Tuesday, December 6, 2016

SAGE-547 Expedited Pathway Revealed

We initially wrote about Sage here, SAGE-547 for Postpartum Depression.  Today SAGE revealed through this press release Sage Therapeutics, the expedited pathway for drug SAGE-547 for Postpartum Depression.  The important news was that the FDA in agreement with Sage, anticipates that no additional controlled studies will be necessary to file an NDA.  The company believes that they may be able to file for a new drug application for Postpartum Depression in 2018.  If approved by the end of 2019, the company will have patent until around 2034, or approximately 15 years of exclusivity.  Below are the important aspects of the expedited pathway for SAGE-547, agreed upon by the FDA.
  • Current SAGE-547 clinical studies confirmed as appropriate to support registration, if successful
  • No additional efficacy studies expected to be required beyond those currently underway
  • Trial design of studies 202B and 202C are considered appropriate for registration, with increase in size and other minor modifications
  • The primary clinical endpoint for these pivotal trials was unchanged and agree upon with FDA
  • Additional patient safety data may be acquired through an open-label program
Below is a year-to-date chart of SAGE.  Despite the company having an extraordinary year with SAGE-547 the stock is down -4.49% this year.  The company currently has $432 million in cash, or about $13.00 per share in cash. 
Source: Shaw Investments, StockCharts.com
Thank you for reading.

Contact: portfoliomgt1@gmail.com
      

Friday, December 2, 2016

Janus Kinase (JAK) Inhibitors

Janus Kinase Inhibitors - JAK's have shown to be successful in a variety of different disease indications.  The science of these inhibitors is still in the early stages of understanding.   They operate by inhibiting one or more of the family of enzymes, (JAK1, JAK2, JAK3, TYK2), and interfering with the signaling pathway.  They have shown to be successful in cancer and inflammatory diseases to date.  Concert Pharmaceuticals currently owns patents for the following two deuterated JAK inhibitors, with indications that each has shown to be effective in, prior to the company adding deuterium to the entity.

D-Ruxolitinib
Selectivity: JAK1,2 
Indication:  Myelofibrosis, Polycythemia Vera, Alopecia Areata 
Patent: 2032 US

D-Baricitinib
Selectivity: JAK1,2, TYK2
Indication: Rheumatoid Arthritis, Psoriasis
Patent: 2032 US

The non-deuterated versions of these JAK's have already shown proof-of-concept (POC) in the above indications, essentially reducing the risk for Concert to bring the drugs to market, for previously tested indications.  It's rare to have a full runway of patent years ahead, with clinically tested drugs, at your disposal.  We'll follow the Janus Kinase landscape with any new findings in the future.  Thank you for reading. 

Contact:  portfoliomgt1@gmail.com

Tuesday, November 29, 2016

CTP-656 Phase 2 Clinical Trial Initiated

CTP-656 for cystic fibrosis patients with CFTR gating mutations is now loaded in the clinicaltrials.gov website here NCT02971839.  The phase 2 trial is expected to start enrollment in January of 2017 to avoid the busy holiday season approaching.  The company has decided not to disclose the three once daily dosages that will be tested.  The readout completion date is by the end of 2017.  Sweat chloride will be the primary endpoint of the study with FEV1 secondary.  With only 6-8 patients in each arm, the trial is not specifically powered for efficacy, but more likely to compare the three different dosages, and decide which one will be taken further into a phase 3 clinical trial, where FEV1 will be the primary endpoint.

