Sunday, January 31, 2016

CTP-730 Advancing

Celgene held their fourth quarter conference call on Thursday.  This is what Scott Smith, head of Global Inflammation and Immunology had to say regarding Otezla, and the 2016 pipeline of indications that Otezla could potentially get approved for.

"In 2016, we should see continuing flow of data for OTEZLA.  As mentioned earlier in the year at the JP Morgan Conference, we recently received the two year radiographic data from the Phase III Ankylosing spondylitis study.  Although, the study did not meet its primary endpoint, we are very encouraged by the data which show a lack of progression of disease for a majority of patients.  In addition to seeing these data in the major medical meeting in 2016, we also hope to get data from the Phase II proof-of-concept studies in atopic dermatitis, and also colitis, as well as data to support our QD formulation".

Bottom Line:  Looks like Celgene liked what they saw in the phase 1 clinical trial that Concert completed in 2015.  CTP-730 has the potential for once daily, and has an extended patent to 2030.  Thank you for reading.  

Saturday, January 23, 2016

Galapagos Updates Cystic Fibrosis Clinical Progress

Galapagos (GLPG) and AbbVie (ABBV) developed a partnership aimed at treating 90% of the Cystic Fibrosis population with a triple combination drug therapy.  The triple combo will involve a potentiator and two correctors for patients with the F508del mutation.  Under the agreement dated back to September of 2013, Galagapos leads discovery and development through phase 2, shares Phase 3 responsibility with AbbVie.  Below is a list of potential candidates that GLPG will be taking to the clinic for further exploration. 

GLPG1837  Completed phase 1 multiple dosing trial, and heading into phase 2 for G551D and S1251N CF 2016.  
GLPG2451  Additional potentiator expected to move into a phase 1 clinical trial 2Q 2016.

GLPG2222  First generation corrector began dosing in healthy volunteers January.  Expects top line results in Q2 2016.  GLPG receives $10 million milestone from ABBV.
GLPG2851  Another first generation corrector, aiming to initiate phase 1, end of 2016.  
GLPG2665  Next-generation corrector, expected to enter phase 1, middle of 2016.  
GLPG2737  Next-generation corrector, expected to enter phase 1, Q4, 2016.  

Bottom Line:  It's good to see a company attempt to improve upon the currently approved combo Orkambi for Cystic Fibrosis people.  By the end of 2016, we should at least have some indication how corrector GLPG2222 and possibly GLPG2665 have done in phase 1 clinical trials.  Thank you for reading.  


Monday, January 18, 2016

uniQure: Gene Therapy ($15.90)

QURE is an interesting European company located in the Netherlands, that specializes in gene therapy for various genetic or acquired diseases. The goal of the company, is to deliver single treatments with potentially curative results.  A quick catch up from significant press releases the past few years.

1-7-16  uniQure announces preliminary top line results from low dose cohort in Hemophilia-B phase I/II Gene Therapy Clinical Trial.

12-8-15  uniQure appoints Dan Soland as Chief Executive Officer.

9-19-15  Positive topline results announced from from phase I/II trial in Sanfilippo B Syndrome patients using uniQure's novel AAV5-Based Gene Therapy.

8-10-15  uniQure announces receipt of $53 million from Bristol-Myers Squibb for Target Selection Payment and additional equity investment.

4-6-15  Bristol-Myers Squibb and uniQure enter into exclusive strategic collaboration to develop gene therapies for Cardiovascular Disease.

8-11-14  uniQure acquires cardiology gene therapy company InoCard.

2-10-14  uniQure announces closing of initial public offering.

7-20-12  First gene therapy in western world to receive positive opinion in Europe from CHMP.  uniQure's gene therapy Glybera recommended for approval.

The company plans on initiating a high dose cohort in their continuing phase I/II Hemophilia-B gene therapy clinical trial here NCT02396342 in the first quarter of 2016. The company is well capitalized, and has some early impressive clinical results for Sanfilippo B Syndrome, and Hemophilia-B. The company press releases can be viewed here  uniqure press releases.   We will have more to say regarding QURE in the near future.  Thank you for reading. 

