Saturday, June 27, 2015

NMDA Receptor Modulators for Depression

NMDA (N-mythel-D-asparate) roots track back to a drug known as Ketamine or street name Special K, with hallucination effects.  Ketamine is an NMDA receptor antagonist originally used as an anaesthetic.  The glutamate receptor subtype known as (NMDA) plays a central role of modulating brain activity in the central nervous system, such as synaptic transmission, synaptic plasticity, and excitotoxicity. Pharmaceutical firms have been developing NMDA type drugs for over two decades, and a few including Memantine, and Nuedexta are being marketed for other indications outside of depression.
There have been several studies modulating the NMDA receptor, that have shown efficacy in patients with treatment-resistant depression.  A trial performed by Avanir Pharmaceuticals for pseudobulbar affect with drug AVP-923 (Nuedexta), showed efficacy in a subset of patients for depression using the Beck Depression Inventory II or BDI-II. Data showed that the dextromethorphan (an NMDA receptor antagonist, sigma 1 agonist) / quinidine combination was effective in patients with BDI-II scores greater than 18 at inclusion with AVP-923 30/10, and was associated with a statistically significant improvement of (p=0.03). What's also significant is that major depression was an exclusion into the trial.  Avanir is now in a phase 2 clinical trial with AVP-786, for major depressive disorder patients as adjunct to current antidepressant here NCT02153502.  I think the chances of success are high, based on how the dextromethorphan/quinidine combination performed in the subset of patients in prior trials.
Private company Naurex, is also working on NMDA drugs for depression patients. The company has displayed good data in early clinical trials using IV, and soon to be launched an oral NMDA drug for depression.  Thank you for reading.


Tuesday, June 23, 2015

AVP-786 Clinical Trials

AVP-786 is the deutered version of AVP-923, an Avanir drug that has been FDA approved for pseudobulbar affect (PBA) since 2010. Since then AVP-786 has expanded out to other indications, such as alzheimer's, depression, and now residual schizophrenia. Below is a list of current and clinical trials that are close to being initiated. Otsuka acquired Avanir in 2014.

Phase 2 Major Depressive Disorder (Adjunct)
Phase 2 Residual Schizophrenia
Phase 3 Agitation in patients with dementia of Alzheimer's
Phase 3 Agitation in patients with dementia of Alzheimer's
Phase 3 Long term, extension study agitation in patients with dementia of Alzheimer's

AVP-786 is the Concert Pharmaceutical deuterated version of AVP-923.


Friday, June 19, 2015

Triglyceride-Lowering Agents

Omega - 3 fatty acids sourced from fish oil have been shown to be beneficial to patients with high triglycerides. In 2004 while at Reliant Pharmaceuticals, current Matinas CEO Rongen and other employees led the FDA approval and launch of Lovaza (omega 3-acid-ethyl esters) for severe "hypertriglyceridemia greater than 500 mg/dL".  In 2007 GSK (Glaxo Smith Kline) purchased privately held Reliant Pharmaceuticals for $1.65 billion.  Lovaza at the time of acquisition was the only drug approved by the FDA for very high triglycerides, ranging from greater than 500 to 2000 triglyceride level.

In July 2012.  Amarin Pharma received U.S. FDA marketing approval for Vascepa, also referred to as AMR-101 in the severe triglyceride range of greater than 500 and higher, same as Lovaza.  In clinical trials, Vascepa also lowers LDL-C, Lovaza does not.

Vascepa Phase 3 Trial Results:  
- Phase 3 12 week "Marine" clinical trial results 500 and greater TG, with or without statin,  4g / day -45.4% reduction TG, and LDL -2.3%.
Phase 3 12 week "Anchor" clinical trial results 200 - 500 (73% in treatment arm had diabetes), and on statin therapy, 4g / day, -17.5% TG (median reduction from baseline) and +1.5% LDL.
Amarin is also in a clinical trial here called REDUCE-IT for patients with high triglycerides.  The study is a time to first event, which in this case happens to be a first major cardiovascular event.  

Matinas is developing MAT9001 initially for very high triglycerides in the range of 500 to 2000.  In a head to head clinical trial with Vascepa (200 - 400), MAT9001 had a 33.2% reduction compared to 10.5% for Vascepa (p value = .001).  Also reduced LDL by 2.4% vs. 4.3% for Vascepa.  The trial was well designed, as the same patients were used twice, first with MAT9001, than there was a washout period, and those patients were tested again with Vascepa. The company feels that the greater than 500 triglyceride level is a good first step to pursue for FDA approval, prior to the high 200 - 499 level.

