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Catalyst Using the Expanded Access Program to Conduct Phase IV Study with LEMS Patients

OCTOBER 29, 2014
James Radke

Patients with Lambert-Eaton Myasthenic Syndrome (LEMS) may now have access – free access – to a drug in development for the condition. 

Catalyst Pharmaceuticals has announced they are offering an Expanded Access Program (EAP) for Firdapse™ (amifampridine phosphate tablets equivalent to 10 mg amifampridine). Eligible patients will be part of a Phase IV open label study the company is conducting as they complete the submission requirements for regulatory approval.

 Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare autoimmune disease with the primary symptoms of muscle weakness. The muscle weakness in LEMS is caused by autoantibodies to voltage gated calcium channels leading to a reduction in the amount of acetylcholine released from nerve terminals.  One possible way to increase acetylcholine release is to prolong periods of depolarization at the nerve terminal. The potassium channel blocker amifampridine is believed to do this and it is the active ingredient of Firdapse.

Phase 3 Trial Results

Recent data indicates that Firdapse is safe and effective.  Last month, the company reported their pivotal phase 3 trial met its primary endpoint. The clinical trial was a double blind, randomized, "withdrawal trial" in which all patients were initially treated with Firdapse during a 91 day run-in period followed by treatment with either Firdapse or placebo (randomly assigned, about 1:1) during a 2 week randomization period. A total of 38 patients completed the 3 month run-in period and subsequent 2 week randomization period. A "withdrawal trial" is designed to see if the placebo group’s symptoms worsen more than the treatment groups.   What the trial found was:

  • Primary endpoints
    • The primary endpoint of change in quantitative myasthenia gravis (QMG) score at day 14 reached statistical significance (p=0.0452) with a clinically significant worsening of 2.2 points observed in the placebo group.
    • The primary endpoint of change in subject global impression (SGI) at day 14 was highly statistically significant (p=0.0028) with a clinically significant worsening of 2.6 points observed in the placebo group.
       
  • Secondary endpoints
    • The secondary endpoint for the physician's clinical global impression of improvement (CGI-I) reached statistical significance (p=0.0267) with a clinically significant observation at day 14 of 4.7 points in the placebo group.
    • The secondary endpoint of change in walking speed at day 14 showed a worsening of 9.67 ft/min in the placebo group.
       
  • Safety
    • Firdapse was generally safe and well tolerated.
    • All subjects who were randomized into the trial elected to continue with Firdapse in the safety follow-up phase of the study.

Eligibility for Phase 4 Study (Expanded Access Program)

To be eligible for the program, patients must be 10 years or older and  have a diagnosis of: Lambert-Eaton Myasthenic Syndrome (LEMS), Congenital myasthenic syndrome (CMS), or Downbeat nystagmus and meet the inclusion and exclusion criteria. Patients should talk to their physician when considering enrollment in the Firdapse EAP and the physician should call 1-844-347-3277 (844-Firdapse). Additional information is available on the Catalyst website and www.clinicaltrials.gov (NCT02189720).
 
The inclusion/exclusion criteria are listed below.

Inclusion Criteria:

  • Confirmed physician diagnosis of LEMS, CMS or downbeat nystagmus
  • Completion of anti-cancer treatment at least 3 months (90 days) prior to treatment
  • Ability to swallow sufficiently to take oral tablet medication without difficulty
  • Negative urine pregnancy test for females of childbearing potential at Registration
  • If sexually active and of childbearing potential, willing to use 2 acceptable methods of contraception from patient Registration until 3 months after the last dose of investigational product. No adequate clinical data on exposed pregnancies are available for amifampridine. No non-clinical safety data are available regarding the effects of amifampridine on reproductive function. Amifampridine phosphate should not be used during pregnancy. It is unknown whether amifampridine is excreted in human breast milk. The excretion of amifampridine in milk has not been studied in animals. Amifampridine phosphate should not be used during breast-feeding.
  • Willing and able to provide written informed consent after the nature of the study has been explained and prior to the start of any research-related procedures

Exclusion Criteria:

