Monday, May 25, 2015

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 differences and exclusion criteria 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   NCT02442765NCT02442778
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 2028-2030. Thank you for reading.


Friday, May 22, 2015

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

A 505(b)(2) application differs from a 505(b)(1) 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.


Saturday, May 16, 2015

What is CTP-656

CTP-656 is the name of the deuterated version of Vertex's Ivacaftor (commercially known as Kalydeco).  Ivacaftor was initially approved for Cystic Fibrosis patients with various mutations, and soon to be approved again as a combo with Lumacaftor known as Orkambi, for patients who have two copies of the F508del mutation 12 years and older. The hope is that CTP-656 enhances therapy for patients by improving the metabolic profile, reduce dosage to once daily, or ameliorate the drug interaction profile.
Concert ran pre-clinical studies on two candidates for their lead potentiator D9 and D18 in this PDF here Pre-Clinical D-Ivacaftor.  Then entered a first in human clinical trial to assess which deuterated analog (D9 or D18) would advance based on PK data here Phase 1 NCT02392702.  That phase 1 trial will continue to evaluate the chosen deuterated analog in single and multiple dosages against placebo (Kalydeco) on a pharmacokinetic basis with a readout end of 2015 or early 2016. Even though the deuterated potentiator candidate has been chosen from the first part of the phase 1 trial in May, the CEO plans on holding off on the data until a medical conference abstract is presented in the near future by the lead scientist. The only indication on how the data looks was expressed by CEO Tung as "very happy" with the data.  Thank you for reading.


Friday, May 15, 2015

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% over placebo on FEV1 test.

Study 809-104
Lumacaftor 400 mg + Ivacaftor 250 mg q12 at week 24 = 3.0% over placebo on FEV1 test.

Lumacaftor 200 mg + Ivacaftor 125 mg, proposed dose (2) tablets twice daily.

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.    


Friday, May 8, 2015

CNCE First Quarter Conference Call

It was a volatile day for the stock of Concert Pharmaceuticals.  The company announced both good and bad news as it pertains to their product pipeline.  First the not so great, but not totally unexpected either news.  JZP-386 will not be advancing to phase 2 clinical trials at this time.  The phase 1 results were not strong enough to be considered for advancement.  JZP-386 is the deutered version of Xyrem a drug approved for symptoms from Narcolepsy.  The better news is that the company finished the early part of the phase 1 clinical trial for d-Ivacaftor, or now referred to CTP-656.  The first part of the phase 1 trial was designed to select one of two analogs for further dosage testing.  In general at this time, the CEO is "very happy" with what they are seeing, and will be presenting an abstract at an upcoming medical conference to be named.  With that process complete, the second stage of the phase 1 trial will have multiple ascending doses for the selected potentiator CTP-656 compared to placebo Kalydeco.  Other parts of their pipeline are progressing, either from FDA meetings, or through clinical trials. Below is a daily chart of CNCE as it trades above support of around $13.00.
Bottom Line:  Concert Pharmaceutical has around 60 patented drugs in their pipeline.The main focus at this time is on CTP-656, and AVP-786.  There will be a new drug to be named, that will start a clinical trial in 2016.  Thank you for reading.


Friday, May 1, 2015

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 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.


Friday, April 24, 2015

Cystic Fibrosis Clinical Study Timelines

There is a wealth of information at about the disease.  The definition of the disease from the CFF web page, "a life-threatening genetic disease that primarily affects the lungs and digestive system.  An estimated 30,000 children and adults in the U.S. and 70,000 worldwide have CF". There is not a cure available for Cystic Fibrosis (CF) patients, but science has come a long way in developing therapies to make life easier for these people. Below is a timeline of important dates in 2015 that relate to companies working on CF.

July 5th, 2015 - PDUFA date for Lumacaftor plus Ivacaftor (Orkambi) for people with CF who have two copies of the F508del mutation 12 years and older.
Fourth Quarter EU Approval -  Lumacaftor plus Ivacaftor for people with CF who have two copies of the F508del mutation 12 years and older.
October 2015 - NCT01897233 Phase 3, Lumacaftor plus Ivacaftor for people with CF, homozygous for the F508del mutation, 6-11 years of age.

October 2015 - NCT02190604 Phase 2, safety, tolerability, PK and PD, of drug QBW251 in healthy subjects, and CF patients.

September 2015NCT02325037 Phase 1, dose escalating study of GLPG1837, against placebo.
Second Quarter 2015 - Pre-clinical, corrector studies, for triple therapy potential.

Concert Pharma:
May 2015NCT02392702 Phase 1, D-9 and D-18 analog PK comparison, healthy subjects.
December 2015 - Phase 1 continuation, CTP-656 single ascending dosage study compared to Kalydeco single dosage, healthy subjects.

