Saturday, August 29, 2015

CNCE Quarterly C.C.

This conference call was actually completed on August 5th, as I have been behind on posting relevant notes from that presentation.  The highlights primarily involved CTP-656, which is known as d-Ivacaftor, or Vertex Pharmaceuticals commercial drug known as Kalydeco, for Cystic Fibrosis.  Some bullet points below for reference.
  • The first part of the phase 1 that led to the selected compound CTP-656, could be presented as interim data at any time, or the company may elect to wait until the second part of the phase 1 clinical trial is complete, which includes single and multiple ascending doses against placebo Kalydeco, to be completed around years end 2015.
  • The company intends to progress CTP-656 for CF patients that have the G551D mutation first as mono therapy, than later consider any combo therapy.
  • The company believes once daily dose for CF patients with CTP-656 is a potential.
  • Open discussions with companies working in the CF area have been an ongoing process, but only completed details will be released to the public.  
  • The cash balance of $151 million, is believed to be sufficient to fund operations into 2018. 
Bottom Line:  This was a good conference call, with meaningful analyst questions following the presentation. The company reserves the right to present interim data of CTP-656 as sees appropriate, or hold the data until the phase 1 clinical trial has been completed, which includes single and multiple ascending doses against Kalydeco, as placebo in the control arm.  The company is scheduled to appear at the UK Cystic Fibrosis Conference on September 22nd, with deuterated Ivacaftor as the subject of presentation.  Thank you for reading.


Friday, August 28, 2015

AVP-786 for Disinhibition Syndrome

The number of clinical trials utilizing Avanir / Otsuka NMDA modulator drug AVP-786 is increasing with each quarter. The number now stands at six with the addition of the latest posting at Clinical that pertains to Disinhibition Syndrome here Treatment of Disinhibition. There is not a drug specifically approved for Disinhibition Syndrome, or Frontal Temporal Dementia (FTD) that I can find.  The main inclusion into the trial is as follows.
  • Documented diagnosis of a Neurodegenerative Disorder including frontotemporal dementia, Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), dementia with Lewy bodies (DBL), vascular cognitive disorders, or Huntington's disease, at least 3 months prior to Baseline.
This is a very broad inclusion into this phase 2 clinical trial, with only 12 patients aged 50-90 being recruited.  In general the patient must have some sort of Neurodegenerative Disorder. The list of AVP-786 clinical trials that are in progress or set to start soon is below.  

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
Phase 2 Treatment of Disinhibition

Bottom Line:  It's easy to see why Otsuka bought Avanir Pharmaceuticals for $3.5 billion in 2014. They see the potential for NMDA drug AVP-786, and it's use for many indications.  Thank you for reading.  


Tuesday, August 25, 2015

Still A Bull With Volatility

Weekly charts are a valuable tool to understanding a more distant look into market comparisons. Then we can decide whether we are still in an up trending market or we have turned downward, based on the technical pattern.  Below is a weekly chart of the S&P 500 Index.
Source:  Shaw Investments,
From the weekly chart above.  The current correction low that we achieved yesterday, is above the correction low that was achieved in 2014, still creating an upward trend line, based on the weekly chart.  
Source:  Shaw Investments,
The $VIX chart above has not seen high levels like this since 2011.  Expect volatility in the near term, until the $VIX reading declines to more normal historical levels, which could take a few weeks.  

Bottom Line:  The S&P 500 Index above put in a correction reading (greater than -10% from peak), but remains above the 2014 correction low, creating an upward trending market.  So we are in a long term bull market, and an intermediate term up trending market.  The $VIX remains very high historically, so expect a whip lashing type market in the near term or until the $VIX declines to more historical average levels.  Thank you for reading.


Sunday, August 23, 2015

Cystic Fibrosis Clinical Studies - Update

We previously wrote about CF clinical studies here Cystic Fibrosis Clinical Studies.  When analyst predict peak drug revenue in the $6 billion range, like they have done for Vertex Pharmaceutical's combo Orkambi, other companies take notice.  The other major players that are interested in developing Cystic Fibrosis drugs are Galapagos (AbbVie), and Novartis.

This is a phase 1 study to read-out fall of this year.  The trial is first in human study of GLPG1837 in healthy human subjects to test the safety and tolerability of the drug.

This trial is a phase 2 study that has been running since mid 2014, and is scheduled to read-out by end of 2015.  This trial is testing QBW251 in healthy and CF patients.  Safety, PK, PD, and FEV1 will be measured.

