A $2 Million Therapy About to Hit Market

choi

Denise Roland, A $2 Million Therapy About to Hit Market. Wall Street Journal, May 8, 2019, at page B1.
https://www.msn.com/en-us/money/ ... e-market/ar-AAB1eN9

Quote:

"Novartis AG has yet to set a price for the gene therapy called Zolgensma, but executives say the drug's potential to cure [heed the word 'cure,' not treat or alleviate] spinal muscular atrophy, an inherited disease that typically kills babies before they turn two, justifies a seven-figure price [$2 million].

"Luxturna, the only gene therapy on sale in the US so far to treat a form of inherited sight loss, costs $850,000 a patient [the most expensive to date].

"Zolgensma is expected to go on sale soon, with an FDA decision due this month. The treatment tackles spinal muscular atrophy, whose sufferers lack a gene essential for muscle control. Without treatment, victims of the most severe form typically die before their second birthday, making SMA the most common genetic cause of infant death. Between 400 and 500 babies are born with SMA every year in the US [CDC: 3,855,500 births in 2017], around 300 of whom have the most severe version.

"Andrea James, whose 9-month-old son Axel has SMA, is worried her insurer will refuse to pay for the therapy when it goes on sale. * * * Her son is already taking a treatment called Spinraza, given by spinal injection every few months, she said. * * * Biogen Inc's Spinraza, which is a lifelong treatment, is priced at $750,000 for the first year, and then $375,000 for each year after.

Note:
(a)
(i) The report is available to the public.
(ii) Print ends with the paragraph that begins with the sentence: "One problem is the lack of an agreed way to determine a reasonable price for new drugs."
(iii) If you read Quote above, you need not read the rest of text. Because FDA has not formally approved it yet, there is little information on the Web about this gene therapy.

(b) I was aware of Luxturna's debut in US market. But FDA first halted three clinical trials of gene therapy (in humans) in 2002, and 27 more (trials) in 2003, each prompted by a death. See
Brendan Maher, More Gene Therapy Trials Halted; New questions after second X-SCID patient develops leukemia. TheScientist, Jan 16, 2003
https://www.the-scientist.com/ne ... trials-halted-52247
(To cure X-linked Severe Combined Immune Deficiency (X-SCID), "Alain Fischer's group at the Necker Children's Hospital in Paris carried out what was largely considered the first unequivocal success in gene therapy. * * * Fischer told the FDA last fall and again a month ago that patients were exhibiting leukemia-like symptoms.  The first announcement prompted the FDA to place three SCID trials in the US on clinical hold")

Both Luxturna and Zolgensma uses adeno-associated virus (AAV) 9 as a vector to bring the double-stranded gene (RPE65 in the former and SMN1 in the latter; no viral genome) into patients. The gene then inserts itself into patients's DNA. . There is no control over where the insertion may be. And research in animals shows that insertions may activate or silence critical genes, causing cancers. I do not know why FDA is more confident than in the past.
(i) Weiss MS et al, A Critical Examination of the Recently Reported Crystal Structures of the Human SMN Protein. Human Molecular Genetics, 25: 4717 (2016).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418738/
(Introduction: "The two genes [SMN1 and SMN2, both in chromosome 5; SMN stands for 'survival of motor neuron'] differ by five nucleotide changes, only one of which is located within the protein coding region [the other four in non-coding regions], a C to T transition located at position 6 inside exon 7 of SMN2. This mutation greatly enhances skipping of SMN2 exon 7, resulting in production of a truncated polypeptide, called SMNΔ7. * * * the SMNΔ7 protein is unstable and degradation-prone, resulting in drastically reduced levels of functional SMN protein produced from the SMN2 gene. In SMA patients, SMN2 is the only source of functional SMN protein * * * The SMN complex functions in the biogenesis of pre-mRNA processing UsnRNP [uridine-rich small nuclear ribonucleoproteins] particles. In this reaction, a set of 7 Sm proteins is loaded onto the snRNA to form the common core structure of these RNPs")

Please read Abstract and Introduction sections. Sm in "Sm proteins" represents Smith. See Lsm
https://en.wikipedia.org/wiki/LSm
("Stephanie Smith, a patient who suffered from" systemic lupus erythematosus  (SLE) )

