Repligen and quinazoline for a SMA treatment

Families of Spinal Muscular Atrophy (FSMA) announced that it has entered into a groundbreaking exclusive license agreement with Repligen Corporation for the development of a potential treatment of Spinal Muscular Atrophy (SMA).
FSMA made investments of $13 million during the last decade to bring this specific program to the cusp of clinical development. Through FSMA’s leadership, the research has resulted in a drug candidate, Quinazoline495, that treats the underlying cause of SMA. In fact the licensed compounds increase the production of SMN in cells derived from patients. In preclinical studies, the drug has been shown to efficiently cross the blood brain barrier - a critical feature for a neurological drug - and prolong survival significantly in two different transgenic mouse models of SMA.

Often an orphan disease, such as SMA, will not be "adopted" by the pharmaceutical industry because there is limited financial incentive to make new medications to treat smaller patient populations. This license agreement marks a significant milestone for the SMA community by securing the commitment of an industrial partner to develop potential treatments through the highly expensive human clinical trial phases.
“At this point in the program, joining forces with a corporate partner to advance into clinical studies is the best way to meet our objective of accelerating drug development for SMA,” said Kenneth Hobby, President of Families of SMA. “Repligen is an ideal partner for this program with the necessary resources and expertise to invest in and focus on successfully developing this new treatment for SMA. We are very excited to partner with Repligen and look forward to making our combined efforts successful in delivering an effective treatment to our patients.”
“Families of SMA has made remarkable progress in defining a series of highly potent compounds which may be clinical candidates for SMA,” stated Walter C. Herlihy, President and Chief Executive Officer of Repligen Corporation. “We look forward to working with FSMA and their collaborators in the development of what we hope will be an important new treatment for SMA.”
Through the agreement with Repligen, Families of SMA has the potential to recover its investments through a series of milestone payments if the program successfully progresses through clinical stages and eventually reaches market approval.

The licensed compounds, of the class of Quinazolines, were identified as potent SMN2 inducers by ultrahigh-throughput screening. The drug-like properties of the initial screening hits were optimized through directed medicinal chemistry. This resulted in series of C5-Quinazoline derivatives. The first tests of this class of compounds in SMA mice show potential therapeutic benefit. The clinical lead in this series, called Quinazoline495 (D157495), is a more optimized compound than other three (D152344, D153249 and D156844); all have been assessed in animal model with similar, good results. The lead compound Quinazoline495 recently received orphan drug designation from the FDA for the treatment of spinal muscular atrophy. 

A first publication, showing data from the testing of Quinazoline derivatives in a SMA mouse model, has been published in Human Molecular Genetics by lead author Dr. Matthew Butchbach from the laboratory of Dr. Arthur Burghes at the Ohio State University. Oral administration of compounds D152344, D153249 and D156844 to neonatal mice resulted in a dose-dependent increase in SMN promoter activity in the central nervous system. The authors then examined the effect of these compounds on the progression of disease in SMA mice. Here the abstract:
Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy
Proximal spinal muscular atrophy (SMA), one of the most common genetic causes of infant death, results from the selective loss of motor neurons in the spinal cord. SMA is a consequence of low levels of SMN protein. In humans, the SMN gene is duplicated; SMA results from the loss of SMN1 but SMN2 remains intact. SMA severity is related to the copy number of SMN2. Compounds which increase the expression of SMN2 could, therefore, be potential therapeutics for SMA. Ultrahigh-throughput screening recently identified substituted quinazolines as potent SMN2 inducers. A series of C5-quinazoline derivatives were tested for their ability to increase SMN expression in vivo. Oral administration of three compounds (D152344, D153249 and D156844) to neonatal mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system. We then examined the effect of these compounds on the progression of disease in SMN 7 SMA mice. Oral administration of D156844 significantly increased the mean lifespan of SMN 7 SMA mice by 21-30% when given prior to motor neuron loss. In summary, the C5-quinazoline derivative D156844 increases SMN expression in neonatal mouse neural tissues, delays motor neuron loss at PND11 and ameliorates the motor phenotype of SMN 7 SMA mice.

A second study, on the lead compound Quinazoline495, has been published by lead author Christine DiDonato, Children’s Memorial Research Center of Chicago. Here the abstract:
In vivo testing of D157495, a novel quinazoline compound, for the treatment of SMA
It is clear from both family and mouse studies that SMN2 is the major disease modifier for SMA and has the potential to be activated to increase SMN dosage and abrogate disease. A hit from a HTS screen for SMN inducers was identified and moved forward through the medicinal chemistry process to develop a clinical lead compound, D157495, that is orally bioavailable, has a known cellular protein target, DcpS, whose inhibition results in increasing SMN transcripts and protein both in vitro and in vivo. We have tested the ability of D157495 to enhance survival and function in a blinded study using a mouse model of SMA that we have developed. This model does not contain SMN2, but we know from prior work that the quinazoline compounds induce Smn expression from the endogenous mouse gene. For this study, entire litters were dosed once daily by oral gavage from P4-P20 or until death with either D157495 (20mg/kg formulated in water) or vehicle (water). By P16 it was clear which mutant mice received compound simply by the overall appearance of the SMA pups. The median survival of untreated mutant mice (n=15) is 21 days with a maximum lifespan of 25 days. In contrast, treatment of SMA pups with compound extended survival in 100% of the treated mutants (n=27), with the first drug-treated animal dying at P26, which is beyond the longest day of survival for the vehicle-treated and untreated mice. We ended the study at 110 days. At this time 37% (10/27) of the mutant mice were still alive. The median survival of this cohort was 87.5 days, more than a 400% increase in survival over vehicle treated SMA pups. We will present our current data along with phenotype information for these studies and a plan for future studies.

(sources: FSMA, Repligen)