Vertex, Novartis, Galapogos, and Concert Pharma are the primary companies that are developing or trying to improve the efficacy or safety profile of Cystic Fibrosis drugs for people.  The future will probably have a triple combination, one potentiator, and two corrector's combined to increase efficacy, which both Vertex and Galagopos are working on at present.  Concert has shown in pre-clinical studies that the deutered version of Ivacaftor (d-Ivacaftor) has pharmacokinetic (PK) improvement compared to Ivacaftor. So, 2015 should tell plenty about the future of some of these companies and their plans to develop new, or improve Cystic Fibrosis therapies.  Thank you for reading.


Wednesday, April 22, 2015

Deuterated Drugs For Hematologic Diseases

Concert Pharmaceutical is actively pursuing patent applications for deuterated drugs for hematologic diseases.  The company has run a pre-clinical drug trial for the deutered lenalidomide (Concert drug named CTP-221), and is pursuing patents related to Rigosertib, a drug that is used by Onconova (ONTX) in clinical trials. Each drug is primarily directed toward some form of  Myelodysplastic Syndrome (MDS) or AML.
Lenalidomide was approved in 2005 for low to intermediate-1 risk MDS with deletion 5-q chromosomol abnormality.
Rigosertib has been used in several clinical trials as both monotherapy and as co-therapy, intravenously and orally, primarily for intermediate-2 to higher risk MDS, and for patients who have failed prior therapies. For some of these patients who have failed previous therapy (refractory MDS), the prognosis is less than 12 months survival, and the drug side effect profile is quite adverse.  
I really like the direction CNCE is taking in pursuing patents for hematological indications such as intermediate-2 to higher risk MDS, where there remains an un-met need for longer and better tolerated drug therapies.  I am looking one to two years out into the future direction of the company, and believe Concert may be able to get both of these deutered hematological drugs into clinical trials for different MDS patients in 2016, after all patents have been secured.  At this time we do not know if CTP-221 will ever make clinical trials due to competing patent issues.  Thank you for reading.


Friday, April 17, 2015

Concert Pharmaceutical: JZP-386

JZP-386 is the deutered enhanced version of sodium oxybate or commercial drug known as Xyrem, which is manufactured by Jazz Pharmaceuticals.  The drug was approved in 2002 for cataplexy in narcolepsy, and 2005 for excessive daytime sleepiness (EDS) in narcolepsy.  The patents run from 2019 through 2024 at the latest.  Xyrem is administered twice daily as a liquid dose, once before bed and again after about four hours of sleep. Xyrem has a side effect profile that includes headaches, dizziness, nausea, and potentially more serious side effects in higher doses such as convulsions, respiratory depression, coma and death, according to Xyrem prescribing information.   Concert is currently in a phase 1 trial to evaluate the deutered Xyrem version called JZP-386, compared to Xyrem, with a readout on the trial any day now.  The goal of the deutered version JZP-386, could be once daily dosing, lower dosing, or a reduction in side effects that currently exists with Xyrem. Concert would have a chance to receive royalties that run from mid single digits to low double digits, not to exceed 20% on a country-by-country basis, and licensed product-by-licensed product basis. The patent for JZP-386 runs from 2030 to 2032, U.S. EU, and Japan. Thank you for reading.


Sunday, April 12, 2015

Concert Pharmaceutical: CTP-221

Investing in Concert Pharmaceuticals, is like investing in several companies under one umbrella. The reason being, is that they are applying their DCE platform (deuterated chemical entity) to several drugs already in existence for different indications. CTP-221 is the deutered enhanced drug for lenalidomide, or commercial drug known as Revlimid, which is manufactued by Celgene.  The drug targets indications in Myelodysplastic Syndrome (MDS) and Multiple Myeloma amongst others, and is expected to produce revenue up to seven billion annually for the company. This is the second Celgene drug after CTP-730 that Concert has considered for clinical trials. The patent for Revlimid gets a little more complicated as generic companies are interested in the drug, and legalities have been ongoing. But in general, I would say Revlimid is protected until around 2024 at the latest. CTP-221 has shown to be approximately 5-6 fold greater potency in animal models with similar antitumor effects.  At this time we do not know if CTP-221 will ever make clinical trials due to competing patent issues. Thank you for reading.


Friday, April 3, 2015

Concert Pharmaceutical: CTP-730

CTP-730 is the deutered enhanced version of Apremilast (Otezla), that is manufactured by Celgene.  The drug was approved in March of 2014 for psoriatic arthiritis, and again in September of 2014 for moderate to severe plaque psoriasis. The patent for Otezla runs until 2024 US and EU.  The drug is forecasted to bring in around $2 billion in revenue by 2020. The typical dose is 30 mg twice daily, and the drug is known to exhibit side effects such as diarrhea, nausea, and headache. A deuterated version could potentially reduce the dosage to once daily, improve the efficacy, and side effect profile.
Concert is currently in phase 1 testing to explore the safety and pharmacokinetics profile compared to placebo with a full readout around September 2015.  Once the trial is complete a one time $8 million milestone will be awarded to Concert from Celgene. More importantly, will be the trial results....the first in human trials for CTP-730.  The relevance for increased efficacy, or safety with a once a day tablet, would be valuable to Celgene, not to mention the increased patent life that the D-Apremilast version would have, to 2030. Thank you for reading.  

