Wednesday, May 4, 2016

What is CTP-543

Concert just announced, that they are bringing CTP-543 into clinical trials.  CTP-543 is the deuterated version of the currently FDA approved drug Ruxolitinib, produced by Incyte Pharmaceuticals, and approved for the indications of myelofibrosis and polycythemia vera.  CTP-543 will be tested in a new indication known as Alopecia Areata.  The phase 1 clinical trial will start in the second quarter of 2016.  The patent for CTP-543 runs until June 2032 in the USA. 

Concert mentioned in their press release that academic studies have been completed with Ruxolitinib for Alopecia Areata.  I believe they were referring to this phase 2 study by Columbia University that shows completed.  The dosage was 20mg, twice daily up to 24 weeks, NCT01950780Also, a nice press release from Columbia University that gives quite a few details about JAK inhibition, and the effect on Alopecia Areata here, FDA-approved-drug-restores-hair.

First Quarter Conference Call
During the first quarter conference call, a question was raised at the 29:00 minute mark regarding the safety profile observed in myelofibrosis, against what has been observed in healthy patients, thus far.  In myelofibrosis, thrombocythemia was the number one observed adverse effect.  The CEO stated that in healthy patients the side effect profile was rather benign in comparison.  This leaves me to believe that the company may have obtained access to the above Columbia University study that was dosed with 20 mg of Ruxolitinib twice daily, for up to 24 weeks.

Bottom Line:  I like that Concert is seeking an unmet need with a previously FDA approved drug for other indications.  They should be able to utilize the 505(b)(2) pathway to get approval sooner than normal with less expense.  I expect that CTP-543 will be dosed once daily, and possibly with a lower dose, than what Ruxolitinib was used in the Columbia University phase 2 clinical trial, completed recently.  Thank you for reading. 


Tuesday, May 3, 2016

Nuplazid Gets FDA Approval

Acadia Pharmaceuticals Nuplazid, was FDA approved on Friday for the indication of Parkinson's Disease Psychosis, and will carry a black box warning as seen below.
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. NUPLAZID is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis.
QT Interval Prolongation: NUPLAZID prolongs the QT interval. The use of NUPLAZID should be avoided in patients with known QT prolongation or in combination with other drugs known to prolong QT interval including Class 1A antiarrhythmics or Class 3 antiarrhythmics, certain antipsychotic medications, and certain antibiotics. NUPLAZID should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and presence of congenital prolongation of the QT interval. 
Now it's on to commercialization. We initially came up with a valuation for Acadia stock and wrote about it here.  Future Value of ACAD.  After that assessment the company had two secondary offerings that brought their share count to around 130m shares outstanding.  So what is the stock worth today based on the expected selling price of the drug, and the new share count.  We are using the same calculations as in September 2013, but with a different share count and price to consumer.
I am going to refer to different analyst revenue prediction reports and Acadia presentations to draw further conclusions on future revenue based on the overall US Parkinson's Disease Psychosis market.
1,000,000 With Parkinson's in US.
30% develop PDP or Parkinson's Disease Psychosis at some point.
300,000 total patients with PDP.
50% penetration rate of those with the psychosis.
150,000 the actual number treated for PDP with Nuplazid out of 1 million Parkinson's total victims.
$37.00 = retail price per tablet per day of treatment, higher than the Abilify retail pharmacy prices.  Equates to around $13,000 per year. 
$20.40 = Sales to Acadia per 34 mg tablet before all the wholesale roughly (35%) and retail (35%) markups prior to being sold to the consumer.
$7,344 = Per patient ACAD annual revenue, ($20.40 per day * 30 days * 12 months)

$1,101 billion = Total peak revenue to ACAD, (150,000 patients * $7,344 annual revenue to ACAD) U.S. Parkinson's Disease Psychosis only.

The average biotechnology acquisition is a market capitalization of 3-4 times peak sales. So, at four times peak sales from Nuplazid for U.S. PDP, we calculate a share price by taking peak annual revenue of $1,101 billion * 4 =  $4,404 billion market capitalization / 130M (approx. shares outstanding) = $33.87 stock price. The stock is currently trading around $33.00 per share, or 4x peak sales.

At this time we are assigning zero revenues for Alzheimer's Disease Psychosis, and Alzheimer's Disease Agitation, as the current label specifically relates to Parkinson's patients who are experiencing psychosis, and revenues based in the US only. 

Bottom Line:  We currently do not hold shares of ACAD, and believe that the stock is fully valued at current prices.  Thank you for reading. 


Thursday, April 28, 2016

CTP-656 Progressing Nicely

Concert just completed a phase 1, multiple ascending dose study of CTP-656, with placebo.  Some additional value can be found in the following press release from Concert regarding this study.
Pharmacokinetics:   "Across all doses, the average plasma half-life of CTP-656 was approximately 18 hours at steady state.  CTP-656 showed a dose-proportional increase in exposure with repeated dosing for the 75 mg and 150 mg doses. The 225 mg dose group showed higher than dose-proportional exposure."