Monday, January 11, 2016

CTP-656 Revenue Potential

CTP-656 is the deutered version of Vertex drug Kalydeco which we wrote about here What is CTP-656.  Today, Vertex gave an updated sales forecast for Kalydeco at the JP Morgan Healthcare Conference.  The company expects 2016 revenues in the range of $675 million. 
Kalydeco is provided to Cystic Fibrosis patients as mono therapy for the G551D and R117H mutation.  The annual cost of the therapy is approximately $300,000 annually.
In a phase 1 crossover comparison clinical trial, CTP-656 compared well from a pharmacokinetic (PK) standpoint, which showed major metabolite differentiation, and potential to be dosed once daily.  Kalydeco is currently dosed twice daily.
The company has stated that they have no plans at this time to partner out CTP-656 as mono therapy for the above indications mentioned.  In Concert presentations, partnering out as a combo therapy would make sense with companies that are developing CF correctors.
Some quick back of the envelop calculations could be significant for the company even if they sell the drug at a discount to the current Kalydeco price.  The worldwide patient population for Kalydeco below, as mono-therapy, excluding any combination therapies for the most common form of CF, the F508del mutation, for which Orkambi is prescribed for.
  • G551D ages 6+ (US) 
  • G551D ages 6+ (EU, AUS & CAN)  
  • Gating, R117H & Ages 2-5
  • 4,000 eligible patients  (Vertex Pharmaceuticals 2015 Year End)
The unique situation Concert finds itself in, if CTP-656 potentially does get FDA approval as mono-therapy, is that the footprint for those 4,000 patients available, may already be established from being prescribed Kalydeco.  The switch to CTP-656 from Kalydeco, could happen seamlessly if the drug is marketed right.
50% penetration, = 2,000 patients
33% discount to the currently priced annual therapy of $300,000 = $200,000 annually (conservative).
$400 mn in potential revenue (2,000 patients * $200,000 annual therapy).
If 50% (conservative) falls to the bottom line after expenses = $200 mn.  
With 25 million shares outstanding (currently 22.5 mn), the company could potentially earn $8.00 per share in earnings ($200 mn / 25 mn).  For CTP-656 as mono-therapy treatment for G551D and R117H CF patients.
There are several ways to calculate a future and present price target for the common stock. We chose to use a potential buyout calculation of four times peak revenue of $400 mn. Over the past several years, we have seen small to mid capitalization biotechnology buyouts range from 3 to 10 times peak revenue, so 4 times is conservative, considering that the patent life for CTP-656 is 2032.  At 4 times peak revenue for CTP-656 of $400 mn, yields a $1.6 bn market cap. Take the $1.6 bn market cap, and divide it by 25 mn shares outstanding, ($1.6 bn / 25 mn shares outstanding), we come to a target price for Concert stock of $64.00 per share, just for drug CTP-656 as mono-therapy, for select CF patients worldwide. Thank you for reading.
The patent for CTP-656 runs until 2032 in the U.S.


Saturday, January 2, 2016

2015 Portfolio Returns

Portfolios managed by Shaw Investments had the following returns before fees in 2015.

*The average portfolio returned +30.05% in 2015.
The average monthly return was +2.50%.
The highest performing month was +20.10%.
The lowest performing month was -11.70%.
There were 7 out of 12 positive months 58%.
Monthly standard deviation was 8.50%.
Monthly correlation to the S&P 500 was .369.

*Past performance is not necessarily indicative of future results.

Shaw Investments is an investment advisory firm that invests primarily in early to mid-stage biotechnology companies, and separately, custom manages retirement based portfolios. Thank you for reading. 


Monday, December 28, 2015

TRIAD 1 & 2 Recruiting

Avanir Pharmaceuticals, a subsidiary of Otsuka, has initiated both arms of the phase 3 clinical trial for Alzheimer's Agitation termed TRIAD, and the Long Term Extension Study for patients who have completed 12 weeks of  either TRIAD 1 or 2.  Patients will be enrolled into the long term extension NCT02446132 study based on the following criteria:
  • Patient has successfully completed Studies 15-AVP-786-301, 15-AVP-786-302, or 12-AVR-131.
  • Patients will be enrolled in the study for approximately 52 weeks.
  • Approximately 550 patients will be enrolled at approximately 110 centers in the US.
  • All patients enrolled will receive AVP-786, the treatment dose assigned will be masked to the patient, investigator, study staff, and the sponsor.
The long term extension study is scheduled to complete in July of 2019, approximately 52 weeks after TRIAD 1 and 2 have completed dosing with AVP-786.  This long term extension study may be important for the drug label the FDA assigns during the approval process, for agitation in patients with dementia of the Alzheimer's type.  
AVP-786 (AVP-923) has exhibited a consistent and mild safety profile, making the drug a unique candidate for elderly patients with behavioral problems due to Alzheimer's or other dementia related diseases.  A mild safety profile, compared to current anti-psychotics could also promote off-label prescribing potential, for the drug.  The safety profile of AVP-923 was written about in a post here Rexulti & AVP-923 Safety Profile Comparison. Thank you for reading. 


