Status: development halted; abandoned

Organizations involved:

Cephalon, Inc. – R&D; Tech.

Chiron Corp. – Manuf.; R&D; Tech.

Novartis AG – Parent

Market: See the entries for insulin-like growth factor products currently marketed – IGF-1 from Tercica and IGF-1/IGFBP-3 from Insmed.

Description: Myotrophin was a formulation of recombinant yeast (presumably Saccharomyces cerevisiae) expressed human insulin-like growth factor-1 (IGF-1), a 70 amino acid nonglycosylated protein with a molecular mass of 7.649 kDa, molecular formula of C331H512N94O101S7, substantially similar to human IGF-1, except having L-arginine at amino acid three.

Myotrophin was originally developed for the treatment of amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease). However, clinical trials were halted after the FDA indicated that Myotrophin was not demonstrating sufficient efficacy.

Nomenclature: IGF-I, rDNA [BIO]; Myotrophin [TR]; mecasermin rinfabas [USAN INN]; insulin-like growth factor I (human), 3-L-arginine- 70 [CAS]; 68562-41-4 [CAS RN; reported by USP]; 39659-92-0 [CAS RN; reported by NLM; less reliable]; somatomedin-C [SY]; IGF-I [SY]; rhIGF-1 [SY]; CEP-151 [SY]; somatomedin-1 [SY]

Companies.: Cephalon, Inc. developed Myotrophin through a joint venture with Chiron Corp., Cephalon Clinical Partners, L.P. (CCP). Cephalon began clinical testing Myotrophin in Feb. 1993, and reportedly invested over $130 million in its development. Chiron merged into Novartis AG in Oct. 2005.

FDA class: Drug NDA

Status: Cephalon and Chiron first filed an NDA in 1995. In Jan. 1996, FDA refused the companies’ application for an ALS “early access” program (expanded access, involving limited free distribution of a drug not yet approved for marketing). In June 1996, this expanded access program was approved and began shortly thereafter.

On Feb. 11, 1997, Cephalon and Chiron submitted their NDA for Myotrophin for ALS, based on two double-blind, placebo-controlled Phase III studies in 449 patients with ALS. In May 1997, the Peripheral and Central Nervous System Drugs Advisory Committee, FDA, voted of 6 to 3 against approval. The committee was especially concerned that, in one of the Phase III trials (European trial) more patients died in the treated groups than in the untreated group. While in Myotrophin’s Phase III North American trial, patients on Myotrophin fared somewhat better than untreated patients. Also, increased retinopathy had been reported in Phase III trials for diabetes. The committee requested additional data (meaning a third Phase trial would be required). The ALS community loudly protested and demanded approval, and the FDA announced it would make a final decision by Aug. 11, 1997, and further formally postponed this until Nov. 11.

In May 1998, FDA issued Cephalon and Chiron a letter stating Myotrophin is “potentially approvable, subject to submission of additional information from ongoing studies which demonstrates that Myotrophin is effective in the treatment of ALS,” with this effectively requiring another Phase III trial. Many is the ALS community were upset with FDA, particularly since Myotrophin was considered relatively safe and would have been welcome, even if only partially effective or effective in only a subset of patients.

In late 1999, Cephalon discontinued the Myotrophin Expanded Access Program, which started in 1996, through which nearly 200 ALS patients had received Myotrophin.

Tech. transfer: U.S. patents assigned to Cephalon and/or Chiron include 6,756,484 and 6,207,806 and 5,650,496 (and related 6,117,983). These concern processes to obtain purified, monomeric, intact, correctly-folded IGF-1. By addition of an IGF-I unfolding/refolding step and the substitution of a reverse phase chromatography step for a gel filtration chromatography step, this resulted in a 3-fold increase in final yield, relative to the process described in 5,231,178 assigned to Salk Institute Biotechnology/Industrial Associates, Inc. The process includes, in this order, cation exchange chromatography, unfolding/refolding, hydrophobic interaction chromatography, cation exchange chromatography, and reverse phase chromatography.

U.S. 6,706,496, “Method for expression of heterologous proteins in yeast;” U.S. 6,642,029, “Hybrid DNA synthesis of mature insulin-like growth factors;” U.S. 6,033,875, “Methods and constructs are provided for efficient yeast production of human insulin-like growth factor;” and other patents assigned to Chiron claim recombinant yeast constructs and methods for expression and manufacture of proteins including IGF-1. U.S. 6,342,227, “Use of IGF-I or analogues thereof in the prevention of diabetes,” assigned to Chiron, claims use of IGF-1 for treatment of diabetes.

Cephalon received a number of IGF-1 use patents, including U.S. 5,093,317, 5,776,897, 5,703,045 and 5,093,317. These include claims for treatment of neurological disorders, including enhancing the survival of neuronal cells due to injury, Alzheimer’s disease, stroke, epilepsy, amyotrophic lateral sclerosis, Parkinson’s disease, etc.; and treatment of eye diseases, including promoting the survival of retina photoreceptors.

Trials: Two pivotal placebo-controlled Phase III trials, one in North America and one in Europe, tested subcutaneous injections of 50 or 100 µg/kg/day in 147 and 266 patients, respectively, with mild to moderate sporadic ALS. In one trial, patients who had received 100 µg/kg/day, but not the lower dose, showed significant slowing of improvements in functional impairment, disease symptom progression, and loss of quality of life, compared to placebo. But this was not confirmed by the other trial in which 100 µg/kg/day showed no statistically significant improvement (and with higher mortality) vs. placebo.

Myotrophin was generally well tolerated in its trials. Injection site reactions were the most common adverse event. In a long-term follow-up of patients in one trial, significant improvement in survival was observed between treated and placebo patients, when age and lung function were taken into account (but this was not a trial endpoint).

Disease: Amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) is a rapidly progressive neurological disorder in which muscle-controlling nerve cells die, causing paralysis and ultimately death. IGF-1 has been shown in in vitro and animal studies to prolong survival of neurons, providing a basis for its development for ALS.

Medical: Myotrophin was administered as twice-daily subcutaneous injections, with patients in later-stage trials receiving either 50 or 100 µg/kg/day.