Estimated Enrollment:40
Study Start Date:January 2017
Estimated Primary Completion Date:December 2017 (Final data collection date for primary outcome measure)
ArmsAssigned Interventions
Experimental: CTP-656, Dose 1, QD
Oral tablet dosed once-daily for 28 days
Drug: CTP-656, Dose 1 (QD)
Experimental: CTP-656, Dose 2, QD
Oral tablet dosed once-daily for 28 days
Drug: CTP-656, Dose 2 (QD)
Experimental: CTP-656, Dose 3, QD
Oral tablet dosed once-daily for 28 days
Drug: CTP-656, Dose 3 (QD)
Active Comparator: Kalydeco, 150 mg Tablet (open label)
150 mg, oral tablet dosed twice-daily for 28 days
Drug: Kalydeco, 150 mg Tablet (BID; open-label)
Placebo Comparator: Placebo, Oral Tablet, QD
Oral tablet dosed once-daily for 28 days
Drug: Placebo (QD)

Detailed Description:
This is a randomized, parallel-group, double-blind, placebo controlled multicenter study to evaluate the safety and efficacy of CTP-656 in CF patients with CFTR gating mutations, compared to Kalydeco, for a total of 28 days. Subjects will be randomized to receive either double-blind CTP-656 or placebo, or open-label Kalydeco.
 

 

Wednesday, November 16, 2016

STAT3 Phosphorylation with CTP-543

Concert Pharmaceuticals is currently running a phase 1 pharmacodynamics (PD) clinical trial, before heading into a phase 2 clinical trial for patients with moderate to severe Alopecia Areata.  The goal of the (PD) part of the phase 1 trial, will test CTP-543's ability to affect downstream gene regulation similar to ruxolitinib, with results in Q1 2017.  Ruxolitinib which is already an FDA approved drug for various cancer indications has been tested for it's ability to affect downstream gene regulation STAT3.  The results for ruxolitinib are below, and which can also be found in this link JAKAVI-ruxolitinib. 

Pharmacodynamics 
Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy subjects and MF patients.  Jakafi administration resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 8 hours in both healthy subjects and myelofibrosis patients.

Metabolism
In vitro studies indicate that CYP3A4 is the major enzyme responsible for metabolism of ruxolitinib.  Parent compound is the predominate entity in humans representing 60% of the drug-related material in circulation.  The two major and active metabolites were identified in plasma of healthy subjects representing 25% and 11% of parent AUC.  These metabolites have one-half to one-fifth of the parent JAK-related pharmacological activity.  The sum of all active metabolites contribute to 18% of the overall pharmacodynamics of ruxolitinib. 

Bottom Line:  CTP-543 will be compared to the above ruxolitinib data, after completion of the current phase 1 clinical trial.  The drug will be advancing into a phase 2 clinical trial for patients with moderate to severe Alopecia Areata, in the first quarter of 2017.  CTP-543 is the deuterated version of ruxolitinib.  Thank you for reading.  

Contact:  portfoliomgt1@gmail.com  

Friday, November 11, 2016

Axsome Therapeutics Progress Update

We originally wrote about Axsome Therapeutics (AXSM) and their drug AXS-05 here AXS-05 a Novel Mechanism of Action.  Some new information for Axsome occurred this week. 
  • First the company completed an agreement for a term loan of up to $20 million dollars from Silicon Valley Bank, with minimal dilution.  This bolsters their cash to around $40 to $50 million.  The company plans to move AXS-05 into a phase 2/3 clinical trial for Alzheimer's patients with agitation symptoms with this new capital.
  • Other news that could have an impact on Axsome and their NMDA / bupropion drug combination AXS-05 for TRD (treatment resistant depression), is that competitor Otsuka, who was also pursuing the same indication with AVP-786 (NMDA, Sigma-1), has decided not to advance the drug past their recently completed phase 2 clinical trial.  So at present, AXS-05 is one of the most advanced oral NMDA (dextromethorphan) drug in clinical trials for treatment resistant depression. 
Bottom Line:  The increased cash raise was needed to advance AXS-05 into other clinical trials.  The company is extremely lean, as their quarterly burn rate was just $6.8 million in the second quarter, but is expected to increase with more clinical trials planned.  AXS-05, drug combination for treatment resistant depression, should have phase 3 results mid 2017, with patent into 2034.  Thank you for reading. 

