FDA approves first drug Oxervate (cenegermin) for neurotrophic keratitis, a rare eye disease

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http://www.who.int/medicines/publications/druginformation/issues/77_INN_Recommended_List.pdf

Active Substance General information The active substance in Oxervate, cenegermin, is a recombinant human Nerve Growth factor (rhNGF) produced in E. coli strain HMS174. The molecule is identical to human Nerve Growth factor (NGF), a naturally occurring human protein. In humans, NGF is naturally produced as pre-pro-peptide, secreted into the endoplasmic reticulum and cleaved by furin protease. The pro-sequence is further cleaved during the production process by enzymatic hydrolysis. Therefore these two amino acid changes have no influence on the final active ingredient (rhNGF), which is identical to the naturally secreted human protein. The 3D structure of rhNGF is a non-covalent dimer with three intra-molecular disulphide bridges. Cenegermin contains 118 amino acids and has a relative molecular mass of 13,266 Daltons and the following molecular formula: C583H908N166O173S8. Figure 1 shows the protein sequence of recombinant human ProNGFrh ProNGF (Figure 1A), and a map of the disulphide bridges (Figure IB):

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004209/WC500232107.pdf

Cenegermin sequence:
	SSSHPIFHRGEFSVCDSVSVWVGDKTTATDIKGKEVMVLGEVNIN
	NSVFKQYFFETKCRDPNPVDSGCRGIDSKHWNSYCTTTHTFVKAL
	TMDGKQAAWRFIRIDTACVCVLSRKAVR

CAS 1772578-74-1

rhNGF, Nerve growth factor – Anabasis/Dompe; Oxervate; Sentinel

UNII B6E7K36KT8

OriginatorAnabasis Pharma
DeveloperDompe Farmaceutici; Ospedale San Raffaele
ClassEye disorder therapies; Nerve growth factors; Neuroprotectants; Proteins
Mechanism of ActionNerve growth factor receptor agonists; Neuron stimulants

Orphan Drug StatusYes – Keratitis; Retinitis pigmentosa
Highest Development Phases

RegisteredKeratitis
Phase II Dry eyes; Glaucoma; Retinitis pigmentosa
APPROVED FDA AUG 2018

Most Recent Events

28 Jul 2018No recent reports of development identified for phase-I development in Glaucoma in Italy (Ophthalmic, Drops)
29 May 2018Phase-II clinical trials in Glaucoma (Ophthalmic) (http://www.dompe.com/RnD-Pipeline/)
01 May 2018Dompé Farmaceutici completes a phase I trial in Glaucoma in USA (Ophthalmic) (NCT02855450)

Cenegermin (planned brand names Oxervate, Sentinel), also known as recombinant human nerve growth factor (rhNGF), is a recombinant form of human nerve growth factor (NGF). It was approved in the European Union as an eye drop formulation for the treatment of moderate or severe neurotrophic keratitis in adults on 6 July 2017.^[2]^[3]^[1] As a recombinant form of NGF, cenegermin is a peripherally selective agonist of the TrkA and LNGFR (p75^NTR) which must be administered parenterally.^[3] In addition to neurotrophic keratitis, cenegermin is also under development for the treatment of dry eyes, retinitis pigmentosa, and glaucoma.^[3] It was developed by Anabasis Pharma, Dompé Farmaceutici, and Ospedale San Raffaele.^[3]

Cenegermin is a human beta-nerve growth factor (beta-ngf)-(1-118)- peptide (non-covalent dimer) produced in escherichia coli. It received European Union Approval in July, 2017 for the treatment of moderate to severe neurotrophic keratitis.

In 2013, orphan drug designations in the E.U. and in the U.S. were assigned to the candidate for the treatment of retinitis pigmentosa. The product was granted additional orphan drug designation for the treatment of neurotrophic keratitis in the U.S. and the E.U. in 2014 and 2015, respectively.

Cenegermin, a recombinant human nerve growth factor developed by Dompé was first approved in July 2017 in the E.U. for the treatment of moderate to severe neurotrophic keratitis (NK) in adults

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The U.S. Food and Drug Administration today approved the first drug, Oxervate (cenegermin), for the treatment of neurotrophic keratitis, a rare disease affecting the cornea (the clear layer that covers the colored portion of the front of the eye).

“While the prevalence of neurotrophic keratitis is low, the impact of this serious condition on an individual patient can be devastating,” said Wiley Chambers, M.D., an ophthalmologist in the FDA’s Center for Drug Evaluation and Research. “In the past, it has often been necessary to turn to surgical interventions; these treatments are usually only palliative in this disease. Today’s approval provides a novel topical treatment and a major advance that offers complete corneal healing for many of these patients.”

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August 22, 2018

Release

Neurotrophic keratitis is a degenerative disease resulting from a loss of corneal sensation. The loss of corneal sensation impairs corneal health causing progressive damage to the top layer of the cornea, including corneal thinning, ulceration, and perforation in severe cases. The prevalence of neurotrophic keratitis has been estimated to be less than five in 10,000 individuals.

The safety and efficacy of Oxervate, a topical eye drop containing cenegermin, was studied in a total of 151 patients with neurotrophic keratitis in two, eight-week, randomized controlled multi-center, double-masked studies. In the first study, patients were randomized into three different groups. One group received Oxervate, a second group received an eye drop with a different concentration of cenegermin, and the third group received an eye drop without cenegermin. In the second study, patients were randomized into two groups. One group was treated with Oxervate eye drops and the other group was treated with an eye drop without cenegermin. All eye drops in both studies were given six times daily in the affected eye(s) for eight weeks. In the first study, only patients with the disease in one eye were enrolled, while in the second study, patients with the disease in both eyes were treated in both eyes (bilaterally). Across both studies, complete corneal healing in eight weeks was demonstrated in 70 percent of patients treated with Oxervate compared to 28 percent of patients treated without cenegermin (the active ingredient in Oxervate).

The most common adverse reactions in patients taking Oxervate are eye pain, ocular hyperemia (enlarged blood vessels in the white of the eyes), eye inflammation and increased lacrimation (watery eyes).

Oxervate was granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months of application filing where the agency determines that the drug, if approved, would provide a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious condition. Oxervate also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Oxervate to Dompé farmaceutici SpA.

Cenegermin
Clinical data
Trade names	Oxervate, Sentinel
Synonyms	Recombinant human nerve growth factor; rhNGF; human beta-nerve growth factor (beta-NGF)-(1-118) peptide (non-covalent dimer) produced in Escherichia coli^[1]
Routes of administration	Eye drops
ATC code	S01XA24 (WHO)
Identifiers
CAS Number	1772578-74-1
DrugBank	DB13926
ChemSpider	None
UNII	B6E7K36KT8
KEGG	D11028
Chemical and physical data
Formula	C₅₈₃H₉₀₈N₁₆₆O₁₇₃S₈
Molar mass	13266.94 g/mol

References

^ Jump up to:^a ^bhttp://www.who.int/medicines/publications/druginformation/issues/77_INN_Recommended_List.pdf
Jump up^ “Authorisation details”. European Medicines Agency. Retrieved 19 February 2018.
^ Jump up to:^a ^b ^c ^d http://adisinsight.springer.com/drugs/800035751

External links

////////////fda 2018, Oxervate, cenegermin, orphan drug, priority review, EU 2017, DOMPE, neurotrophic keratitis