Muscular Atrophy (SMA) with Roche and the SMA Foundation (SMAF) initiated a Phase 2 study in pediatric and adult Type 2/3 SMA patients. The study, named SUNFISH, is a two-part study investigating the safety, tolerability and efficacy of RG7916, an oral small molecule survival motor neuron 2 (SMN2) splicing modifier. The first part of the study will evaluate safety and tolerability through escalating doses of RG7916. After dose selection, the study will transition into the pivotal second part evaluating the efficacy of RG7916. Initiation of the pivotal second part of the study is expected to begin in 2017 and will trigger a $20 million milestone payment to PTC from Roche. A similarly designed two-part study to evaluate RG7916 in Type I SMA patients is expected to begin in the coming months.
  • A trial in Type I SMA patients, FIREFISH, is planned to initiate in the coming months. FIREFISH is also planned to be a two-part study. The first part is an open-label, dose-escalation study in at least eight infants for a minimum of four weeks. The primary objective of part one of the study is to assess the safety profile of RG7916 in infants and determine the dose for part two. The second part of FIREFISH is expected to be an open-label, single-arm study in approximately 40 infants with Type I SMA for 24 months, followed by an open-label extension. The primary objective of the second part of the study will be to assess the efficacy of RG7916 at the selected dose after 12 months of treatment.

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