SMN 1 and 2 are found in many cell types, so it is unclear why only motor neurons dies in SMA. *The same happens in poliomyelitis: poliovirus (composed of positive-stranded RNA) binds to polio virus receptor (PVR) on cell surface and enters cells. But PVR are found in many cell types, so why polio virus kills only motor neurons and how, nobody knows.
(ii) When motor neurons die, muscles lose innervation. The resulting muscle wasting is called atrophy (same in polio).
(iii) Spinraza MOA [Mechanism of Action]. Spinraza.com (for healthcare professionals), undated
https://www.spinraza-hcp.com/en_us/home/mechanism-of-action.html
("SPINRAZA is an antisense oligonucleotide (ASO) targeted to SMN2 pre-messenger ribonucleic acid (pre-mRNA)[:] SPINRAZA increases production of full-length SMN protein by increasing the proportion of SMN2 mRNA transcripts that include exon 7")

(c) Luxturna is a trade name for a gene therapy.
(i) News release: FDA Approves Gene Therapy for Inherited Blindness Developed by the University of Pennsylvania and Children's Hospital of Philadelphia [CHOP], University of Pennsylvania, Dec 19, 2017.
https://www.pennmedicine.org/new ... nnsylvania-and-chop

Jean Bennett, MD, PhD, and Albert M Maguire, MD (the inventors) are married. A researcher who sees no patients, Jean's Web page in Upenn says, "FM Kirby Professor of Ophthalmology * * * BS (Honors Biology) Yale University , 1976. PhD (Zoology; Cell And Developmental Biology) University of California At Berkley, 1980. MD Harvard University, 1986."  Albert's Web page inCHOP says he "is an Attending Physician in the Division of Pediatric Ophthalmology at [CHOP] * * * He is an Associate Professor of Ophthalmology" in U Penn.

(ii) from Luxturna.com (maintained by Sparks Pharmaceutical):
(i) under the heading "Who may be treated": "LUXTURNA is for individuals with an inherited retinal disease caused by mutations in both copies of the RPE65 gene and who have enough remaining cells in the retina * * * [in patients with] Leber congenital amaurosis and retinitis pigmentosa
(ii) under the heading "How it works": "LUXTURNA is a one-time gene therapy for each eye"
(iii) three consecutive paragraphs under the heading "How it is administered":

"LUXTURNA is given by a healthcare professional as a surgical injection beneath the retina of each eye

"One eye is treated at a time. After the first eye is treated, the second eye will be treated at least 6 days later.

"Administration is performed at specific Ocular Gene Therapy Treatment Centers

(iv) RPE65 stands for "retinal pigment epithelium-specific [molecular weight] 65 kDa protein."
https://ghr.nlm.nih.gov/gene/RPE65
("is produced in * * * retinal pigment epithelium (RPE). * * * When light hits photosensitive pigments in the retina, it changes a molecule called 11-cis retinal (a form of vitamin A) to another molecule called all-trans retinal. This conversion triggers a series of chemical reactions that create electrical signals[, which is transmitted from eyes through optic nerves to brain so that we can see]. The RPE65 protein then helps convert all-trans retinal back to 11-cis retinal so the visual cycle can begin again
(A) An eye is an analog camera, both of which needs to be jet black inside. Reflections (diffraction in physics) is not allowed, which is ensured in the eye by RPE whose melanin absorbs light. RPE also produces RPE65 protein, an enzyme (specifically: isomerase) that switches retinal. RPE lines sclera, encasing rods and cones.
https://en.wikipedia.org/wiki/Retinal

A human has 4 types of opsins: one in rod cells (black and white vision suited in the dark) and three in cones (one each for blue, green and red light; ie, color vision). One opsin molecule binds covalently to one retinal molecule. When a photo hits, opsin releases the retinal, which leaves the rod or cone and enters RPE which converts all-trans back to 11-cis. The latter returns to rod or cone and binds covalently to an opsin, waiting for the next photon to hit.
(v)
(A) "Leber congenital amaurosis can result from mutations in at least 14 genes [including RPE65], all of which are necessary for normal vision."
https://ghr.nlm.nih.gov/conditio ... tal-amaurosis#genes

German ophthalmologist Theodor Leber describes what is know known as Leber congenital amaurosis in 1869.  en.wikipedia.org under his name.

amaurosis (n; etymology: Greek)
https://www.merriam-webster.com/dictionary/amaurosis

(B) "Mutations in more than 60 genes [including RPE65] are known to cause nonsyndromic retinitis pigmentosa."
https://ghr.nlm.nih.gov/condition/retinitis-pigmentosa#genes