Lovaza generic is being prescribed for patients in the very high TG levels of  500 - 2000. Below are two phase 3 trials below that led to FDA approval for these patients and in Europe as a supplement to the diet for the treatment of elevated levels of triglycerides. 

Pivotal Studies of Omega-3-Acid Ethyl Esters (Lovaza) For the Treatment of Very High Triglyceride Levels
Study 1 (Harris)Study 2 (Pownall)
No. of patients4240
Inclusion criteriaTG 500–2,000 mg/dLTG 500–2,000 mg/dL
TreatmentEsters 4 g daily or corn oil placeboEsters 4 g daily or corn oil placebo
Duration16 weeks6 weeks
ResultsChange from baseline results of Esters/placeboChange from baseline results of Esters/placebo
Total cholesterol↓15% / ↓2%↓10% / 0%
Triglycerides↓45% / ↑15%↓39% / ↑8%
LDL-C↑31% / ↓5%↑17% / ↓4%
HDL-C↑13% / 0%↑6% / ↓6%
LDL-C = low-density lipoprotein-cholesterol; HDL-C = high-density lipoprotein-cholesterol; TG = triglyceride.
From the two phase 3 trials above. Lovaza did a nice job of reducing triglyceride levels of 45% and 39%, but the drug raised the LDL-C levels in both trials by 31% and 17%.  This was not seen in the phase 1/2 clinical trial with either MAT9001 or Vascepa in the 200 - 500 triglyceride range.  
Bottom Line:  Matinas Biopharma  has a unique agent to reduce triglycerides, and has shown in a head to head phase 1 / 2 clinical trial that it held a significant advantage over Vascepa for patients in the 200 - 400 range.  Next step is to initiate a phase 3 clinical trial for patients with severe triglycerides, in the range of 500 - 2000.  Thank you for reading.

Friday, June 12, 2015

Matinas Biopharma Registration

It takes a good amount of cash to advance clinical trials and eventual FDA drug approval. Matinas will be announcing a registration offering to raise approximately $20.7 million from existing holders exercising their warrant rights.  The company is not offering any securities pursuant to the offering.  Before this pending offering, their financial sheet looks like this.

Quick Facts 
57 million shares outstanding
$70 million market cap
$13 million cash
6.7 million corporate stock options at $0.96 exercise price
39 million warrants outstanding
$0 preferred stock outstanding
$0 debt

This is a non-dilutive way for the company to raise cash, without issuing additional equity.  The shares outstanding will increase from the exercise of warrants, but that eventually had to happen anyway.  After this registration is complete, the company should have enough cash to fund a phase 3 clinical trial for MAT9001, and perhaps some phase 1/2 clincial trials for their existing pipeline.  Thank you for reading.


Friday, June 5, 2015

Matinas Biopharma ($1.33)

Longshot dejour.  Matinas Biopharma is an interesting bulletin board stock that has sound management and a drug that could make it through FDA approval within the next few years depending on how many phase 3 trials the FDA requires.  From Matinas Biopharma website...."Matinas BioPharma is deveolping MAT9001 for the therapeutic applications in dyslipidemia field, with severe hypertriglyceridemia (TG greater than 500 mg/dL) as the primary indication. Based on promising early data, the company filed an Investigational New Drug Application (IND) with the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2014. Matinas Biopharma plans to provide further details on its development program for MAT9001 as well as its plans to commence its Phase 3 registration program in the near future".

Quick Facts:
57 million shares outstanding
66 Million Market Cap
13 Million in Cash
39M Warrants Outstanding

Intellectual Property:
MAT 9001 2033  Expiration
MAT 8800 2033  Expiration
MAT 2203 2027  Expiration
MAT 2501 2027  Expiration

Bottom Line:
Matinas will announce the start of a phase 3 clinical trial (will last approximately one year) to commence in 2015 for lead drug MAT9001, for patients with high triglycerides, reading over 500 mg/dL.  Based on a head to head comparison in a phase 1 trial compared with Vascepa, the phase 3 trial could prove to be statistically significant.  Whether the FDA requires two phase 3 trials, remains to be seen.  The patent for MAT9001 extends to 2033. Thank you for reading.


Tuesday, June 2, 2015

Concert Pharmaceutical: ($16.91)

Quick technical look at Concert Pharmaceuticals with a daily chart below. Everyday the stock closes higher, a new all-time closing high is achieved.
The out performance is evident when shown on a chart that has the XBI Small Cap Biotechnology Fund, and the S&P 500 below over a five day period.  
Bottom Line:  Funds are adding shares, as they see future value at these prices.
Thank you for reading.

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.


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