Monday, December 14, 2015

What is a Priority Review Voucher

As an incentive, the statute authorizes the FDA to award a priority review voucher, to the sponsor (manufacturer) of a newly approved drug or biologic that targets a neglected tropical disease. The provision applies to New Drug Applications (NDAs), Biological License Applications (BLAs) and 505(b)(2) applications. The voucher, which is transferable and can be sold, entitles the bearer to a priority review for another product.  Below is a list of diseases that have been targeted to potentially receive a priority voucher.

Recent selling of the vouchers have bought high payouts over the last year.
AbbVie paid $350 million 
Sanofi paid $250 million
Gilead paid $125 million

The FDA announced two new diseases added to the list in 2015,  Chagas and Neurocysticercosis.  Thank you for reading.  

No positions in the above mentioned companies.

Saturday, December 5, 2015

Assessing the Success of AVP-786 for Patients with Treatment Resistant Major Depressive Disorder

Assessing the success of a clinical trial depends on many factors.  Trial design, primary endpoint, prior drug trials, safety and tolerability, competitor success with similar drug, and what is deemed successful by FDA standards, are just a few factors to consider.  Avanir Pharmaceuticals is nearing the end of a phase 2 clinical trial for AVP-786 as Adjunctive Therapy in Patients with Major Depressive Disorder With Inadequate Response to Anti-Depressant Treatment in clinical trial NCT02153502.

The first important factor to consider is that AVP-786 is the deutered version of AVP-923.  Both drugs were tested in a Phase 1, Single-center, Randomized, Double-blind, Double-dummy, 2-way Crossover Study Comparing AVP-786 with AVP-923 here NCT02336347The two drugs exhibited a similar PK and safety profile.  This is important because we will be using data from two AVP-923 clinical studies that had a subset of patients tested for depression, with either the BDI-2 (Beck Depression Inventory-II) or the Cornell Depression Scale.

Avanir ran a phase 3 clinical trial with AVP-923 evaluating the safety and efficacy of AVP-923 in PBA (Pseudobulbar Affect) patients with ALS or MS, trial named (STAR) here NCT00573443. The mean change from baseline at day 84 in the Beck Depression Inventory (BDI-II) Total Score was used as a secondary endpoint.  Patients with moderate depression on the BDI-II scale, greater than 18, scored a significant p=0.03 while taking AVP-923, 30mg dextromethorphan / 10mg quinidine.  Below is the Avanir, JP Morgan Healthcare Conference presentation in January 2014.

2014 JP Morgan Healthcare Conference

Treatment-Resistant MDD Clinical Rationale
The Beck Depression Inventory-II (BDI-II) was included as a secondary efficacy endpoint in the pivotal phase 3 trial in PBA patients
Major Depression Excluded
Among patients with baseline BDI-II scores >10, AVP-923 treatment was associated with a reduction in depression symptoms
STAR Trial; Avanir data on file

Endpoint BDI-II
(n=50)  -3.36  AVP-923 30/10
(n=55)    -2.3   AVP-923 20/10
(n=52)    -1.1    Placebo

P Value
0.065   AVP-923 30/10
0.378   AVP-923 20/10

"Among a subset of patients with baseline BDI-II scores > 18, AVP-923 30/10 was
associated with statistically significant improvement (p=0.03)".

Using the description below for the (p=0.03) subset, the trial had patients classified primarily in the moderate depression range, as the presentation listed major depression as excluded. The following is a breakdown of the BDI-II, which is a 21-item self-report instrument intended to assess the existence and severity of symptoms of depression, summed to give a single score. The BDI-II uses a 4-point for each item ranging from 0 to 3.

BDI-II Depression Scale

0-13 is considered minimal range 
14 to 19 mild depression
20 to 28 moderate depression
29 to 63 severe depression
In a phase 2 clinical trial for Alzheimer's patients experiencing agitation. Trial NCT01584440 utilized a secondary endpoint called the Cornell Scale for Depression in Dementia (CSDD): which a statistical p=0.02 was observed. 

Bottom Line:

Although the number of patients were relatively small in the two above trials showing benefits of AVP-923 for depression, it does give us some guidelines to the probabilities for potential success in the current clinical trial coming to completion.  Thank you for reading.


Saturday, November 28, 2015

Matinas Biopharma Update ($0.84)

We are updating drug MAT2203, for treatment resistant fungai, as that is the drug furthest along in clinical trials here NCT02629419.