CTP-656 in the previous phase 1 oral solution trial, showed a half-life around 15 hours.  So it looks like an improvement was seen with the solid dosing of CTP-656 over a seven day study, as it pertains to half-life.  CTP-656 was well-tolerated and it's safety profile was comparable to that of Kalydeco. 

Also within the press release "We are pleased to see that full bioavalability of CTP-656 was retained even with a low fat meal," stated Dr. Cassella. 

Additional interest is that the company has announced that they will be participating in 39th European Cystic Fibrosis Conference being held June 8-11, 2016 in Basal Switzerland.  Thank you for reading.


Sunday, April 24, 2016

Inter Partes Review and Drug Patents

There is an important case (Couzzo Speed Technologies V. Lee) scheduled for Monday April 25th, regarding a prior Inter Partes Review IPR, and a subsequent challenge to that outcome, which will be heard in the Supreme Court.  The patent in question has nothing to do with drugs, but an important precedent may be set with the case result.  The questions to be addressed:
1.  May the patent trial and appeal board apply the broadest reasonable interpretation of patent claims during an inter partes review hearing?
2.  Is the patent trial and appeal use of inter partes review judicially reviewable?

Companies such as Auspex, and Concert Pharmaceuticals, both which have a broad pipeline of deuterated patented drugs, may benefit from the inter partes review process, as a way to resolve potential patent issues should one occur.  An IPR, is intended to be quicker, more efficient, and less expensive for post-grant patent challenges.  Thank you for reading.


Friday, April 22, 2016

Concert Pharmaceuticals: Bullish Technical Pattern

Charts (technical analysis) are fun to look at, and are a shorter term traders bible in many cases. Concert made a nice upward move today, with more than twice the average daily volume.  Either investors have found these lower prices very reasonable to purchase shares prior to any significant company news, or traders (short term) have found a very bullish setup from the charts.  Below are a couple of to enlarge.
The above chart is called a Point and Figure Chart (P&F).  The pattern above has what is called a quadruple breakout pattern to the upside, which is very bullish for the short term.  Perhaps this has caught the eye of astute traders as they see higher prices potentially ahead based on this breakout pattern.
This next chart above is a daily, with volume indicated at the bottom as very strong, at more than twice the recent average.  CNCE closed right at prior resistance in the high 14's area.  A clean break and close above that resistance line would exhibit another sign of bullishness, from a technical analysis point of view.  Thank you for reading.


Monday, April 18, 2016

UniQure Upcoming Catalysts

UniQure (QURE) finished their fourth quarter conference call recently.  The company has advanced AMT-060 for Hemophilia-B, and has begun dosing two individuals in the higher dose cohort group as of 4/14/16. 

Clinical Data:  
*Data for 5 patients in the low dose cohort group is expected in Q2 2016.  Early top line results on 2 patients data was released on 1/7/16, showing F9 expression of 5.5% / 4.5% at 20/12 weeks follow-up post treatment. 
*Data for the high dose cohort group to potentially be released by year end 2016.  

UniQure is involved with other programs, but the Hemophilia-B program is a very good opportunity, with near term data readouts by the year end.  Thank you for reading.  

Wednesday, April 13, 2016

NMDA Receptor Modulators for CNS Disorders

We originally wrote about this topic here NMDA Receptor Modulators for Depression. There are now several companies interested in bringing a variety of NMDA drugs into the clinic, either as mono-therapy or coupled with enhancers.  Let's have a look at some of the companies, their drug, and indications that they are targeting.

Avanir:  Otsuka
AVP-786  Dextromethorphan + Quinidine
Ph 3  Agitation in Alzheimer's Disease
Ph 2  Residual Schizophrenia
Ph 2  Major depressive disorder (adjunct)

Axsome: AXSM
AXS-05  Dextromethorphan + Bupropion  
Ph 3 Treatment resistant depression
Ph 1 Agitation in Alzheimer's Disease

Cerecor:  CERC
CERC-301  NR2B Specific NMDA antagonist oral
Ph 2 Major depressive disorder (adjunct)

Naurex:  Allergan
NMDA receptor partial agonist with selective properties
Ph 2 NRX-1074  IV
Ph 1 NRX-1074 Oral
Ph 3 GLYX-13 (Rapastinel) Weekly IV Major Depressive disorder

Vistagen:  VSTA
AV-101  NMDA selective antagonist oral
Ph 2 AV-101 Major depressive disorder 

Over the next couple years, we should see some meaningful clinical readouts from some of these companies.  Potentially NMDA drugs may provide for a more efficacious and safer, sustainable therapy, aside from current antidepressants for some of the above indications. Thank you for reading.

