Spinraza®: Choosing Innovation for Spinal Muscular Atrophy

Spinraza®: Choosing Innovation for Spinal Muscular Atrophy

In Lévis, PQ, the little Lexie, 3, struggles to stand up. It gradually loses the use of its members, may soon no longer be able to eat or breathe without assistance (http://ici.radio-canada.ca/nouvelle/1081208/amyotrophie-spinale-spinraza-ramq-mere- levis-ill child). If the child is at risk of spinal muscular atrophy (SMA), an effective treatment can be given. Problem, if this treatment exists it is expensive, and the National Institute of excellence in health and social services (INESSS) recommends for the moment not to refund it. Other children are in his case in the world, some will be treated others not. An economic and ethical question.

The Odyssey of a major therapeutic innovation 

A new treatment for Spinal Muscular Atrophy (nusinersen, Spinraza®) allows newborns and sick infants to improve their motor skills first to breathe, swallow, and then to sit, stand and walk. This is the result of a rather unusual and exciting journey since 2003. That year, Adrian Krainer demonstrates that synthetic molecules can modify the way a gene is read and promote certain versions of reading.

Franck Bennett, a leader in the development of antisense oligonucleotides (OAS) as drugs, reads the article and calls Krainer. Their project is to treat the SMA. Also in 2003, Loren Eng and Dinakar Singh, parents of a child with SMA, file the statutes of the SMA Foundation (http://www.smafoundation.org/). They will finance the work of Krainer and Benett who joined Yimin Hua. To date, this foundation has funded more than $ 110 million for basic, translational and clinical research, becoming the leading funder of SMA research worldwide.

At the heart of a genetic disease that affects a vital system 

Motor neurons Spinal Muscular Atrophy (SMA) is a motor neuron disease found in the brainstem or spinal cord, the leading genetic cause of infant mortality. These neurons control the muscles and, in the absence of the SMN protein encoded by the failed gene, they degenerate and die. It manifests itself in the first months of life, usually through unexpected episodes of baby hypotonia. The rapid death of motor neurons then leads to muscle weakness, particularly of the respiratory system, which is the most common cause of death. The mortality of severe forms is greater than 90%. The SMN gene of chromosome 5 If about 1/40 - 1/50 of adults have the abnormality, there are only 1/10000 to 1/25000 newborns born because the prevalence of severe spinal muscular atrophy is much lower, due to the very diverse manifestations of this disease.

On chromosome 5 in q13.2 (Figure No. 1) there are two genes SMN1 and SMN2. The first code for SMN protein essential for motor neurons of the brainstem and spinal cord. The absence of a normal gene on both parental chromosomes causes the disease. Nusinersen acts at the genetic level to produce SMN protein (http://www.learnaboutsma.org/science/8.html).

Figure N°1 Copyright of the National Center for Biotechnology Information of the USA

Results that prove that fatality can be defeated

A genetic disease is literally a fatality that does not depend on the environment but on a parental heritage. Since the deciphering of the human genome and the application of genetic engineering techniques, another future is opening up for these children: to survive and to do so by leading a normal life. The United States Food and Drug Administration approved, on December 23, 2016, Spinraza® (nusinersen), the first drug to treat children and adults with spinal muscular atrophy, about 20 years after the gene for this disease was discovered by the team of Judith Melki in France ... In June 2017, the European Medicines Agency (EMA) did the same. Agencies have all used expedited procedures with regard to results. What are they? On November 7, 2016, a trial in children aged 2 to 12 in wheelchairs with ADS was discontinued based on positive results in treated children and the control group receiving treatment. In August, a similar trial in infants was discontinued for the same reason, allowing untreated infants in the control group to receive the drug for ethical reasons. Finally, published in December 2016 an article that provides convincing evidence that nusinersen is effective in treating SMA (Figure N ° 2).

Figure N°2

Need to survive mechanical ventilation in the nusinersen study (D): without treatment few children survive without being dependent on mechanical ventilation. Under nusinersen, 63% of children can do without permanent mechanical ventilation.

https://doi.org/10.1016/S0140-6736(16)31408-8

A rare disease, spinal muscular atrophy is now curable, but what is the cost of treatment?

It is very high, an intrathecal injection (in the cerebrospinal fluid after lumbar puncture) costs about 120,000 US dollars. This price triggered controversy, which is natural. It is true that it is an exceptional drug, that it is a complex therapeutic class whose number of indications is limited, the birth rate with the disease being low. It must also be taken into account that other drugs of this type or different are in development and will come soon to compete with it. But is this price right? It is difficult to say in the absence of medico-economic studies. It would be necessary to know the exact cost of developing nusinersen, to subtract some of the accompanying care that is no longer needed in children treated, to add the complications of treatment (the profile of side effects is quite favorable to nusinersen) and the cost loss of life without treatment. These studies will be done but we do not have time to wait. There is no doubt that the laboratory that markets Spinraza® (Biogen®) has the will to value its innovation but also its lead and manage its drug portfolio. For any new drug, insurers must make choices that depend on many factors and these choices are difficult. One of the innovative ways is to match the repayment of a leverage mechanism on the results. In a way, the reimbursement would be less if the drug does not give results in a particular patient.

Therefore, must we repay or wait? Do we have a rational idea of the effort required?

In terms of overall cost, developed countries can make this expenditure. My opinion is that they have to do it because for many of these children it's the price of life. Everything must be done in the negotiations so that, on the one hand, programs are developed for those who can not benefit from reimbursement for economic reasons, as soon as the developed countries have agreed to pay the nusinersen. But also so that on the other hand, the competition is effective as soon as other treatments will arrive in clinical phase. These rare diseases, whose number of patients is stable, are indeed, it should be remembered, not susceptible to a questionable extension of the indications as for the drugs of acquired diseases or functional treatments. On the other hand, these children, like all patients with a rare disease, have little exposure to the media. There is a certain tyranny in the number of politically considering no reduction in benefits to improbable efficiency that amount to billions but affect millions of citizens, and instead to curb innovation in view of the high price of a vital medicine for a few thousand of our children.

Gene therapies are vital for these children who could not survive without. In the case of Spinraza®, iterative injections are required for the time being and therefore complex and coordinated management in neurogenetic services. But after the OAS it is legitimate to think that there will come other more definitive therapies like those that will replace the defective gene with the hope in the SMA that a single normal SMN1 gene is enough.

The incidence of severe SMA in Quebec is 5.83 per 100,000 births, or 5 infants who are unlikely to reach the age of two, unless treatment is given to them (http: // www. .inesss.qc.ca / fileadmin / doc / INESSS / Inscription_medicaments / Avis_au_ministre / Decembre_2017 / Spinraza_2017_12.pdf? sword_list% 5B0% 5D = spinraza & no_cache = 1). The mission of a health insurer is to make the choice to reimburse all insureds for drugs that change the prognosis of these diseases, by agreeing to reward innovation at a high initial price because, at least for some, it is the price of life now.


This post should be read with this recent paper:
https://www.statnews.com/2018/06/19/what-sareptas-game-changing-data-mean-for-biotechs-other-duchenne-players/?%3Futm_source=facebook&utm_campaign=facebook_sponsored&utm_medium=biotech