Biogen has acquired exclusive rights from Ionis Pharmaceuticals to develop and commercialize the experimental drug BIIB115 (ION306) for the treatment of spinal muscular atrophy (SMA).
The asking price is $60 million upfront plus future payments as the project develops including royalties from its sale.
BIIB115 is an antisense oligonucleotide in preclinical development aimed at enhancing the synthesis of a fully functional survival motor neuron (SMN) protein whose deficiency is responsible for spinal muscular atrophy. BIIB115 modulates the alternative splicing of pre-mRNA of SMN2 gene, functionally converting it into SMN1 gene, thereby increasing the level of the working SMN protein.
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The price tag is over $42 billion.
Spinraza (nusinersen), proposed by Biogen in late 2016, was the first targeted drug against spinal muscular atrophy. Nusinersen (BIIB058) is similarly an antisense nucleotide with the above mechanism of action. BIIB115 is said to offer a less frequent dosing regimen. Spinraza, which is administered intrathecally, requires administration every four months in a maintenance therapy regimen.
Direct rivals of Spinraza are the gene therapy Zolgensma (onasemnogene abeparvovec), which is backed by Novartis and used once in a lifetime, and the oral Evrysdi (risdiplam), promoted by Roche and prescribed daily.
Biogen’s interest in the updated Spinraza is due to two factors. First, competition is heating up: according to industry projections, Spinraza sales will reach $1.3 billion by 2026, while demand for Zolgensma and Evrysdi will reach $1.9 billion and $2.1 billion, respectively.
Second, the pipeline of experimental drug compounds against spinal muscular atrophy in active development is very scarce (there are only two such drug candidates), so it makes sense to strengthen positions.
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Thus, the SAPPHIRE (NCT05156320) phase 3 clinical trial is testing apitegromab (SRK-015) among nonambulatory patients with spinal muscular atrophy type II or III who are already receiving treatment with nusinersen or risdiplam. The hypothesis being examined is whether apitegromab, administered intravenously every four weeks on top of existing therapy, can improve motor function according to the Hammersmith Functional Motor Scale Expanded (HFMSE).
The monoclonal antibody apitegromab, being developed by Scholar Rock, is a selective and local inhibitor of supracellular activation of myostatin precursors — promyostatin and latent myostatin. Myostatin (MSTN), also known as growth differentiation factor 8 (GDF8), is a member of transforming growth factor beta (TGFβ) superfamily. Myostatin is expressed predominantly by skeletal muscle cells and is involved in suppression of myogenesis — myocyte growth and differentiation. In a healthy body, myostatin works in synergy with other growth factors and hormones to maintain proper muscle mass. Targeting and binding myostatin precursors (instead of blocking already activated mature myostatin or its receptor) avoids inhibiting the activity of related members of the TGFβ superfamily, such as growth differentiation factors 2 and 11 (GDF2/11), activin A complex, bone morphogenetic protein 10 (BMP 10), TGF-β1, which could otherwise lead to undesirable side effects.
Biogen itself is trying its hand with the myostatin inhibitor BIIB110, which is in a phase 1 clinical trial. The mechanism of action of BIIB110 is different: the molecule is a ligand trap for type IIA and IIB receptors of activin A (ACVR2A/ACVR2B, ActR-IIA/ActR-IIB) through which myostatin signaling occurs.
In July 2021, Novartis stopped development of branaplam (LMI070, NVS-SM1), a similar drug to PTC Therapeutics’ risdiplam (RG7916, RO7034067), a pre-mRNA splicing modifier of SMN2 gene. The decision was made after it became clear that branaplam, administered orally once a week, could not withstand competition with existing drugs for spinal muscular atrophy because it did not offer any significant clinical advantage over them.
In the meantime, Biogen is studying the treatment of spinal muscular atrophy with Spinraza, which is administered in a doubled dose: it is believed that this will be mirrored by increased therapeutic efficacy. Enrollment in the DEVOTE (NCT04089566) and ASCEND (NCT05067790) phase 3 clinical trials is ongoing; the second trial involves patients previously treated with risdiplam.
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