Should receive European Union approval for Orkambi by the end of 2015, for patients 12 years and older with two copies of the F508del mutation.  The company received U.S. FDA approval in July for the same CF population.  The company is several years ahead of any competition mentioned above. 

Bottom Line:  The Galagapos and Novartis trials, are two clinical studies that many will be waiting for results.  The Galagapos trial is just phase 1, and in healthy subjects.  Adverse events will be the primary endpoint, with PK data as secondary endpoint.  The phase 2 (four part) clinical trial of Novartis drug QBW251, should provide more information about the effect of the drug as it is being tested on healthy, and CF patients, in single and multiple ascending oral doses.  There are a number of smaller companies that are working on related symptoms from having CF, and other companies that are developing drugs that could enhance the effectiveness, of already approved CF drugs like Orkambi.  Thanks for reading. 


Friday, August 21, 2015

Week In Review

Remaining objective during stock market corrections is the best possible solution.  We can remain objective by viewing charts, and by blocking out any emotional related news that seems to circulate, when there is a sell-off at hand.  Remember, market corrections are a healthy process that cleanses out all the excesses, to the point that value creation emerges.  In other words, these are good times to be putting cash to work, which we have this week.  So let's view a couple charts below to understand better, how far down this correction could go.  

Source:  Shaw Investments,
The above chart is of the S&P 500 index, which is one of the world's most watched index.  I tracked last year's market correction loss just to compare what we may be looking for at this precise moment. Last October's correction took the market down -9.89%.  We are currently lower from the recent high at -7.29%.  So we are closing in on last years percentage correction low.  In addition the market at this time is very oversold, and we should get a relief bounce higher at minimum, in the near future. 
Source:  Shaw Investments,
The above chart depicts what is known as the VIX.  The VIX is also known as a fear gauge, based on how much volume is exhibited in the options market with put buying.  The higher the VIX spikes the more fear is said to be in the market.  The important thing here is to observe the extremes of the VIX. Based on that theory, the huge spike in the VIX could signal a sell-off stock market bottom may be getting close at hand.  The move higher is getting very close to matching last years VIX correction high reading.  

Bottom Line:  Great time to be adding to existing positions over the course of this correction.  The sell-off so far, is getting close to last years correction low, so we may be getting close to a bottom, if using last years sell-off on a comparison basis.  Thank you for reading.  

Saturday, August 15, 2015

CTP-499: Special Protocol Assessment (SPA)

Two important FDA designations are Orphan Drug Status and Special Protocol Assessment. Today we'll discuss the SPA and how it relates to CTP-499.  An SPA is a designation from the Food and Drug Administration that an uncompleted phase 3 clinical trials design, clinical endpoints, and statistical analysis are acceptable for FDA approval. Basically means that if the company meets those pre-determined endpoints in the trial, FDA approval should be a very high probability.
We previously wrote about one of Concert's drug for Type 2 Diabetic Nephropathy named CTP-499 here, What is CTP-499. The company has been under negotiations with the FDA for an SPA for that drug for over a year.  The CEO has stated that they should have an SPA for CTP-499 by the end of this calendar year.  After that, a partnership will be selected, and the costs of the lengthy (three years) trial will be split in some equitable way. The selected partner should feel more comfortable about the trial's design being granted an SPA from the FDA, and there will be one pivotal phase 3 clinical trial, as opposed to two phase 3 trials. The trial's design in this case is a result of the completed phase 2 clinical trial's findings, from a subset of patients and their results vs. placebo.  If the phase 3 trial starts the beginning of 2016, lasts three years, and the company files a New Drug Application (NDA) after that, FDA approval could potentially take a year from there.  So, by the beginning of 2020, the drug could go to commercialization and have approximately ten years of patent exclusivity.  
The patent for CTP-499 runs until 2029 - 2030 in the US, EU, and Japan.  The market for Diabetic Nephropathy is estimated to reach $3 billion by 2020 from research here Global Market Study. CTP-499 will be used as co-therapy with ACEI and/or ARB for patients that have advanced to a specified point of disease.  Thank you for reading.  


Wednesday, August 12, 2015

Brean Capital Buy Rating and $21.00 Target

The coverage by Brean Capital was initiated this morning.  Nothing new here, but the stock did respond positive throughout the day, then gave it back late afternoon under high volume.

Brean Capital initiates coverage on Concert Pharmaceuticals (NASDAQ: CNCE) with a Buy rating and a price target of $21.00.

