Saturday, May 28, 2016

Patient-Focused Drug Development Initiative

The Food and Drug Administration (FDA) announced that Alopecia Areata (AA) was one of eight diseases selected to participate in the Patient-Focused Drug Development Initiative (PFDDI) 2016-2017.
 Meetings Planned for FY 2016 – 2017
    • Psoriasis: March 17, 2016
    • Neuropathic pain associated with peripheral neuropathy: June 10, 2016
    • Patients who have received an organ transplant: September 27, 2016
    • Alopecia areata
    • Autism
    • Hereditary angioedema
    • Neuropathic pain associated with peripheral neuropathy
    • Sarcopenia
The FDA will publicly meet with patients who suffer from debilitating conditions without adequate treatment options in the hopes of better understanding their wants and needs in the drug development process.  The meeting will take place in 2016-2017, specific date has not been determined yet.  This can only have a positive impact for disease victims of Alopecia Areata, as the FDA will get a first hand patient perspective of that disease.
CTP-543 is currently in a phase 1 clinical trial for AA, and will commence an efficacy phase 2 trial, first half of 2017.  We have spent extra time evaluating the disease, drug, and competition in regards to AA.  Concert management has taken the initiative to bring CTP-543 into clinical trials for this disease, which has a very high probability of being the first FDA approved drug for AA.  Next, we will examine the potential market for this indication.  Thank you for reading.


Thursday, May 19, 2016

CTP-543 Phase 1 Initiated

Concert Pharmaceuticals has begun dosing in a phase 1 clinical trial with 80 healthy volunteers to assess safety and pharmacokinetics (PK).  From the company press release below.
“Alopecia Areata is a disease that can have devastating effects on patients but which currently lacks approved and effective therapies. We are pleased to broaden Concert’s pipeline of clinical drug candidates with the advancement of CTP-543 into clinical testing. CTP-543 is another example of how we have applied our novel deuterium platform to create medicines that represent new treatment options,” said Roger Tung, Ph.D., President and Chief Executive Officer of Concert Pharmaceuticals. “Recent advances in our understanding of alopecia areata biology, combined with patient data from several investigator-initiated studies, give us confidence that CTP-543 has potential to be an effective treatment. We hope to move this program quickly through Phase 1 evaluation in order to initiate efficacy studies in patients with alopecia areata next year.”

Important questions worth finding the answer to, regarding the competition.

Q)  Which type of JAK inhibitor did Alcaris Therapeutics buy the rights, from Columbia University (Vixen Pharmaceuticals)? Alcaris Pipeline.
A)  It is a JAK3, and believe this is the patent, WO2013149194A that Columbia University through Vixen Pharmaceuticals, sold to Alcaris Therapeutics.

Q)  Has the drug been tested yet?
A)  The drug may be similar to Tofacitinib another JAK3 inhibitor, which has shown promise for AA in mice, and is currently in human trials.  The Alcaris website shows that their AA drug A-201 and A-203 (oral and topical) as being in pre-clinical. 

Dr. Tung, Concert CEO had mentioned that CTP-543 is a JAK1,2 inhibitor, and that the JAK 2 was more important to Alopecia Areata reversal. 

CTP-543 Patent 2032
Ruxolitinib Patent 2026 (before any extensions)

CTP-543 has the potential to advance fairly quick through clinical trials.  They will be dosing as once daily in the phase 1 clinical trial.  Thank you for reading. 


Friday, May 13, 2016

Alopecia Areata - An Unmet Need

Concert has announced their latest candidate to enter clinical trials for Alopecia Areata (AA), with drug CTP-543.  AA can be defined as a common autoimmune disorder that commonly results in unpredictable hair loss.  It affects 2% of Americans (roughly 6.5 million people) and can affect anyone regardless of age and gender.   Below are a some clinical trials that are in progress or completed, outside of the clinical trial that Concert plans to run in the second quarter of 2016.
This clinical trial will be using Tralokinumab subcutaneous injection every two weeks. 
This trial will be using an ointment twice daily.
This trial will be using INCB018424 Phosphate Cream for 24 weeks. 
This is a pilot study with Apremilast, oral 30 mg twice daily.
Phase 2 Secukinumab (300mg) subcutaneous once weekly.
Phase 2 Abatacept (125mg) subcutaneous once weekly.
Phase 2 Tofacitinib oral (5-10mg) twice daily.

The company plans to run a phase 1 clinical trial with an oral CTP-543, and potentially once daily in efficacy trials.  Thank you for reading. 


Monday, May 9, 2016

CNCE Quarterly C.C.

Held their first quarter conference call on May 5th.  Mixed news regarding the company was released.  The good news, is that they have released the details of their next drug candidate for clinical testing, known as CTP-543 for Alopecia Areata, or hair loss, which looks promising.  The drug will enter a phase 1 clinical trial in this second quarter of 2016. 
The other not so great news, was regarding CTP-656 a potentiator for Cystic Fibrosis patients.  The company announced a slight delay, to the fourth quarter of 2016 to run a phase 2 efficacy clinical trial.  Expectations were potentially for mid year of 2016.  The delay was due to the FDA requesting an additional lower dose to be used in the clinical trial.  Postponement is due to Concert gaining the manufacturing capabilities for that additional dosage.  Time, and getting to market is a critical concept when it comes to drug development.   Thank you for reading.


Saturday, May 7, 2016

Nuplazid Priced at $23,400 / Year

Based on the Acadia Pharmaceuticals first quarter conference call, pricing for the recently approved Nuplazid for Parkinson's Disease Psychosis (PDP), will be around $23,400 per year, wholesale acquisition cost (WAC), much higher than we anticipated.  We previously relied on company information of around $13,000 per year for Nuplazid. The adjustment higher makes a large valuation difference, and puts the recent price of ($27.50) rather cheap based on a potential buyout scenario. 

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.
$65.00 = WAC price per tablet per day of treatment.  Equates to around $23,400 per year. 
$32.50 = Sales to Acadia per 34 mg tablet after discounts various distributors.
$11,700 = Per patient ACAD annual revenue, ($32.50 per day * 30 days * 12 months)

$1.755 billion = Total peak revenue to ACAD, (150,000 patients * $11,700 annual revenue to ACAD) U.S. Parkinson's Disease Psychosis only.  If applying a buyout scenario of four times peak revenue = $1.755 x 4 = $7.020b valuation / 130k (shares outstanding) = $ 54.00 share price. 
It would take 85,470 (PDP) patients treated with Nuplazid to achieve $1 billion in revenue.  Acadia did pre-marketing, and estimated around 11,000 Parkinson's Disease doctors in the U.S.  Each doctor would have to treat 7.77 (PDP) patients with Nuplazid to achieve the $1b in revenue.

Thank you for reading.


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.

Bottom Line:  I like that Concert is seeking an unmet need, with a drug that has previously been FDA approved, but 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.


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.