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 AdvisoryCommittee. The 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.

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)  Disinhibition                                   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
(0)
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.
 

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.

QBW251 Clinical Trial Terminated

Novartis was in a phase 2 for healthy and Cystic Fibrosis patients 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 the company completes their phase 2 clinical trial sometime in 2017.  Thank you for reading.          

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. 
 

GLPG1837 for Cystic Fibrosis

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 Galapagos 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.
 

CTP-656 Clinical Trial Chronology

The company has advanced CTP-656 nicely since receiving U.S. patent in the fall of 2014. Below is a chronology of the drug's clinical progress.
    
    First Half 2017 - European switching study CTP-656, and Kalydeco.
✔ January 2017 - Start phase 2 for mono-therapy, various gating mutations.
✔ February 2016 - Food effect study in healthy male volunteers, solid oral dose.
✔ November 2015 - Multiple ascending dose (PK) crossover study, with CTP-656 and         Kalydeco in healthy volunteers, solid oral dose.
✔ March 2015 - Single ascending dose (PK) crossover study, with CTP-656, and Kalydeco in healthy volunteers, oral suspension.  Second part of phase 1.
✔ March 2015 - Phase 1, D9 and D18 analog (PK) comparison in healthy volunteers.  The first part of phase 1.
✔ 2012 - Pre-clinical D9, D18 and Kalydeco plasma study comparison in dogs.

Thank you for reading.

Vertex: Complete Response Letter (CRL) From U.S. FDA

On February 5th it was press released that Vertex Pharmaceuticals received a CRL from the FDA.  A Food and Drug Administration CRL is issued when the FDA communicates to a company that an application to market a drug (NDA, new drug application) will not be approved in it's present form, and that the review by the FDA has been complete.
  
Vertex submitted a supplemental new drug application (sNDA) for the already approved Kalydeco.  The sNDA was filed for Cystic Fibrosis people 2 years and older, who have one of 23 residual function mutations in the cystic fibrosis gene.   Eight of the 23 were represented in a phase 2A study. It is estimated that over 1,500 people in the U.S. have one of the 23 gene mutations. The numbers do not seem all that large.  But if you factor in that Kalydeco is priced around $300k for annual therapy, then the numbers become quite large, up to around $450mn in potential annual revenue for the company if the sNDA was approved.
The 23 residual function mutations included in the sNDA were: 2789+5G- > A, 3849+10kbC- > T, 3272-26A- > G, 711+3A- > G, E56K, P67L, R74W, D110E, D110H, R117C, L206W, R347H, R352Q, A455E, D579G, E831X, S945L, S977F, F1052V, R1070W, F1074L, D1152H, and D1270N.  The press release is here Vertex Complete Response Letter.  More than likely the CRL was issued to Vertex because only eight of the 23 residual function mutations were represented in the phase 2A study.  Thank you for reading.

Galapagos Updates Cystic Fibrosis Program

Galapagos (GLPG) and AbbVie 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, Galapagos 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. 

Potentiators:
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.

Correctors:
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.  

CTP-656 Cystic Fibrosis Market Opportunity

CTP-656 is the deutered version of Vertex drug Kalydeco.  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.
Concert Pharmaceuticals plans on seeking regulatory approval for CTP-656 as mono therapy for people with the G551D and other gating mutations.  What could peak revenue look like for this set of patients excluding the more common F508del.  Below is the worldwide patient population for Kalydeco 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 Presentation)

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, have already been established from being prescribed Kalydeco.  The switch to CTP-656 from Kalydeco, could happen seamlessly if the drug is marketed right.
 

Penetration rate of 70% = 2,800 patients
Annual therapy price of $240,000 (20% discounted)
Potential revenue 2,800 patients * $240,000 annual therapy = $672 million

The advantages that CTP-656 offers is a once daily, with less dietary restrictions, that should lead to higher adherence rates. Thank you for reading.

 

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. 
 

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 NCT02336347.  The 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.