Wednesday, August 24, 2016

Kalydeco for G551D

Vertex Pharmaceutical's Cystic Fibrosis drug Kalydeco has been FDA approved for people with the G551D mutation, starting in 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 the 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:  portfoliomgt1@gmail.com                                   586-431-8000




Wednesday, August 17, 2016

Vertex VX-661 Corrector

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.  Below are the four trials from press release Vertex Provides Update on Ongoing Phase 3 Program for VX-661 in Combination with Ivacaftor for the Treatment of Cystic Fibrosis.

  • Two Copies of the F508del Mutation: In August, Vertex completed enrollment in a study evaluating 24 weeks of treatment with VX-661 in combination with ivacaftor in approximately 500 people with CF who have two copies of the F508del mutation. Data from this study are expected in the first half of 2017.
  • One Copy of the F508del Mutation and a Second Mutation that Results in Residual CFTR Function: In September, Vertex expects to complete enrollment in a study evaluating VX-661 in combination with ivacaftor in approximately 200 people with residual function mutations. The crossover study includes two 8-week dosing periods, separated by an 8-week washout period. The study includes an arm of ivacaftor monotherapy, in addition to an arm evaluating VX-661 in combination with ivacaftor and a placebo arm. Data from this study are expected in the first half of 2017.
  • One Copy of the F508del Mutation and a Second Mutation that Results in a Gating Defect in the CFTR Protein: Enrollment is ongoing in a study designed to evaluate VX-661 in combination with ivacaftor in people with gating mutations that have been shown to be responsive to ivacaftor alone. The study is expected to enroll approximately 200 patients and is evaluating 8 weeks of treatment with VX-661 in combination with ivacaftor. Enrollment is expected to complete in late 2016 or early 2017.
  • One Copy of the F508del Mutation and a Second Mutation that Results in Minimal CFTR Function: In April, Vertex completed enrollment of approximately 150 people in Part A of a two-part study evaluating people with mutations that result in minimal CFTR function.  A planned interim futility analysis was conducted by the study’s independent DSMB after at least 8 weeks of dosing to determine whether to stop the study or to continue the study and initiate enrollment in Part B.  The analysis showed that the combination of VX-661 and ivacaftor did not result in a pre-specified improvement in lung function.  The DSMB recommended that Vertex stop the study and not initiate enrollment in Part B. There were no safety concerns noted in the DSMB’s review of the data. Vertex plans to close this study based on the recommendation of the DSMB, and patients from Part A of the study who enrolled in the long-term extension study will be transitioned off the combination of VX-661 and ivacaftor.
 
The other three phase 3 trials will readout by mid 2017.  If the combination of ivacaftor + VX-661 is effective in any of the other three studies, the company will seek FDA approval, and continue to test with next generation correctors VX-152, and VX-440, as triple combination therapy for F508del minimal cftr function patients.  Thank you for reading.  
   
Contact:   portfoliomgt1@gmail.com                    586-431-8000

Monday, August 15, 2016

Concert Pharmaceuticals Upcoming Milestones

Over the next six months, we are expecting some important events occurring for Concert Pharmaceuticals.  Below is a list of potential milestones that could have an impact on the company. 
  • CTP-656 phase 2 clinical trial initiated by end of 2016
  • CTP-543 phase 1 clinical trial readout end of 2016
  • CTP-543 phase 2 clinical trial initiation early 2017
  • TEVA's Austedo first FDA approved, end of March 2017
  • AVP-786 for treatment resistant depression, Otsuka pending decision
  • AVP-786 residual schizophrenia completes enrollment
  • d-ivacaftor European patent, around 2032 expiration date
  • d-ruxolitinib European patent, around 2033 expiration date
  • Cystic Fibrosis clinical trial readouts, and NACFC conference October 27-29
Bottom Line:  The next six months should be a busy time for information flow, from the company, and competitors of similar indications.  Thank you for reading. 

Contact:  portfoliomgt1@gmail.com                                     586-431-8000 

Tuesday, August 9, 2016

Concert Second Quarter 2016 Conference Call

The design of the phase 2 clinical trial with CTP-656, for cystic fibrosis patients was revealed today.
  • Open IND 2nd half 2016
  • 36-40 G551D patients, 6-8 each arm
  • Three doses of CTP-656
  • 28 days of treatment
  • Placebo and Kalydeco comparator arms
  • Key Endpoints:  Sweat Chloride, and FEV1 (phase 2)
  • FEV1 primary (phase 3) endpoint
  • Designed to support 505(b)(2) registration pathway
  • Topline 2H 2017

Bottom Line:  This design supports the 505(b)(2) registration pathway, which means a single phase 3 clinical trial may be all that is needed, prior to submitting a new drug application to the FDA, for G551D gating mutation approval.   Thank you for reading.