Is an oral drug that addresses chronic or recurring mucocutaneous candidiasis infections (Esophogeal, Oropharyngeal, Vaginal).  The company will be running a phase 2 clinical trial before years end with a beginning oral dose of 200 mg daily for 14 days, but may titrate up to 400mg and 800mg.  The goal of the study is to demonstrate anti-fungal efficacy and to establish safety and tolerability at 28-56 days of treatment duration.  This is an important clinical trial for the success of MAT2203 and the platform as a whole.  The clinical trial will test to significantly improve over current IV-only administration of Amphotericin B.  The drug was granted QIDP and Fast Track by the FDA in August 2015.  The trial readout will be early 2016

Bottom Line:
The success of Matinas Biopharma could lie in the phase 2 clinical trial results that should be complete in early 2016.  If the 200 or 400 mg dose daily is effective, that would be a strong positive, as the 800mg dosing in healthy humans showed a more adverse side effect profile. If the results show efficacy, and is safer than current standard of care, IV Amphotericin B, than I would expect a potential partnership to emerge, and an infusion of cash that could allow them to move their pipeline into the clinic.  Thank you for reading.


Monday, November 16, 2015

Avanir Initiates (TRIAD) for Alzheimer's Agitation

Today it was announced that Avanir Pharmaceuticals (Otsuka) has initiated what they call their TRIAD clinical programs.  The clinical trials will utilize AVP-786 for the treatment of agitation in patients with Alzheimer's disease.  There will be two parts to the initial TRIAD program, Triad-1 which has been initiated, and Triad-2, which will be initiated in 2015 also. The clinicial trial should last around two years.  
TRIAD-1  NCT02442765
Dosing will be (DM/Q)  18/4.9 mg, or 28/4.9 mg over 12 weeks, and enroll 380 patients.
TRIAD-2   NCT02442778
Dosing will be (DM/Q)  28/4.9 mg, over 12 weeks, and enroll 325 patients.

Avanir also announced that the company has received "Fast Track" for this indication, and that AVP-786 used for their phase 2 clinical trial as adjunct for major depression disorder, will complete enrollment by the end of 2015.  

Bottom Line:  
The TRIAD program that has been announced today, is a big commitment to drug AVP-786, not only for agitation in Alzheimer's, but also adjunct for major depression disorder, residual schizophrenia, and disinhibition syndrome.  Thank you for reading.  


Saturday, November 7, 2015

Agitation in Alzheimer's Disease - An Unmet Need

Finding an effective and safe drug to treat agitation associated with Alzheimer's disease has been a challenge.  Currently there are no drugs approved for this indication.  Three drugs hold potential to treat this growing population.  

AVP-786  (AVP-923)

Avanir (owned by Otsuka) is planning two phase three pivotal clinical trials for treatment of agitation in patients with dementia of the Alzheimer's type.  In a phase 2 clinical trial with the primary endpoint being the NPI Agitation/Aggression Domain, a statistically significant p=.001 was achieved from publication released here Avanir JAMA Publication.  The drug was generally well tolerated. The two planned phase three trials will last around two years to complete, then another year to potential FDA approval.  In three years from the beginning of 2016, AVP-786 could be the first FDA approved drug for this indication, and reach commercialization in 2019.  The patent extends until 2030 in the U.S., and 2028 in the EU.

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 with a completion date around mid 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!

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.   


Owned by Acadia, is currently in a phase 2 clinical trial for Alzheimer's patients experiencing psychosis, with other secondary endpoints such as agitation included.  The company has stated that they have received anecdotal evidence of the drug having an effect for agitation in the current phase 2 trial.  The company is planning a phase 2 clinical trial in 2016 for agitation associated with Alzheimer's disease. 

Bottom Line:  Atypical drug therapy for elderly patients with dementia has been deemed unsafe by the FDA, with black boxed warnings for certain indications.  AVP-786 (via AVP-923) is the only drug of the three that has been proven in a clinical trial for Alzheimer's Agitation.  The drug was generally well tolerated.  The drug is conservatively two years ahead of  ITI-007, and Pimavanserin.  At present AVP-786 holds the most promise from proven clinical data, and is much further along in the FDA approval process. Thank you for reading.    


Friday, November 6, 2015

CNCE Third Quarter Conference Call

Concert completed their conference call yesterday.  A couple important highlights below.

There will be a small 40 patient phase 2 clinical trial in the second half of 2016, that will evaluate single dosing of CTP-656 in CF patients, that are already taking Kalydeco for the G551D mutation. There will be a washout period of a few days, and after that, the patients will be given CTP-656 for around a month.  So the company will have a FEV1 and sweat chloride baseline for the patients that are currently prescribed Kalydeco.  A comparison after the washout period over a month's time frame on CTP-656, could be the endpoint.  This will be a short efficient study, with an important comparison to the already approved standard of care Kalydeco, for CF patients with the G551D mutation.  