Contact:   586-431-8000

Friday, April 1, 2016

Nuplazid: FDA Safety Label

Acadia Pharmaceutical's completed their advisory committee meeting (ADCOM) on March 29th.  After receiving a positive review from the committee, the next issue to be determined will be the box safety labeling.  Below is wording from the FDA Breifing Documents.

This sample of patients compared to their appropriate control group demonstrates more than double the risk of serious adverse events (SAE) in the PDP6 trial population (Observed Risk of death or SAE is 2.38 times greater [95% CI 1.00 to 5.73, p=0.05]) for 34 mg pimavanserin vs. placebo.

Let's have a look at a mortality black box label that many of the anti-psychotics currently carry, including the newly approved Rexulti (brexpiprazole) for acute Schizophrenia and as adjunct for Major Depression Disorder. 

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.

I think the above is a likely label scenario for Nuplazid.  In addition, the FDA may advise Acadia to run a phase 4 confirmatory clinical trial as part of approval.  

Bottom Line:  Acadia has completed some nice pre-marketing research for Nuplazid, and found that a black box warning label was not high on the list of doctors when deciding whether or not to prescribe this drug.  In other words, they would still prescribe the drug, as the best alternative for an unmet need regardless of the safety label, as Nuplazid has shown in clinical trials to not contribute to motor impairment.   May 1st, is the scheduled day that the FDA should approve the drug.  Thank you for reading. 


Thursday, March 31, 2016

Nuplazid: FDA Briefing Documents

Acadia Pharmaceuticals drug Nuplazid, for Parkinson's Disease Psychosis (PDP) should get FDA approval by May 1st.  The link to the documents are here FDA AdvisoryCommitteeThe Advisory Committee (ADCOM) will meet on Tuesday to give their opinion on the efficacy and safety of the drug.  Nuplazid will be the only drug approved to treat the disease, and will have patent protection to 2028, prior to any Hatch-Waxman additions.  The labeling for the drug will be revealed upon approval.  I am expecting a black-box label at that time.  Thank you for reading.


Saturday, March 19, 2016

Otsuka's Commitment to AVP-786

Otsuka a focused CNS company, and the producer of Abilify, purchased drug AVP-786 for $3.5 billion through their acquisition with Avanir on November 13, 2014.  To get a sense of just how committed the company is to AVP-786, we have to look at the clinical trials that have started since the acquisition, and compare that to the number of clinical trials the company has started with another Otsuka drug Brexpiprazole, deemed the second generation drug of Abilify, that would compete in the indications similar to AVP-786.

Clinical Trials Started Since Acquisition
(3)  Alzheimer's Agitation - U.S.        phase 3
(1)  Residual Schizophrenia                phase 2
(1)  Alzheimer's Agitation - Japan     phase 3

Ongoing Trials With AVP-786
(1)  Treatment Resistant Major Depression Disorder  phase 2

New Otsuka Clinical Trials with Brexpiprazole
The company was previously in clinical trials prior to the acquisition of AVP-786, for Alzheimer's Agitation, MDD, and Schizophrenia as co- partner with Lundbeck.  But has not initiated anything new since agreeing to acquire AVP-786 from Avanir late 2014.  

Bottom Line:  Some significance into the timing of initiating clinical trials, may help us identify a companies priority in their clinical pipeline.  Thank you for reading. 


Saturday, March 12, 2016

N91115 CFTR Stabilizer

Nivalis Therapeutics (NVLS) is a clinical stage company that specializes in treatments for Cystic Fibrosis, with it's lead candidate stabilizer N91115.  N91115 is the only clinical stage candidate designed to stabilize CFTR (Cystic Fibrosis Transmembrane Conductance) inside the cell and at the cell surface.  The company expects N91115 to be complimentary to existing and future CFTR modulators, and is currently in a phase 2 clinical trial with approved drug Orkambi for people with the F508del mutation.  The trial is designed to see what effect N91115 may have as addition to what Orkambi achieves.  Below is the clinical trial and efficacy goals the company expects from this trial.

N91115 in Patients With CF Homozygous for the F508del-CFTR Mutation.
- The company is targeting a 5% improvement, up and over Orkambi's 3% range in ppFEV1.
- Readout of data will be 2nd half 2016.
- First readout for a triple with three distinct therapies, for F508del homozygous patients.
- Have received Orphan and Fast Track designations from FDA in 2016.
- The patent for N91115 runs until 2031 at the very earliest.

The company plans to couple N91115 with leading potentiator's to potentially increase efficacy for combo therapy.  Either Kalydeco, CTP-656 or GLPG1837 are the current group of potentiator's that hold the most promise to date.  Thank you for reading.