Analyst Participation:  Defei Yang - Brean Capital, Bert Hazlett - Ladenburg, Robert LeBoyer - Aegis Capital, Constantino Aprilopski - JMP, Jeff Hung - UBS

 

Contact:  portfoliomgt1@gmail.com                                  586-431-8000

Friday, July 29, 2016

Galapagos Updates Cystic Fibrosis Program (4)

Galapagos held their second quarter conference call today and updated their CF program. 

Below was the last update (3), June 15, 2016.

Galapagos Updates Cystic Fibrosis Program (3)
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. 

7-29-2016
The significant news today, was that the company was expected to test potentiator GLPG2451 with corrector GLPG2222, from the press release above 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.
     
Contact:  portfoliomgt1@gmail.com                                                 586-431-8000

Thursday, July 28, 2016

AXS-05 Phase 1 Results

Completed Phase 1 Trials of AXS-05
 
We have completed two Phase 1 pharmacokinetic clinical trials of AXS-05. The objectives of these trials were to assess the pharmacokinetics of DM when co-administered with bupropion, and to assess the safety and tolerability of the combination. In these Phase 1 trials, the components of AXS-05, DM and bupropion, were co-administered as separate tablets. In both studies, administration of bupropion in combination with DM resulted in substantial increases in DM plasma concentrations measured using Cmax and AUC at all doses tested.
The first Phase 1 trial was a randomized, multiple-dose, open-label study to determine the pharmacokinetics of DM when various doses of DM are administered concomitantly with bupropion under fasting conditions, as well as the safety of the combination. Subjects were randomized to receive twice-daily administrations of 150 mg of bupropion in combination with DM at various doses up to 60 mg, or 60 mg of DM alone, for 8 consecutive days. Bupropion was titrated with subjects being dosed once daily for the first 3 days, then twice daily thereafter. A total of 32 healthy, adult volunteers were included in this study in four treatment groups. Full pharmacokinetic assessments were made on Day 1 and Day 8. As shown in the figure below, for the dose of 60 mg of DM / 150 mg of bupropion, AUC0-12 and Cmax values on Day 8 for DM when dosed in combination with bupropion were approximately 60 times and 40 times, respectively, the values for DM when dosed alone. For all doses tested, administration of DM in combination with bupropion resulted in substantial increases in AUC0-12 and Cmax values of DM on Day 8 as compared to Day 1 of dosing. DM exposure measured using AUC and Cmax increased in a dose dependent manner with increasing doses of DM. Administration of DM did not appear to affect the pharmacokinetics of bupropion.
  There were no reported serious adverse events in the trial. The majority of treatment-emergent adverse events experienced were graded as mild or moderate in severity, and had resolved by the end of the study. The most commonly reported adverse events were dizziness, nausea, headache, insomnia, dry mouth, constipation, hypoesthesia, palpitation, disturbance in attention, tremor, and hyperhidrosis. Adverse events were reported more frequently in the AXS-05 arm as compared to the DM-only arm. The majority of these adverse events were expected with the administration of bupropion, having been already reported in the FDA package inserts for products containing bupropion.
        The second Phase 1 trial was a randomized, multiple-dose, open-label study to determine the pharmacokinetics of DM when various doses of DM are administered concomitantly with various doses of bupropion and to assess safety during co-administration of bupropion and DM. A total of 40 healthy, adult volunteers were included in this study in five treatment groups. Subjects were randomized to receive twice-daily administration of either 150 mg of bupropion alone, or combinations of varying doses of bupropion and DM for 8 consecutive days. Bupropion was titrated with subjects being dosed once daily for the first 3 days, then twice daily thereafter. Full pharmacokinetic assessments were made on Day 1 and Day 8. Similar to the results in our first study, administration of DM in combination with bupropion resulted in substantial increases in AUC0-12 and Cmax values of DM on Day 8 as compared to Day 1 of dosing for all combinations tested. DM exposure measured using AUC and Cmax increased in a dose-dependent manner as doses of either DM or bupropion were increased. Administration of DM did not appear to affect the pharmacokinetics of bupropion.
       There were no reported serious adverse events in the trial. The majority of treatment-emergent adverse events experienced were graded as mild in severity, and had resolved by the end of the study. The most commonly reported adverse events were headache, nausea, dizziness, fatigue, increased heart rate, palpitations, constipation, diarrhea, increased blood pressure, and tremor. No particular trend was observed when comparing the rates or types of adverse events in the combination groups as compared to the group receiving bupropion alone.
   
Bottom Line:  The above is from Axsome's prospectus.  The combination of dextromethorphan / bupropion is a novel combination.  The safety profile of DM is well documented in many clinical trials.  Bupropion acts as an inhibitor of DM similar to what quinidine does for AVP-786.  Bupropion brings the added CNS benefit of an antidepressant, but also a potentially more adverse safety profile with it.  AXS-05 is expected to enter a phase 2 / 3 clinical trial for Alzheimer's Agitation in 2016.  How that safety profile plays out in this population and in comparison to AVP-786 will have to be  seen.  Below is the side effect profile for Wellbutrin (Bupropion) in clinical trials. 

Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials:
Adverse events from Table 5 occurring in at least 5% of patients treated with WELLBUTRIN SR Tablets and at a rate at least twice the placebo rate are listed below for the 300- and 400-mg/day dose groups.
 WELLBUTRIN SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.
 WELLBUTRIN SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.

Thank you for reading.
 
                   586-431-8000

Thursday, July 21, 2016

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

WILMINGTON, Del.--(BUSINESS WIRE)--Jun. 6, 2016-- Incyte Corporation (Nasdaq:INCY) today announces five-year data from the Phase 3 COMFORT-I study evaluating the long-term safety and efficacy of Jakafi® (ruxolitinib) in patients with intermediate-2 or high-risk myelofibrosis (MF). These follow-up results showed an overall survival (OS) benefit among patients treated with ruxolitinib with a 31 percent reduction in the risk of death (HR=0.69; 95% CI: 0.50, 0.96; P=0.025) compared to patients randomized to placebo. Because the majority of patients on the placebo arm crossed over to receive ruxolitinib therapy (median 41.1 weeks after randomization), these data suggest that earlier treatment with ruxolitinib may be associated with improved long-term survival in patients with intermediate-2 or high-risk MF.
Additionally, over the five-year period, 59 percent (92/155) of patients who continued on treatment with ruxolitinib achieved at least a 35 percent reduction in spleen volume at any given time. The median duration of spleen response was 168.3 weeks. The mean spleen volume reduction from baseline at five years was 37.6 percent for patients who continued on treatment with ruxolitinib. After week 24, hemoglobin and platelet count remained stable through 5 years.

“Nearly, five years after the launch of Jakafi for the treatment of intermediate and high-risk MF, these findings provide important insight into the treatment’s long-term clinical benefits,” said Steven Stein, M.D., Incyte’s Chief Medical Officer. “The overall survival benefit observed in the COMFORT-I study, along with sustained reductions in spleen volume, are meaningful for patients with this rare disease who often experience significant, debilitating symptoms, and even mortality, as a result of their disease.”
These data are scheduled for presentation at the American Society of Clinical Oncology (ASCO) Annual Meeting 2016 taking place June 3–7, 2016 in Chicago, Illinois.
“Previous findings from this study and overall survival trends reinforce the benefits of long-term treatment with ruxolitinib in patients with intermediate and high-risk MF. Achieving outcomes such as reduction in spleen volume is critical to the successful management of patients with this chronic and debilitating disease," said Ruben A. Mesa, M.D., FACP, Chair, Division of Hematology & Medical Oncology, Deputy Director, Mayo Clinic Cancer Center, Chair, Arizona Cancer Coalition, and Professor of Medicine.
Results from the COMFORT-I Study
COMFORT-I, a randomized (1:1), double-blind, placebo-controlled Phase 3 study, compared the efficacy and safety of ruxolitinib to placebo in 309 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis.
Of the 155 patients randomized to ruxolitinib, 28 percent of patients were still on treatment at the time of this analysis (median follow-up 268 weeks). Of the 111 patients originally randomized to the placebo arm who crossed over to ruxolitinib (median 41.1 weeks after randomization), 25 percent remained on treatment at the time of this analysis (median follow-up 268 weeks).
Overall, 69 (45%) and 82 (53%) deaths were reported in the ruxolitinib and placebo arms, respectively. Median OS has not been reached for patients randomized to receive ruxolitinib.
Adverse events (AEs) were consistent with those reported in previous studies of ruxolitinib and there was no increase in the incidence of AEs with longer exposure to treatment.
COMFORT-I (Abstract #7012) is scheduled for presentation by Dr. Mesa on Monday, June 6, 2016, 8:00–11:30 a.m., E354b Hall A.
Bottom Line:  The safety information cited in this press release is important, because Concert will be advancing d-ruxolitinib (CTP-543), for Alopecia Areata potentially on a long-term therapy basis.  Thank you for reading.

Contact:   portfoliomgt1@gmail.com
                  586-431-8000 

Wednesday, July 13, 2016

JAK Inhibitors for Alopecia Areata

Janus Kinase Inhibitors (JAK)'s, have shown to be effective for AA reversal and hair growth.  Is there one JAK inhibitor more effective than others for inhibition for this indication.  This link to Nature.com is a very good tutorial regarding Ruxolitinib (JAK) 1,2 and Tofacitinib (JAK) 1,3 in vitro and in mice.
 
Bottom line:   Both Janus Kinase Inhibitors show very similar in vitro, topical and systemic. Both JAK's have also shown to be effective in academic studies with humans. Thank you for reading. 

Contact:  portfoliomgt1@gmail.com                         586-431-8000   

Tuesday, July 12, 2016

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:  299m
Patent:  2033

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.

Contact:   portfoliomgt1@gmail.com
                  586-431-8000