"We are encouraged by the favorable pharmacokinetic profile of 730 observed in our phase 1 clinical trial compared to historical data for Apremilast.  Going forward, Celgene will be responsible for any post phase 1 development for the program."
"The next development milestone that we could see would be either, the dosing in the phase three trial, or an acceptance of an NDA filing, and that would be a $15 million dollar milestone."

The company ended the quarter with $142 million in cash, which is expected to last into 2018.  Thank you for reading.


Friday, October 9, 2015

CTP-656 & GLPG1837 Drug Comparison

The North American Cystic Fibrosis Conference began yesterday.  Concert presented some new data for CTP-656, and Galagapos released phase 1 data for drug GLPG1837 today.  Below is new data for drug GLPG1837, and an early comparison of CTP-656 and GLPG1837.

GLPG 1837
The half life (t 1/2) of 1837 runs between 6 and 15 hours depending on the dosage.  I selected a middle of the range dosage of 500 mg used in the phase 1, for comparison to CTP-656, regarding plasma concentration, and their distinct profiles.  

plasma concentration 500 mg 12 hours fed around 200 (ng/mL) 

The half life of CTP-656 is 15 hours with a 150 mg dose.  
plasma concentration 150 mg 12 hours fed 1306 (ng/mL)

The half life (t 1/2) of Kalydeco is around 11 hours for a 150 mg dose.
plasma concentration 150 mg 12 hours fed 412 (ng/mL)

-Concert said CTP-656 was similar to Kalydeco at all dose levels, and well tolerated up to 300 mg.
-Galagapos 500 mg dosed twice daily with six participants, all experienced tiredness, and five experienced headache, in healthy subjects.  Galagapos says final safety data is pending.

Bottom Line:
From the data above, it looks like GLPG1837 will have to be dosed twice daily judging by the half life range of 6-15 hours, and Galagapos did not breakout each individual dose with half life. Two distinct drugs, as plasma levels with CTP-656 150 mg at 12 hours is substantially higher than GLPG1837 500 mg.  Concert believes that QD dosage (once daily) is possible with CTP-656.  The company still has to run a multiple ascending dose phase 1 trial, evaluating CTP-656 against Kalydeco.  Galagapos plans to initiate a phase 2 clinical trial for CF patients by the end of 2015. Thank you for reading.  No positions in Galagapos.  


Monday, October 5, 2015

Is Adherence to Ivacaftor Suboptimal

From a recent issue of the Journal of Cystic Fibrosis, the authors make a strong case that twice daily Ivacaftor adherence is suboptimal.  Although used interchangeably, let's attempt to differentiate between compliance and adherence. If a doctor prescribes Ivacaftor 150 mg twice daily, and you accept and fill the prescription, you are in compliance with your doctor.  Taking Ivacaftor twice daily is adherence to the prescription requirements.  The link to the article is below.  
In the small sample study, the authors found that adherence was 61% among patients prescribed Ivacaftor.  Keep in mind they studied patients taking Ivacftor for the G551D mutation, which showed an improvement of over 10% percentage points in clinical trials, in the percent predicted FEV1.  The latest  FDA approved combo Orkambi (Ivacaftor and Lumacaftor) scored much lower on FEV1 for patients with F508del, than what Ivacaftor alone did for G551D patients. There are a few companies currently working on a once daily for CF patients, which could increase adherence rates to a higher level. Thank you for reading.


Tuesday, September 22, 2015

CTP-656 Phase 1 Single Dose Comparison

Just released today at the UK Cystic Fibrosis Trust Conference.  Data looks good, as the half life +34% compared to Kalydeco, and other PK measures by far outperformed.  Data below is a single dose of CTP-656 150 mg, compared to a single dose of Kalydeco 150mg.

C 12hr          +320%

C 24hr         +420%
AUC 24hr   +280%
C max          +100%
T 1/2              +34%

Of note, at steady state, Kalydeco exposure is predominately to less active metabolites compared to CTP-656.  This could potentially have CTP-656 being more efficacious than Kalydeco.

Bottom Line:  This was a good 15 minute presentation that displayed CTP-656 from a comparison, to Vertex drug Kalydeco.  The company reported that "CTP-656 was well-tolerated across all dose groups (75, 150, and 300 mg).  There were no serious adverse events reported in subjects who received CTP-656."  Vertex at present, holds a monopoly drug for CF patients, $300,000 per year therapy.  I think in two to three years, there could potentially be a competing therapy of drugs, lower priced, with a better drug to drug interaction profile, with potential for single daily dosing.  Thank you for reading.