Analyst Difei Yang commented, "Concert Pharmaceuticals is a drug discovery platform company with a core science in deuterium chemistry. Concert replaces the hydrogen atom of an already approved drug, or a first-in-class drug candidate, with a deuterium atom. The deuterium atom can enhance the clinical safety, tolerability, or efficacy of the drug while causing no material change to a compound’s biochemical potency or selectivity. Thus, Concert’s approach has inherent reduced R&D risk relative to a company pursuing a novel molecule discovery. Currently, Concert has six drug candidates in clinical development and a strong track record, having previously developed and sold two compounds at multiple-billion dollar valuations. With multiple shots on goal, we think the sale of just two of the six compounds Concert has under development could drive substantial upside to current valuation."


Friday, July 31, 2015

Concert Pharmaceuticals Pipeline Potential

Three is the number of indications (in house or licensed out) that I believe Concert Pharmaceuticals could have in pivotal phase 3 clinical trials in 2016. The three indications are as follows.

1.  AVP-786 - Agitation in patients with dementia of the Alzheimer's type.
2.  CTP-499 - For diabetic nephropathy (kidney disease or kidney damage that occurs in people with diabetes).
3.  AVP-786 - Adjunctive therapy in patients with major depressive disorder with an inadequate response to anti depressant treatment.  

AVP-786  has two phase 3's for agitation listed in the clinical government documents, but not ready to recruit just yet.  I expect the recruitment to be in progress by September end.  

CTP-499  for diabetic nephropathy is in negotiations for a Special Protocol Agreement with the FDA. Once that is achieved the company would then look for a partnership to license out and split costs of the lengthy phase 3 clinical trial.  
AVP-786  for major depressive disorder, will complete their phase 2 clinical trial by mid year 2016. If the results are good, I would expect Avanir (Otsuka) to file for a pivotal phase 3 clinical trial or trials by the end of 2016.  

The optimistic view, is that the company could potentially have five indications (a combination of in house and licensed out) in phase 3 clinical trials in 2016.  This could happen if CTP-730 and CTP-656 whom both will have completed phase 1 clinical trials in 2015, 
apply for the 505(b)(2) New Drug Application path, and be able to move right to phase 3 clinical trials in 2016. The phase 1 clinical trials are being run against the already approved drugs as placebo, which in this case is Otezla and Kalydeco.  In the case of CTP-730, Celgene will be responsible for any clinical trials from phase 2 onward.  

Bottom Line:  Concert is having a very productive year, by advancing clinical trials, and by increasing their cash position by about $100 million, from a combination of a secondary offering, and $50 million from a previous agreement with Auspex Pharmaceutical.  The company could have three pivotal phase 3 clinical trials running in 2016, with the optimistic view of up to five indications in phase 3 in 2016.  Thank you for reading.  


Sunday, July 26, 2015

Allergan Buys NMDA drug for $560 Million

Allergan says yes to CNS (central nervous system) and NMDA (N-methyl-D-aspartate) modulating drugs for depression, with the purchase of private company Naurex for $560 million.  We previously wrote about NMDA drugs and Naurex here, NMDA Receptor Modulators.  NMDA drugs are rapidly gaining press as mono and adjunct therapy for depression patients.  Avanir is currently in a phase 2 clinical trial with their NMDA modulator AVP-786, as an adjunctive therapy in patients with Major Depressive Disorder, with an inadequate response to anti depressant treatment. Avanir will complete their phase 2 clinical trial in the first half of 2016.  Naurex has already tested NRX-1074 as an IV as adjunctive in a phase 2 study for patients with Major Depressive Disorder.  Next, the company will test an oral NRX-1074 in a planned phase 2 clinical trial as mono-therapy for Major Depressive Disorder (MDD).

Bottom Line:  At this point we have no idea how NRX-1074 oral will perform, compared to their completed intravenous phase 2 clinical trial for patients with Major Depressive Disorder (MDD). Avanir with drug AVP-786, is most likely two years ahead of NRX-1074 in the clinical trial process. Thank you for reading.      


