Trofinetide

{{Drugbox | IUPAC_name = (2S)-2-{[(2S)-1-(2-aminoacetyl)-2-methylpyrrolidine-2-carbonyl]amino}pentanedioic acid | image = Trofinetide_structure.png | tradename = | legal_status = Investigational New Drug

| bioavailability = | metabolism = | elimination_half-life = | excretion =

| CAS_number_Ref =  ^Y | CAS_number = 853400-76-7 | PubChem = 11318905 | DrugBank_Ref =  ^Y | ChemSpiderID =

| C=13 | H=21 | N=3 | O=6 | molecular_weight = 315.322 | smiles = C[C@]1(CCCN1C(=O)CN)C(=O)N[C@@H](CCC(=O)O)C(=O)O | StdInChI = | StdInChIKey = }}

Trofinetide (NNZ-2566) is a drug developed by Neuren Pharmaceuticals that acts as an analogue of the neuropeptide (1-3) IGF-1, which is a simple tripeptide with sequence Gly-Pro-Glu formed by enzymatic cleavage of the growth factor IGF-1 within the brain. Trofinetide has anti-inflammatory properties and was originally developed as a potential treatment for stroke, but has subsequently been developed for other applications and is now in Phase II clinical trials against Fragile X syndrome and Rett syndrome.

Origin of Neuren Pharmaceuticals

Neuren Pharmaceuticals was created in 2004 via a merger of two companies that were formed around the University of Auckland in Auckland, New Zealand. The company now has registered offices in Australia and New Zealand. In 2005, Neuren Pharmaceuticals was listed on the Australian Securities Exchange (ASX) As a company that is publicly traded, Neuren Pharmaceuticals receives a large portion of its current funding from shareholders, since it currently has no drug products on the market. It is also largely funded by grants from companies or agencies with an interest in their project. In 2007, acquired venture-backed Hamilton Pharmaceuticals for $4.4 million in stock. Since the acquisition was stock-based, the three venture funds that had previously backed Hamilton Pharmaceuticals, Vivo Ventures, CNF Investments, and Index Ventures, became stockholders in Neuren Pharmaceuticals. As a result of the acquisition, Neuren pharmaceuticals gained control of the drug Motiva, a drug to aid treatment of neurological disorders such as Parkinson's and Alzheimer's disease. Motiva did not pass phase 2 clinical trials.

Neuren Pharmaceuticals received several grants from various sources for research on Trofinetide, including $26 million in funding from the United States army, who was interested in the drug for its use on TBI. This grant did include one point stating that an army scientist had to be used as a principal investigator. They also received funding from International Rett Syndrome Foundation, FRAXA, and National Fragile X Foundation at significantly lesser value.

Commercialization of Trofinetide

Neuren's analyst through Bell Porter reported that the company's estimated earnings before interest, taxation, depreciation, and amortization will be 84$ million at the end of 2016. This amount is expected to decrease by the end of 2017 to $27 million. The promising results include estimates from upcoming licensing deals for Trofinetide and payment milestones from those deals. The product is expected to be available for commercial sale in 2019 for Rett Syndrome and in 2020 for Fragile X Syndrome.

Clinical Trials

Rett Syndrome

Because there is no treatment available for Rett Syndrome, Trofinetide was fast-tracked for approval by the FDA and it was also given an orphan drug designation by the FDA and EMA (European Medicines Agency) Development costs for rare or orphan drugs are less, because the FDA allows companies to do less trials and to use less subjects in their trials. This Phase 2 trial was double-blind and placebo controlled, lasted for 28 days, and included 35mg/kg and 70mg/kg doses twice daily. The 56 patients ranged from 16-45 years old. 3 patients did not complete the trial. No safety concerns were identified, and both doses were well tolerated by the patients. The trial endpoints included safety, seizure activity, cardiac and respiratory irregularities, and caregiver and clinician assessment of symptoms and severity of behavior.

The company intends to do a pediatric Phase 2 clinical trial using the funding that they received from rettsyndrome.org. After completion of a single Phase 3 trial, which they will be able to complete due to their fast-track and orphan drug designation, Neuren will file a New Drug Application with the FDA to be able to market Trofinetide.

Fragile X Syndrome

Because there is no treatment available for Fragile X syndrome, Trofinetide was fast-tracked for approval by the FDA and it was also given an orphan drug designation by the FDA and EMA. Neuren has recently completed their Phase 2 trial, which was a double-blind, placebo-controlled, 28 day trial with 35mg/kg and 70mg/kg doses twice daily. There were 70 patients involved in the trial, with ages ranging from 12-45 years. 2 patients did not complete the trial. No safety concerns were identified, and both doses were well tolerated. Endpoints of the trial included safety, seizure activity, and caregiver and clinician assessments of symptom severity of behavior. Neuren has not yet begun a Phase 3 trial.

Traumatic Brain Injury

It is thought that since Trofinetide inhibits inflammatory cytokines, pathological microglial activation, apoptosis, and necrosis, as well as improves functional recovery, preserves cognitive function, and inhibits post-injury seizures that it will be effective at preventing and/or aiding in the rehabilitation in traumatic brain injury. Neuren's Phase 2 trial called INTREPID was completed in April, 2016. The trial was a randomized, placebo-controlled, fixed dose escalation study of safety and efficacy. 260 patients were studied, with ages ranging from 16-75 years, each having a moderate to severe TBI. An IV solution of Trofinetide was administered within 8 hours of injury as a bolus dose of 20mg/kg, followed by 72 hours of infusion at 1, 3, or 6mg/kg/hr. The endpoints of the trial were safety, functional status at 1 and 3 months, cognitive neuropsychological function at 1 and 3 months, and non-convulsive seizures and biomarkers in the first 5 days. Unfortunately, Trofinetide had no difference in efficacy than the placebo at 3 key endpoints. Continuation of research of Trofinetide in this field is dependent on funding from the US army, and a lack of efficacy may hinder this. Trofinetide was otherwise proven safe in the trials.

Concussion

Neuren is currently enrolling in Phase 2 trials in concussion. These trials are expected to be completed at US military training facilities. The trials are to be completed on patients with mild traumatic brain injury. The endpoints of the trial will be safety, and change from baseline cognitive function and time to return to pre-injury baseline cognitive function assessed at 1, 2, 4, and 8 weeks.

Intellectual Property

Neuren Pharmaceuticals has issued 7 patents covering the composition, oral formulation, and methods of use of Trofinetide. There are 7 additional pending patent applications covering the same or similar topics. Neuren has between 9 and 15 years left of patent life on Trofinetide between these different patents.