Agitation in Alzheimer's Disease - An Unmet Need

There is not an FDA approved drug for Agitation in Alzheimer's disease.  This unmet need has seen an increase in clinical trials recently.  Below are a few companies that are either in, or entering into a clinical trial for agitation in Alzheimer's Disease with various drug candidates.

AVP-786                                      
Avanir (owned by Otsuka) is running two phase 3 clinical trials for the treatment of agitation in patients with dementia of the Alzheimer's type NCT02442765, NCT02442778.
In a phase 2 clinical trial with the primary endpoint being the NPI Agitation / Aggression Domain, a stastistically significant (p=.001) was achieved with the non-deuterated version of called AVP-923. The results and publication of that trial is here Avanir JAMA Publication.  The drug was generally well tolerated. The current clinical trials will complete July 2018.  In four years from the beginning of 2016, AVP-786 could be the first FDA approved drug for this indication, and reach commercialization in 2020.  The patent extends until 2030 in the U.S., and 2028 in the EU.

AXS-05                                           
Owned by Axsome Therapeutics, is a combination of Dextromethorphan / Buproprion.
The company expects to enter a clinical phase 2/3 trial in 2016.  
7-21-17: Axsome has now entered into a Phase 2/3 Dementia via Agitation with potential readout first half of 2020.  

4-27-20: Results of phase 2/3, CMAI p=0.010

Brexpiprazole                           
Owned by Otsuka, with a revenue sharing agreement with Lundbeck.  There are two phase 3 clinical trials for patients with agitation associated with dementia of the Alzheimer's type currently running NCT01862640, NCT01922258, with a completion date of around June 2017.  This drug could prove effective for this indication, but the drug, like it's predecessor Abilify, has a black box label.  Also, Otsuka chose to buy drug AVP-786 (via Avanir acquisition) for this indication, while two clinical trials with Brexpiprazole were over a year into progress.       
1-9-2017:  Both clinical trials are now active, but not recruiting participants.  There will be 12 weeks plus a 30 day follow-up period.  Participants that have completed the 12 weeks double blind trial, are eligible to enroll in a 2 month observational study. 
6-7-2018: Otsuka is taking another try with Brexpiprazole with this US only clinical trial to complete in December of 2020 NCT03548584.

Lexapro (Escitalopram)                           
4-17-2017: This phase 3 clinical trial with 15mg Lexapro (escitalopram) is being sponsored by John Hopkins School of Public Health (JHSPH) for patients with agitation associated with Alzheimer's disease. The clinical trial is here NCT03108846, and has a completion date of August 2022. This is the first of potentially two phase 3 clinical trials that may be required by the FDA prior to filing an NDA if the drug is effective.

ITI-007                                     
Intra-Cellular Therapies is planning on a phase two clinical trial in the first half of 2016 with ITI-007.  The company does not have any significant findings with the drug for this indication in prior clinical trials.  ITCI ran a phase 1/2 clinical trial primarily for cognition, as there were no patients that exhibited agitation at baseline.  The press release is here Intra-Cellular.  
6-28-16:  Intra-Cellular has now entered into a phase 3 clinical trial for Alzheimer's patients experiencing agitation here NCT02817906 with readout August 2018. Results: Terminated study.

Pimavanserin                        
12-12-2016:  Acadia has now entered into a phase 2 clinical trial for Alzheimer's patients experiencing agitation with their 5HT2A Pima here NCT02992132, with readout June 2019.
12-20-2016:  ACAD releases top-line phase 2 ADP data.  But does not break out the sub-category of the primary endpoint NPI-NH, such as agitation and aggression.  The company announced in their conference call, that agitation and aggression was no different than placebo group.

Bottom Line Update 12-21-2019:  AXS-05 and Escitalopram, are the two drugs that hold the most promise for their respective clinical trial for Alzheimer's Agitation. AXS-05 should have phase 2/3 readout in the first half of 2020, and Escitalopram in 2022. Thank you for reading.    
 