  • History of epilepsy or seizure (including single 1-time seizure, but excluding generalized febrile seizures occurring before the age of 5 years)
  • Known active brain metastasis. Patients with treated brain metastasis (radiotherapy and/or surgery) who have completed treatment for their brain metastasis >90 days prior to Patient Registration, are neurologically stable (neurological symptoms grade <1), are on a stable dose of corticosteroids, and have no evidence of new disease on magnetic resonance imaging (MRI), are eligible provided they meet the other inclusion/exclusion criteria
  • Use of Fampridine (Ampyra®; 4-aminopyridine), and any form of 3,4-diaminopyridine other than the investigational product provided, such as amifampridine base
  • Use of medications containing acetaminophen for chronic pain or migraine
  • Use of medications known to lower the epileptic threshold (e.g. antidepressants such as tricyclics and bupropion; neuroleptics such as phenothiazines, butyrophenones, clozapine, olanzapine, quetiapine; immunosuppressants such as cyclosporine, tacrolimus; centrally active cholinesterase inhibitors such as donepezil, rivastigmine, galantamine; me- floquine) within 7 days or 5 half-lives, whichever is longer, prior to initiation of amifampridine phosphate treatment. Selected antidepressants of the selective serotonin uptake inhibitor (SSRI) class (ie, escitalopram, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine) are acceptable provided the dose regimen has been stable for > 90 days prior to Patient Registration without evidence of seizure; Tramadol is acceptable provided the dose regimen has been stable (not as needed) for > 90 days prior to Patient Registration without evidence of seizure
  • Use of medications which inhibit neuromuscular junction function (e.g. chloroquine and other quinine derivatives; aminoglycosides such as amikacin, gentamycin, neomycin, and tobramycin; other antibiotics such as clindamycin, lincomycin, clarithromycin, azithromycin, telithromycin, erythromycin, polymyxin B, and colistin; muscle relaxants and anesthetics such as curare, non-polarising muscle block [vecuronium], polarising muscle block [succinylcholine]; botulinum toxin, quinidine, procainamide, procaine, magnesium, phenytoin, d-penicillamine, and interferon-alfa) within 7 days or 5 half- lives, whichever is longer, prior to initiating treatment with amifampridine phosphate
  • Use of guanidine hydrochloride within 7 days of starting amifampridine treatment
  • History of drug allergy to any pyridine-containing substances or any amifampridine phosphate excipient(s)
  • Use of any other investigational product other than amifampridine phosphate or investigational medical device within 30 days prior to starting treatment or requirement for any investigational agent prior to completion of all scheduled study assessments
  • Treatment with a concomitant medication that prolongs the QT/QTc interval within 7 days or 5 half-lives, whichever is longer, prior to starting amifampridine phosphate treatment
  • Treatment with sultopride (4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethylsulfonyl-2- methoxybenzamide) within 7 days prior to starting treatment
  • An electrocardiogram (ECG) prior to starting treatment that shows clinically significant abnormality(ies), in the opinion of the treating physician
  • Documented history of arrhythmias (e.g. ventricular arrhythmias and atrial fibrillation)
  • History of additional risk factors for torsade de pointes (e.g. history of surviving a near drowning due to loss of consciousness, family history of congenital QT syndrome, long QT syndrome, family history of unexplained early sudden death, or heart failure)
  • Breastfeeding or pregnant or planning to become pregnant (self or partner). Male patients with breastfeeding partners are not excluded from the study
  • Likely or expected to require treatment for cancer within 3 months (90 days)
  • History of severe renal impairment or evidence of severe renal impairment at time of Patient Registration on laboratory tests, specifically a creatinine clearance < 30 mL/min
  • History at time of Patient Registration of laboratory tests indicating severe hepatic impairment;
    • In patients without liver metastases from cancer, ALT, AST, and/or total bilirubin > 1.5 ULN
    • In patients with liver metastases from cancer, ALT/AST > 5 X upper limit of normal (ULN) and/or total bilirubin > 3 × ULN
  • Any condition that, in the view of the investigator, places the patient at high risk of poor treatment compliance or of not completing the study

The Cost

There is no cost to patients who are eligible. Catalyst Pharmaceutical has stated they will absorb all costs and the drug Firdapse will be shipped to the patient’s home on a periodic basis (usually 90 days’ supply). Costs for other diagnostic tests or routine medical treatment will need to be covered by the patient’s insurance or at the patient’s expense.

If Firdapse is approved by the FDA, Catalyst will work with EAP physicians to help their patients understand how to transition to the approved drug and make sure all patients who need Firdapse have access to the drug, regardless of their ability to pay.

Image of the neuromuscular junction courtesy wikimedia commons. 

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