AVP-923 and AVP-786

Avanir Pharmaceuticals with drug AVP-923 completed a very successful phase 2 trial for symptoms of agitation in Alzheimer's patients.  Avanir now under the Otsuka umbrella, is conducting two phase 3 trials with the deuterated version of AVP-923, known as AVP-786 for the same patients.  So what are the drug dose differences and exclusion criterias between the successful phase 2 AVP-923 clinical study, and the AVP-786 phase 3 clinical trials for the treatment of agitation in patients with dementia of the Alzheimer's type?

AVP-923  NCT01584440
Phase 2 for the treatment of agitation in patients with dementia of the Alzheimer's type.
Dextromethorphan 20 mg / Quinidine 10 mg
Dextromethorphan 30 mg / Quinidine 10 mg

Exclusion Criteria:

• Patient has other type of dementia (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease, substance-induced dementia).
• Patients with co-existent clinically significant or unstable systemic diseases that could confound the interpretation of the safety results of the study (e.g. malignancy, poorly controlled diabetes, poorly controlled hypertension, unstable pulmonary, renal or hepatic disease, unstable ischemic cardiac disease, dilated cardiomyopathy, certain cardiac conduction abnormalities including QTc prolongation, or unstable valvular heart disease).
• Patients with myasthenia gravis.

AVP-786   NCT02442765, NCT02442778
Phase 3 for the treatment of agitation in patients with dementia of the Alzheimer's type.
Dextromethorphan 28 mg / Quinidine 4.9 mg
Dextromethorphan 18 mg / Quinidine 4.9 mg

Exclusion Criteria:

• Patient has dementia predominantly of non-Alzheimer's type (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease, substance-induced dementia)
• Patients with co-existent clinically significant or unstable systemic diseases that could confound the interpretation of the safety results of the study (e.g., malignancy, poorly controlled diabetes, poorly controlled hypertension, unstable pulmonary, renal or hepatic disease, unstable ischemic cardiac disease, dilated cardiomyopathy, or unstable valvular heart disease)
• Patient with myasthenia gravis

The difference in the exclusions from the phase 2 AVP-923 trial and the deutered version using AVP-786 is that QTc prolongation, which was an exclusion in the phase 2 is not listed in the current phase 3 trials.  The reduction in the dose of quinidine to 4.9 mg from 10 mg could be the prime reason for the two new phase 3 trials not including QTc prolongation as an exclusion criteria.  I expect these two phase 3 trials to recruit at a much faster rate, than the AVP-923 trial achieved. I also expect that patients currently taking AVP-923 for other indications, will eventually switch to the deutered version AVP-786, which has a similar PK profile to AVP-923, favorable dosing, and has a longer patent that extends to 2030 US and 2028 EU. Thank you for reading.

What is a 505(b)(2) New Drug Application

A 505(b)(2) application differs from a typical new drug application, in that the process to approval could potentially be quicker with less expense.  The 505(b)(2) process takes drugs that have already been approved and makes small modifications to them. Typically a company will perform a phase 1 bridging study to compare the systemic levels of the proposed drug product and the reference product.  A bridging study also allows a company to reference the safety and efficacy information that is known for the original drug.
There are three advantages for a company that pursues a 505(b)(2) application.
1.  It is a relatively lower risk process because the original drug may have already been proven to be safe.
2.  The entire process is lower cost.
3.  The pathway to approval can be quicker because of the fewer studies required.
Companies such as Auspex, and Concert Pharmaceuticals, who attempt to improve the metabolic, safety, or efficacy profile with the use of deuteration, could benefit greatly by following the pathway of a 505(b)(2) submission application to get to market quicker, with less expense.  As those drugs get approved quicker, with less expense, the benefit should fall to the patient in need, and our medical healthcare system that provides insurance coverage.  Thank you for reading.

Vertex Pharmaceuticals Passes Advisory Committee

Vertex's (VRTX) drug combo named Orkambi faced the advisory committee on Tuesday this week. The FDA document is here Orkambi Advisory Committee .  The advisory committee voted 12-1 to approve the combination for patients with Cystic Fibrosis who have two copies (homozygous) of the F508del mutation, 12 years and older.  So that opens their market to a substantially much larger population of 20,000 patients. The results from the two phase 3 studies 890-103 and 890-104 are as follows.

Study 809-103

Lumacaftor 400 mg + Ivacaftor 250 mg q12 at week 24 = 2.6% mean absolute improvement over placebo on FEV1 test.

 

Study 809-104

Lumacaftor 400 mg + Ivacaftor 250 mg q12 at week 24 = 3.0% mean absolute improvement over placebo on FEV1 test.

Orkambi 

Lumacaftor 200 mg + Ivacaftor 125 mg, proposed dose every 12 hours.

Lumacaftor and Ivacaftor was administered twice daily, with the safety profile seen as well tolerated. What's intriguing is the fact that Orkambi the proposed combo up for FDA approval is administered as Lumacaftor 200 mg, and Ivacaftor as 125 mg twice daily. In prior trials, Lumacaftor dosages at the 600 mg level, achieved better efficacy than the 400 mg Lumacaftor dose on FEV1.  The reason for using 400 mg instead of 600 mg, is because the drug-drug interaction of Lumacaftor tends to lessen the effects of Ivacaftor up to 80% as dosages increase. The final date for FDA approval falls on July 5th, of 2015, and in the fourth quarter for EU approval. With an annual therapy per patient price of around $300,000, the potential to achieve revenue up to six billion is attainable. Thank you for reading.                                                                                                                       

Patent Infrigement: Obvious or Nonobvious

As companies file for new chemical entity patents, the question of infringement on an existing drug becomes either obvious or nonobvious.  This link to an article titled Deuterated Drugs: Unexpectedly Nonobvious? is a nice paper by Ms. Kristen Buteau on what constitutes obvious from nonobvious inventions, and how it relates to drug companies such as Auspex, and Concert Pharmaceuticals.  The company that is applying for a new patent must present an unexpected difference between the claimed structures and the prior art. That difference may be the new drugs unexpected metabolism rate, other pharmacokinetic advantages, or a reduced dosing regimen compared to the prior drug.  But any unexpected difference must not be obvious, must be a skill or art in itself, such as the placing of deuterium on a drug that could have many options to choose from, potentially thousands, as the drug Cymbalta has.

Concert Pharmaceuticals is currently in a phase 1 trial to test d-Ivacaftor, which is the deuterated version of Ivacaftor, a drug that is currently approved for the treatment of Cystic Fibrosis.  Not only was the deuterated drug (d-Ivacaftor) patent filed before any mention of deuterium from Vertex Pharmaceutical, but the unexpected differences in pre-clinical studies suggest, that the deutered Ivacaftor version from Concert, improved pharmacokinetics to a high degree, both in-vitro and in-vivo, and may have the convenience of single 24 hour dosing compared to twice daily.  This phase 1 trial will show how (deuterated) d-Ivacaftor does in it's first in human clinical trial on safety, tolerability, and PK, versus the placebo Ivacaftor, and demonstrate whether some of the pre-clinical results are equally impressive in healthy human subjects. Thank you for reading.

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