Contact: 586-431-8000

Inter Partes Review - The Verdict Is In

We originally wrote about this here Inter Partes Review .  The verdict of the Supreme Court supports the Inter Partes Review processes.  A summation of the inter partes review is below.
In Court Litigation, which is how patents were typically challenged in the past, patents are presumed to be valid and understood by their "plain and ordinary meaning".  But in these new inter partes reviews, as established by the administration through, patents are interpreted more broadly.
This could be a positive for companies like Concert in that it could limit the legal delaying options that large pharmaceutical companies could use to protect their patent.  Thank you for reading. 
 

GLPG2222 and GLPG2451 for Cystic Fibrosis

In their most recent press release http://www.glpg.com/press-releases, dated June 15th, 2016, Galapagos (GLPG) reported the following. 
 
Galapagos reports that GLPG2222, the first early binding (C1) corrector, passed the safety hurdle in Phase 1 studies in healthy volunteers. GLPG2222 was tested in single ascending doses up to 800 mg, and in multiple ascending doses up to 600 mg qd for 14 days in a double-blind, randomized, placebo-controlled study. The candidate drug was shown to be well-tolerated and no emerging safety signals observed in the dose range studied. Absorption of GLPG2222 was rapid and favorable. Pharmacokinetics of GLPG2222 support once-daily dosing regimens to be explored in further development. Corrector GLPG2222 will be tested next with potentiator GLPG2451 in healthy volunteers. Corrector GLPG2222 is one of the potential modulator compounds for the triple combination therapy that Galapagos and AbbVie are developing, aiming to address 90% of all CF patients.

The corrector GLPG2222 is dosed once daily, and will now be tested with the potentiator GLPG2451 which is also a once daily dosing, in a phase 1 clinical trial for healthy volunteers, with readout by the end of 2016.  Thank you for reading. 

 

CTP-656 Multiple Dosing Phase 1 Results

Concert presented at the European Cystic Fibrosis Society today, and presented phase 1, multiple dosing with solid tablet results, for CTP-656 in healthy volunteers.  We initially were given top-line results in April, so there were not many surprises today.  The important information to consider from this completed phase 1 clinical trial with 7 days of dosing, is the following below under fed conditions.

CTP-656 to M1 Ratios
Single dose CTP-656 to M1 ratio = 1.5
7th day dose CTP-656 to M1 ratio = 1.8

With CTP-656, the highest exposure is to the most active species (parent). 
With Ivacaftor, the highest exposure is to the less-active metabolite (M1) (20% active relative to Ivacaftor).

Next step for Concert and CTP-656, is to initiate a phase 2 efficacy clinical trail by the end of 2016.  Thank you for reading.

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.  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.

D-Ivacaftor US Patent 9,181,192 B2

This is a new d-ivacaftor patent listed on Concerts website.  This looks like an add on to the original US patent regarding d-ivacaftor for Cystic Fibrosis, except that it has a section that relates to COPD (chronic obstruction pulmonary disease).  The added section of the patent is below.

15. A method of treating COPD in a subject comprising administering to the subject a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, wherein the compound of Formula I has the following structural formula:

Concert is currently assessing the possibility of entering clinical trials for COPD, which would be an extremely large potential market to pursue.  The patent runs to 2032.  Thank you for reading.
 

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.”

Aclaris Therapeutics acquired the rights, Aclaris Pipeline of a JAK inhibitor, and this is the patent, WO2013149194A that Columbia University through Vixen Pharmaceuticals, sold the rights to Aclaris Therapeutics.

CTP-543 Patent: 2032
Ruxolitinib Patent: 2028

Thank you for reading. 
 

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.
 

Nuplazid Gets FDA Approval

Acadia Pharmaceuticals Nuplazid, was FDA approved on Friday for the indication of Parkinson's Disease Psychosis, and will carry a warning as seen below.
 

IMPORTANT SAFETY INFORMATION AND INDICATION

INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
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. 

 
Bottom Line:  Now it's on to commercialization.  Thank you for reading. 

 

CTP-656 Multiple Ascending Dose Study

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. Multiple Ascending Dose Phase 1.

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.

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.

 

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)

JNJ / Janssen
Esketamine  intranasal
Phase 3 adjunct with anti-depressant for TRD

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.