CRISPER-Cas9

CRISPR-Cas9 is a new gene-editing technology that has gained enormous press the last few years for it's accuracy.  The science is being used to address the underlying genetic causes of human disease. The advantages seen thus far, is that it is faster, less expensive, and more accurate than prior gene-editing technology.  CRISPR-cas9 enables geneticists and medical researchers to edit parts of the genome, by cutting out, replacing or adding parts to the DNA sequence.  There are a few publicly traded companies.  The companies include the following. 

Intellia Therapeutics:  NTLA
Editas Medicine:  EDIT
Cellectis:  CLLS
Crispr Therapeutics: CRSP

Bottom Line:  The above names are worth following, and learning more about the science of CRISPR-cas9 gene-editing.  Thank you for reading.                

Kalydeco for G551D

Vertex Pharmaceutical's Cystic Fibrosis drug Kalydeco has been FDA approved for people with the G551D mutation since 2012.  Kalydeco has been proven very effective for these patients, as the results from clinical trials reveal.  Below (Vertex 2012 presentation) is sweat chloride, and FEV1 results from the phase 3 G551D clinical trial that led to FDA approval.

 

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The results above at 24 and 48 weeks show extremely sustainable efficacy, versus placebo. Other improvement considerations, would be the dosing of once daily to improve adherence, and bio-availability for oral consumption, with  low or moderate fat containing food.  Kalydeco is currently dosed 150 mg every 12 hours, and prescribed to be taken with fat-containing food. Thank you for reading. 

 

Contact: 586-431-8000                            

VX-661 Corrector for Cystic Fibrosis

Vertex is currently involved with four phase 3 cystic fibrosis clinical trials for people with the F508del mutation, and the combination of potentiator Ivacaftor + corrector VX-661.  Today they gave an update regarding one of the four phase 3 clinical trials that are in progress.  The complete press release is here Vertex Provides Update on Ongoing Phase 3 Program for VX-661 in Combination with Ivacaftor for the Treatment of Cystic Fibrosis. 

                 

GLPG2222 and GLPG2451 for Cystic Fibrosis

Galapagos updated their cystic fibrosis program.  The significant news today, was that the company was expected to test potentiator GLPG2451 with corrector GLPG2222, from a press release on June 15th.  Today, they have not made up their mind in full whether they are going to do a combination with 2451 and 2222, as potential for part of a triple combination.  GLPG2451 phase 1, will have a slight delay with results in early 2017, from expected end of 2016.   Thank you for reading.                                             

Ruxolitinib Five Year Safety and Efficacy

Below is a press release from Incyte Corporation with data that was presented at ASCO early June. 

- COMFORT-I data demonstrate that treatment with Jakafi resulted in a 31 percent reduction in the risk of death and sustained durable spleen volume reduction in patients with MF
- These five-year data support previously published findings for Jakafi

SAGE-547 for Postpartum Depression

Sage Therapeutics (SAGE) stock soared higher by 37% on the companies phase 2 data release, for the indication of severe Postpartum Depression or PPD.  SAGE-547 has a differentiated mechanism of action (moa), and clean safety profile.  From their press release today.  

"SAGE-547 achieved primary objective with a significant reduction in HAM-D total score compared to placebo at 60 hours (p=0.008).  Baseline mean HAM-D scores were severe (28.1 for SAGE-547; 28.8 for Placebo), SAGE-547 showed reduction in HAM-D of greater than 20 points at 60 hours.  Improvement was 12 points greater vs. placebo.  Improvement maintained through 30-day follow-up (p=0.01)."

Quick Facts:
Shares Out 32M
Market Cap:  $1.2b
Cash:  150m
Patent:  2034

These results in PPD, signal the potential for other CNS uses.  SAGE-547 works very rapidly, and maintained the results through the 30 day follow-up period.  Thank you for reading.
 

AXS-05 A Novel Mechanism of Action

Axsome Therapeutics (AXSM) is a company working to bring drugs into the clinic, and through FDA approval for the indications of pain, and CNS disorders.  We are focusing on their unique mechanism of action CNS drug, AXS-05 at this time.  AXS-05 combines dextromethorphan (DM), and bupropion (BP), and is targeting the indications below. 

• Treatment Resistant Depression Disorder:  phase 3 initiated NCT02741791.
• Agitation in Alzheimer's disease phase 2/3 planned end of 2016.

Quick Facts:
Share Out:  19M
Market Cap:  135M
Cash:  44M
Patent:  2034

Like other drug development companies, Axsome has identified Dextromethorphan as a potential treatment for CNS disorders, and is using bupropion as an inhibitor, with potential increased efficacy affect.  I  expect the company to raise cash soon through a secondary offering, to fund future clinical trials.  Thank you for reading.

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.   

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.