Thursday, July 23, 2015

CTP-730: Potential Milestone and Royalty Winner

We originally wrote about CTP-730 here, What is CTP-730.  Today Celgene held it's second quarter conference call this morning.  This is what Scott Smith head of Global Inflammation and Immunology had to say regarding the launch of Otezla, and the future pipeline of indications that Otezla could potentially get approved for.  
Scott Smith President, Global Inflammation and Immunology
"Thank you, Jackie.  Q2 was a great quarter for Celgene I and I.  During the quarter, we saw significant acceleration of prescriptions and revenues for OTEZLA in the U.S. and strong initial uptake in the early launch countries internationally. We also made progress on indication expansion for OTEZLA advancing a global Phase III program in Behcet's Disease and Phase II studies in atopic dermatitis and ulcerative colitis.
Now turning to OTEZLA, were seeing a substantive uptick in revenues and demand in the U.S. Total prescriptions far outpace the recent launch analogs in the I & I space and currently measure over 4,500 TRx' per week based on the latest data. Revenues for the quarter grew to $90 million worldwide and we're tracking well in line with internal plans. We're very encouraged at the progress we're seeing outside of the U.S., both in Canada and in early launch countries in the EU.  After only five months, we're outpacing all recent launches in Germany.  Still very early in the launch, but this initial success helps reinforce the global value proposition of OTEZLA and the need for novel approaches to the treatment of I & I disease.
The trends in the U.S. are supported by positive launch metrics.  While the PSA launch continues to make strong and steady progress, the launch of psoriasis indication has fueled much of the recent acceleration.
Access to new therapies is a critical component of success in the market.  And it's important to note that over 70% of OTEZLA prescriptions in pre-biologic patients are being approved on first pass.  Total U.S. patient share for OTEZLA in psoriasis surpassed ALLERA some months ago and passed ENBREL's overall patient share in June.  The source of business in psoriasis continues to be heavily weghted towards the pre-biologic sector with 75% of patients coming to OTEZLA from topical therapy or no therapy at all over the past 12 months".

Bottom Line:  CTP-730 is Concert Pharmaceutical's deutered enhanced Otezla, that just finished a phase 1 clinical trial.  CTP-730 has been licensed to Celgene, with future milestone, and royalty payment potential for Concert.  Otezla has had a very strong launch, and could expand into Behcet's Disease, atopic dermatitis, and ulcerative colitis. Thank you for reading.

Saturday, July 18, 2015

Rexulti & AVP-923 Safety Profile Comparison

When prescribing drugs for the elderly population with neurological conditions, it is important to recognize the side effect profile for this fragile population.  There is not an FDA approved drug for the treatment of agitation in patients with dementia of the Alzheimer's type.  Otsuka Pharmaceuticals has a total of five phase 3 clinical trials that have been in progress, or about to start.  The two drugs that are addressing this indication are Rexulti (Brexpiprazole), and AVP-923 (AVP-786). Rexulti is a joint 50% ownership between Lundbeck and Otsuka.  AVP-923 (AVP-786) is 100% owned by Otsuka, with a milestone and royalty licensing agreement with Concert Pharmaceuticals. The side effect comparison between Rexulti and AVP-923 is below.

Rexulti (Brexpiprazole)
In clinical trials here phase 3 Schizophreniathe 2 mg group of Rexulti exhibited the following side effect profile.
Insomnia 13.4%
Headache 9.3%
Agitation 8.6%
In clinical trials here phase 3 Depression, the 2 mg group of Rexulti exhibited the following side effect profile.
Weight Increase 8.0%
Akathisia 7.4%

The newly approved Rexulti for schizophrenia and depression, has the following safety label information below.

"Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs. 2.6%, respectively).  Although the causes of death varied, most of the deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g.,pneumonia) in nature. Rexulti is not approved for the treatment of patients with dementia-related psychosis".

AVP-923 (AVP-786)
In a phase 2 clinical trial here AVP-923 Phase 2 Results for patients with agitation with dementia of the Alzheimer's type, the following side effect profile was exhibited.
Falls 8.6%
Diarrhea 5.9%
Urinary Tract Infection 5.3%

Falls had a baseline skew, that had more patients in the treatment group (20% to 12%) than the placebo group, at the start of the trial.  In addition from that phase 2 clinical trial, there were no new cardiovascular safety signals and no clinically significant changes in QTc observed in the study.  These results above are consistent with several other clinical trials that Avanir has run with AVP-923, for traumatic brain injury, or stroke here Prism IIwith diarrhea being the most commonly reported adverse event.

Bottom Line:  Otsuka has advanced the deutered version of AVP-923, (known as AVP-786) into three phase 3 clinical trials for the treatment of agitation in patients with dementia of the Alzheimer's type, to begin soon.  The company also has two ongoing clinical trials in progress with Rexulti for the same patients, that started in 2013. The patent for Rexulti runs until 2027 US and until 2025 EU. Thank you for reading.


