Risdiplam levels equivalent to, or higher than, the total plasma levels in bone, mucosa of the GI tract, pancreas, liver, lung, heart, kidney, and spleen were therefore confirmed in rodents and nonhuman primates. As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Roche says the data keeps it on course to file for the approval of risdiplam before the end of the year in the US and other world markets, setting up possible approvals in 2020. Symbols represent mean with standard deviation. In C/C‐allele SMA mice dosed once daily for up to 30 days, RG7800 increased SMN protein levels in blood and to a similar extent in brain and muscle (Figure 4A,B). The electronic images were analyzed using a validated PC‐based image analysis package (Seescan2 software, LabLogic). SMN protein was quantified using electrochemiluminescence immunoassay utilizing a Meso Scale Discovery Sector Imager 6000 instrument as previously published. Roche’s risdiplam will find it challenging to wrest market share from Biogen’s approved similar-in-class Spinraza (nusinersen) in spinal muscular atrophy (SMA) due to the latter’s extensive data. We use cookies on this website. Spinraza is more established – having been approved in 2017 – and made $1.55bn in sales in the first nine months of the year, while Zolgensma’s made third-quarter sales of $160m, its first full quarter on the market, from use in around 100 infants across all forms of SMA. Risdiplam is advancing in an increasingly competitive space, with Biogen's Spinraza already on the market and Novartis' gene therapy Zolgensma due for a Food and Drug Administration decision any day. Agnès Poirier and Marla Weetall are joint first authors. The Genentech spokesperson declined to comment on risdiplam’s market share, but noted that the drug may be an option for SMA patients who also have scoliosis or fused spines, given they may not be eligible for intrathecal injections. F, female; M, male; CSF, cerebrospinal fluid; PND, postnatal day; PO, per os; IP, intraperitoneal; PK, pharmacokinetics (measure of the compound exposure); QWBA, quantitative whole‐body autoradiography. The dotted lines represent threefold variation around unity. De Vivo said that SUNFISH and FIREFISH will eventually have data that if positive will be sufficient for approval, but its duration of use in patients does not compare against Spinraza, which has years of clinical use. Tissue/plasma ratios of radioactivity were high in the bone marrow (5.5), kidney cortex (9.1), kidney medulla (4.1), liver (7.2), lung (7.1), heart (2.4), pancreas (4.7), spleen (8.0), trachea (2.7), mucosa of small intestine (3.4), large intestine (1.5), and rectum (4.1) 2 hours after oral administration. Compared with Spinraza, Schwan said, the big difference is that the antisense product is delivered to the central nervous system via an intrathecal injection, whereas risdiplam is … In conclusion, this study demonstrates that risdiplam distributes well into the CNS and peripheral tissues, including muscle, blood, and brain, of mice, rats, and monkeys following single or repeated oral or IP dosing. Risdiplam’s convenient oral dosing and existing data are not enough to allay concerns about retinal toxicity and risk-benefit profile. Get Free Report Roche’s risdiplam will find it challenging to wrest market share from Biogen’s approved similar-in-class Spinraza (nusinersen) in spinal muscular atrophy (SMA) due to the latter’s extensive data.. Risdiplam’s convenient oral dosing and existing data are not enough to allay concerns about retinal toxicity and risk-benefit profile. The company presented results from SUNFISH and FIREFISH at the 2019 American Academy of Neurology (AAN) Annual Meeting in May and at Cure SMA’s recently concluded 2019 Annual SMA Conference, though the latter have not been made public. With threats coming from two angles, it is no wonder that numbers for Biogen’s Spinraza have come down: over the past 12 months 2024 consensus has fallen by 22%, to sales of $1.7bn, according to EvaluatePharma. D, Time course of plasma and brain in juvenile FVB mice (PND10) following a single dose of 3 mg/kg IP (Study 1, n = 3 per time point). The largest dataset was obtained on brain tissue concentrations in 189 animals (Figure 1A). var arr3= [ 'Roche', 'Risdiplam', 'Spinraza', 'Zolgensma', 'Spinal muscular atrophy' ]; Risdiplam concentrations in duodenum, spleen, and larynx were below 1 ng/g and around 4 ng/g in both liver and kidney. Spinal muscular atrophy: more than a disease of motor neurons? Characterization of behavioral and neuromuscular junction phenotypes in a novel allelic series of SMA mouse models, SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full‐length SMN, SMN protein can be reliably measured in whole blood with an electrochemiluminescence (ECL) immunoassay: implications for clinical trials, PK/PD assessment in CNS drug discovery: prediction of CSF concentration in rodents for P‐glycoprotein substrates and application to in vivo potency estimation, The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery, Breast cancer resistance protein interacts with various compounds in vitro, but plays a minor role in substrate efflux at the blood‐brain barrier, Prediction of human brain penetration of P‐glycoprotein and breast cancer resistance protein substrates using in vitro transporter studies and animal models, Pharmacokinetics, pharmacodynamics, and efficacy of a small‐molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy, Nusinersen versus sham control in infantile‐onset spinal muscular atrophy, Clinical studies of RG7916 in patients with spinal muscular atrophy: SUNFISH part 1 study update. Denervation and atrophy of skeletal muscles, as well as intrinsic abnormalities in SMA skeletal muscle cells, are thought to contribute directly to SMA disease pathogenesis.6, 12 The free drug hypothesis applies to all tissues and unbound drug in plasma is also expected to be in equilibrium with free drug in the muscles. Risdiplam’s oral dosing is highly attractive over intrathecal Spinraza, but the latter’s robustness in clinical use and trial data make for a difficult change. Part 1 of the 231-patient SUNFISH had an exploratory primary efficacy measure that was not powered, using the Motor Function Measure-32 scale. Browse over 50,000 other reports on our store. A different motor scale was used, called MFM32; among 43 patients for whom 12-month follow-up was available, 58% saw an improvement of at least three points. Unbound (free) plasma concentrations (Cu_p) were calculated by multiplying the measured total concentration in plasma by the measured free fraction in plasma (16% in adult rat). To measure SMN protein in blood, blood was obtained by cardiac puncture. But the price of Evrysdi might be the biggest convincer; it is dependent on weight and capped at $340,000 per annum once a patient reaches 44 pounds, meaning that the cost for younger children will be much lower. CONTINUUM: Lifelong Learning in Neurology. For repeat administration, the compounds were administered once daily. However, dosing was suspended due to off‐target retinal findings of RG7800 in long‐term, nonclinical safety studies in monkeys. SMN protein was quantified using Homogeneous Time Resolved Fluorescence (HTRF, Cisbio Bioassays) as previously published.14 Total protein content was quantified in each tissue homogenate using the BCA assay according to the manufacturer's protocol. Spinal muscular atrophy (SMA) is caused by the deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene, resulting in insufficient levels of functional SMN protein and selective vulnerability of motor neurons.1, 2 A second SMN gene, SMN2, produces only low levels of functional SMN protein which are insufficient to fully compensate for the lack of the SMN1 gene.3, 4 The orally administered small molecules risdiplam (RG7916; RO7034067, 7‐(4,7‐diazaspiro[2.5]octan‐7‐yl)‐2‐(2,8‐dimethylimidazo[1,2‐b]pyridazin‐6‐yl)pyrido[1,2‐a]pyrimidin‐4‐one)) and RG7800 (RO6885247, 2‐(4‐ethyl‐6‐methyl‐pyrazolo[1,5‐a]pyrazin‐2‐yl)‐9‐methyl‐7‐(1‐methyl‐4‐piperidyl)pyrido[1,2‐a]pyrimidin‐4‐one) were designed to modify SMN2 mRNA splicing, by promoting inclusion of exon 7, thereby increasing full‐length SMN2 mRNA production and levels of functional SMN protein in patients with SMA. Roche says the data keeps it on course to file for the approval of risdiplam before the end of the year in the US and other world markets, setting up possible approvals in 2020. As analysts speculate about the future of Biogen’s pricey spinal muscular atrophy treatment Spinraza, the company is hoping it can corner the market before competitors take the field. The entire brain was collected into labeled 7 mL Precellys® homogenization tubes (CK14), snap‐frozen in liquid nitrogen and stored on dry ice. A strong correlation was observed between concentrations of risdiplam in plasma and levels of risdiplam in tissues over a wide range of concentrations (Figure 1A‐C), indicating that the total plasma is representative of tissue concentrations. Roche is also emphasising the safety of risdiplam, saying that “no treatment related safety findings leading to study withdrawal have been seen in any risdiplam trial to date”.

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