Wednesday, April 1, 2015

Deuteration Validation

On March 30th, Teva Pharmaceuticals agreed to acquire Auspex Pharmaceuticals for $3.5 billion, or around $100.00 per share.  A few points to consider as it relates to Concert Pharmaceuticals, which is one of our holdings.

1. This acquisition instills confidence in the science of deuterium-based chemistry.  Both Auspex and Concert are applying deuterium to existing drugs to potentially enhance their efficacy, half-life or safety profile.
2. In 2011 Concert assigned patent rights for the deuterated drug Pirfenidone to Auspex.  Under the agreement, if a change in control of ASPX, Concert would be due 1.44% of the purchase price, in this case, approximately $50 million.
3.  After completing a recent secondary offering for up to $46 million and considering the newly acquired $42 million, the company should hold approximately $154 million, after retiring $7 million in debt.  Thank you for reading.


Friday, March 27, 2015

Concert Pharmaceutical: CTP-499

CTP-499 is the deuterium-containing pentoxifylline.  CTP-499 is the companies most advanced drug, which is for the treatment of diabetic nephropathy (kidney disease or kidney damage that occurs in people with diabetes). The company completed a phase 2 trial that missed the primary end point, which was to measure the change in urinary albumin to creatinine ratio, Urine Albumin-to-Creatinine Ratio (UACR).  What the company did find was that at 48 weeks, six patients out of 58 in the placebo group saw their serum creatinine levels spike more than 50%, versus just one patient out of 65 in the treatment group.
Concert is seeking a Special Protocol Assessment (SPA) from the FDA for CTP-499. In general, a SPA is an agreed upon endpoint that a company and the FDA use for a clinical trial.  If that primary endpoint data is statistically significant, than a new drug application could be filed and potential FDA approval.
A reduction in the rate of renal disease measured by a time-to-event analysis of the composite of increase of serum creatinine (greater than or equal to 50%) or end stage renal disease versus placebo treated patients, was agreed to be an acceptable Phase 3 endpoint to support the filing of a new drug application (NDA).  In addition, patients with a higher level of serum creatinine at baseline (above-median UACR) saw more pronounced benefits with CTP-499, compared to patients with below median UACR levels baseline, at 48 weeks. That could potentially be an inclusion into the study criteria, which could also benefit the results CTP-499 achieves in the trial.  I am expecting the company to announce the start of a pivotal phase 3 trial in 2015, after the FDA approves the SPA for that trial. The company has mentioned that they may seek a partner for this indication. I give this upcoming phase 3 trial a high probability of success, if the FDA approves the Special Protocol Assessment that the company has submitted.  Thank you for reading.

Thursday, March 19, 2015

Concert Pharmaceuticals - Secondary Offering ($14.76)

CNCE has issued a secondary offering to raise around $52 million dollars in additional capital.  The company is issuing 3.3 million shares, and an additional 495,000 thousand shares, as an over allotment that the underwriters can purchase at the public price (less discounts and commissions) within 30 days.  The CEO has stated that they planned on retiring the $7 million in debt this year. After the company completes this offering, and assuming that the underwriters do take the additional 495,000 shares, the company should net around $46 million after all expenses on the offering, and an additional $6 million on the over allotment. Once the company retires the $7 million debt, they should have approximately $120 million cash on hand with zero debt.  The timing was right for this offering.  The company is taking advantage of a hot biotech market, (their stock hit a new high just this week at $18.29) to complete this offering. Thank you for reading.


Monday, March 16, 2015

Lundbeck - New Holding ($19.19)

We recently purchased shares of Lundbeck under the symbol (HLUYY).  I previously mentioned this company before here Lundbeck and here Clinical Trial Update.  The company is located in Copenhagen Denmark, and their description from their website is as follows.
Lundbeck's R&D strategy is aimed at enabling the discovery and development of new pharmaceuticals targeting the underlying mechanisms of brain disorders. This approach allows us to treat the symptoms more effectively and also to potentially alter the course of the diseases.  The strategy requires comprehensive research into the brain and the biology and mechanisms of brain diseases, as well as improved understanding of research targets and clinical outcomes. 
The company falls into the catagory of a CNS, (central nervous system) research and development company. I best describe this as a value investment and a turnaround story. The company and its partner (Otsuka), have suffered from patent expiration from their main producer Abilify. But during the past two years the company has produced some successful clinical trials with extended patent dates for drugs that treat MDD, (major depressive disorder) and acute schizophrenia, both of which I am expecting FDA approval mid 2015.  The new products coming on line with extended patent dates, makes this a lower risk value proposition.  My initial price target on the stock is around $27.00 in the intermediate term.  Thank you for reading.

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