Saturday, July 11, 2015

FDA Approves Rexulti (Brexpiprazole)

Late Friday the FDA approved Otsuka and Lundbeck's atypical antipsychotic drug Rexulti (Brexpiprazole), as mono therapy for Acute Schizophrenia, and as adjunct therapy for Major Depressive Disorder. We previously wrote about Brexpiprazole here Lundbeck Clinical Trials Update .  Otsuka, the maker of Abilify has been under pressure to replace lost sales of the world's number one selling drug Abilify (Top Selling Drugs) in 2014, due to patent expiration in 2015. Rexulti (Brexpiprazole) has been the drug to replace Abilify for several similar CNS indications. Under the marketing agreement Lundbeck (co-developer and co-commercialization) will get 45% of Brexpiprazole U.S. net sales, and 50% net sales in Europe.  The patent for Rexulti runs until 2027 US, and 2025 in the EU. The label for Rexulti is below.

REXULTI is indicated for:
  • Use as an adjunctive therapy to antidepressants in adults with major depressive disorder
  • Treatment of schizophrenia in adults
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs 2.6%, respectively). Although the causes of death were varied, most of the deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. REXULTI is not approved for the treatment of patients with dementia-related psychosis.

Rexulti (Brexpiprazole) deemed the second generation Abilify, is getting a similar safety label as Abilify, even though the side effect profile between the two drugs varies, with Rexulti showing improvement in some areas such as akathisia.  It will be interesting to see what kind of label AVP-786 gets for the Treatment of Agitation in Patients with Dementia of the Alzheimer's Type.  AVP-786 is about to enter phase 3 clinical trials in September. Thank you for reading.


Sunday, July 5, 2015

Aquarius Biotechnologies

Private company Aquarius Biotechnologies was acquired by Matinas Biopharma on January 30th, 2015 here, Matinas Biopharma Acquires Aquarius Biotechnologies. This was a good acquisition for Matinas as it gives the company a more broad and differentiated pipeline of indications.  Aquarius specializes in a lipid based chochleate drug delivery system.  Their goal is to improve current drugs for anti-fungal; like Amphotericin (MAT2203), and for bacteria in the body; like Amikacin (MAT2501), with their chochleate technology.  The strong point of the technology is in it's oral delivery, which is an improvement over currently available standard of care intravenous (IV), and the safety profile on a comparable basis.
Aquarius (now Matinas) is not the only company that is targeting bacterial and fungal indications.  AstraZeneca has also funded a start-up with $40 million here Entasisfor Gram-negative infections including Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae.  Also, a single dose oral therapy for susceptible and drug-resistant Neisseria gonorrhoeae, which is currently in a phase 2 clinical trial with drug EXT0914. Thank you for reading.


Thursday, July 2, 2015

Orkambi Gets FDA Approval

Today the FDA approved the combination of Vertex's Lumacaftor and Kalydeco (Orkambi) for cystic fibrosis people, 12 years and older, with two copies (homozygous) of the F508del mutation. We originally wrote about Orkambi here Vertex Pharmaceutical Passes Advisory Committee, when they were front and center with the FDA advisory committee.

Orkambi has been appoved for CF patients despite the relatively small improvement in FEV1 in two F508del clinical studies.  How high is the bar set for other companies to get clinically significant improvement over Kalydeco as mono therapy for the G551D mutation, and Orkambi combination therapy, for patients 12 years and older, with two copies of the F508del mutation?

G551D Through 24 weeks Kalydeco 150 mg bid
10.6% and 12.5% FEV1 improvement vs. placebo
G551D Through 48 weeks Kalydeco 150 mg bid
10.5% and 10.0% FEV1 improvement vs. placebo
3,000 Worldwide Patients

F508del Through 24 weeks Lumacaftor - Kalydeco 400/250 mg
2.6% and 3.0% FEV1 improvement vs. placebo
26,000 U.S. + EU Orkambi Patient Potential

These are the FEV1 (forced expired volume) numbers that other companies will be considering as significant, to improve current therapy for CF patients.  The side effect profile was mild, as a high percentage of patients completed the Vertex clinical trials.  The annual wholesale acquisition cost (WAC) will be priced at around $259,000 per patient for the Orkambi combination.  Thank you for reading.


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.

AVP-786 is Concert Pharmaceutical's deutered enhanced version of AVP-923.


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