Sunday, March 6, 2016

QBW251 Clinical Trial Terminated

We have been updating Cystic Fibrosis clinical trials over the past year.  Our last update was here Cystic Fibrosis Clinical Studies - Update.  Novartis was in a phase 2 for healthy and CF since 2014, and in February terminated the trial prior to completion, and readout.  The link is NCT02190604.  QBW251 was one of a few potentiators that are being tested for efficacy. Perhaps Novartis may see some value in potentiator CTP-656, once Concert completes their phase 2 clinical trial sometime in 2017.  Thank you for reading.


Friday, March 4, 2016

CNCE Fourth Quarter Conference Call

Was held on Tuesday March 1st.  The highlight was Cystic Fibrosis drug CTP-656, solid dosing of 150 mg in comparison with FDA approved Kalydeco.  CTP-656 was the highlight, because there was not any other significant news released regarding their pipeline.
In September the company announced the results of phase 1 oral suspension dosage of 150 mg of CTP-656.  It compared extremely well against Kalydeco on a pharmacokinetic basis as exhibited in this post CTP-656 Phase 1 Single Dose Comparison.  Let's see how the comparison held up in the solid oral dosing of 150 mg phase 1 clinical trial with CTP-656 that the company released on Tuesday, compared to the September phase 1 oral suspension 150 mg, in healthy volunteers, both compared against Kalydeco.

Oral suspension                  ng/mL                      Tablet 
9/15/2015                                                                      3/1/2016
AUC 24hr   +2.8x            27289      22466              +2.8x
T 1/2             +1.3x              15.00        14.92              +1.4x
Cmax           +2.0x               2212         1803              +2.5x
C 12hr          +3.2x              1306           999               +2.9x  
C 24hr         +4.2x                 712            557              +3.6x

 X = number of times greater CTP-656 has shown against Kalydeco in the two crossover studies.  The second phase 1 study with solid tablet, displayed similar results as the first phase 1, oral suspension clinical trial.

The company is currently testing CTP-656 in a multiple ascending dose clinical trial, designed to find two dosages, to be used in a phase 2 clinical trial for Cystic Fibrosis people later in 2016.  The dosing range in the current trial is from 75 mg to 225 mg.  
Kalydeco Dosage:  Adults and pediatric patients age 6 years and older: one 150 mg tablet taken orally every 12 hours with fat-containing food.  Concert intends to dose once daily in the upcoming phase 2 clinical trial. Another important finding was that the parent drug of CTP-656 exhibited greater exposure than Kalydeco in the first phase 1 results, holding the potential for increased efficacy for CF people.  Thank you for reading.  


Monday, February 29, 2016

Acadia Pharmaceuticals ($17.26)

We started back into Acadia Pharmaceuticals today, after being extremely patient, since selling shares the morning that the CEO announced resignation in March 2015.  We wrote about that here, Acadia CEO Resigns - Effective Immediately.  Fundamentally not much has changed with their lead drug Nuplazid.  They have an FDA potential approval date of May 1st, 2016.  A list of important reiterating facts are below. 

-Nuplazid will be the only approved drug for Parkinson's Disease Psychosis (PDP).
-Their patent runs through 2028 (prior to any Hatch-Waxman addition) in the U.S. and 2025 in the EU.  So approximately 12 years of exclusivity U.S., unless a new drug comes to market during that time frame.  
-The drug could receive premium pricing up to around $15,000 per year for PDP patients, and be seen as a cost savings for family and the medical system.
-Nuplazid may have the potential to treat Alzheimer's Agitation, which at present is another unmet need, as the company plans to run a phase 2 clinical trial mid 2016.  
-The drug could potentially be used as maintenance therapy for schizophrenia patients, as a safer alternative to current anti-psychotics.  
-The company currently has around 124 mn shares outstanding.
-Their cash position is around $500 mn.  
-ADCOM (advisory committee) will meet on March 29th.

Bottom Line:  A weak overall market and biotechnology in particular, has allowed us to buy back shares of ACAD at reasonable prices.  I am expecting a black box warning label upon approval around May 1st, but do not believe that will have a major impact on the success of Nuplazid for PDP.  Thank you for reading. 


Tuesday, February 16, 2016

Galagapos Advances GLPG1837 for CF

GLPG1837 has advanced into a phase 2 clinical trial for Cystic Fibrosis people with the G551D, or S1251N class III mutation.  This will be the first of two, phase 2 clinical trials testing the drug in CF. The Galagapos press release is here Galagapos starts SAPHIRA Phase 2 study.  In a previous post we compared the phase 1 clinical trial results of GLPG1837 and Concert's CTP-656 side by side, CTP-656 & GLPG1837 Drug Comparison.  The drug will be dosed twice daily, and the trial should be complete by the end of 2016.  Thank you for reading.