Contact:  portfoliomgt1@gmail.com

Tuesday, November 8, 2016

Concert Pharmaceuticals Third Quarter 2016 Conference Call

Concert Pharmaceuticals released their 2016 3rd quarter conference call this morning at 8:30 a.m.  The call provided a very detailed description of the overall company, with a focus on CTP-543 for Alopecia Areata.  Below are additional details regarding CTP-543, and the design of a upcoming phase 2 clinical trial to begin in the first quarter of 2017. 
  • Release single and multiple phase 1 results by end of 2016.
  • Initiate a crossover study CTP-543 and ruxolitinib by end of 2016.
  • Pharmacodynamics (PD) phase 1 inhibition of STAT 3 marker, as demonstration of CTP-543's ability to affect downstream gene regulation, results in Q1 2017. 
  • Initiate phase 2 safety and efficacy trial for moderate to severe Q1 2017.
  • Efficacy measurement will be the SALT (Severity of Alopecia Tool Score).
  • Primary endpoint is the percentage of responders with at least 50% improvement from baseline in their SALT score at 24 weeks, 100 SALT =  (zero hair), 0 SALT =  (complete hair regrowth or 100%). 
  • Top line 24 week study readout, by the end of 2017.
  • Extension 28 week safety and efficacy study dosing with CTP-543.
  • The company feels that they are in a very strong position with their patent for CTP-543 (d-ruxolitinib).
There has been significant progress with CTP-543, in a short period of time.  The patent expiration runs to 2032.   Thank you for reading. 

Contact:  portfoliomgt1@gmail.com

Friday, October 28, 2016

Galapagos Updates Cystic Fibrosis Program (5)

Galapagos presented data at the 2016 NACFC conference in Orlando yesterday, with a focus on SAPHIRA (2) results with drug GLPG1837 for CF people with the S1251N mutation.

Galapagos Abstract 253
Phase 2 results from SAPHIRA (2) S1251N
The bottom line with this small clinical trial that included n=7 patients, was that the company monitored in line FEV1, but below expectations for sweat chloride (readings in naïve patients that have never received Kalydeco, did not show a reduction in sweat chloride when administered GLPG1837 for 7 days) both compared against what Kalydeco had previously achieved at two weeks, in clinical trials for similar CF patients.  Sweat chloride readings is a biomarker that the FDA will want to see in clinical trials, prior to any approval.
 
Phase 2 from SAPHIRA (1) for G551D
The company will have top line results by the end of 2016.  The company mentioned that Kalydeco for similar patients in (G551D), the FEV1 was around 6% to 10% improvement at the two week timeframe.  So that may be seen as a close comparison for their top-line results.  Below is a new CF timeline schedule for the company.  

Timeline for Potentiators:
GLPG1837 Phase 2 SAPHIRA (1) G551D readout by end of 2016
GLPG2451 Phase 1 readout first half of 2017
GLPG3067 Phase 1 start in 2017  (NEW)

Timeline for Correctors:
GLPG2222 Phase 2 start Q4 2016
GLPG2737 Phase 1 start Q4 2016
GLPG2851 Phase 1 start 2017

Bottom Line:
GLPG1837 was the first potentiator to enter clinical trials as twice daily dosing for Cystic Fibrosis people.  The company should have a readout by the end of 2016 for n=27 phase 2 clinical trial SAPHIRA (1) participants of the G551D mutation.  This will be an important readout regarding the future of that drug.  Concert should be into a phase 2 clinical trial with drug CTP-656  for G551D participants in the next few months, with readout by the end of 2017.  Thank you for reading.

Contact:  portfoliomgt1@gmail.com 

Saturday, October 22, 2016

SAGE-217

We first wrote about Sage Therapeutics here SAGE-547 for Postpartum Depression.  SAGE-547 was highly effective in a phase 2 clinical trial for postpartum depression.  The future pipeline is more dependent upon SAGE-217, which is built around the same premise as SAGE-547, but as a once daily oral delivery.
The company describes SAGE-217 as "a novel neuroactive steroid that acts as a positive allosteric modulator of synaptic and extra-synaptic GABAa receptor subtypes.  Unlike many of the naturally occurring neuroactive steroids, SAGE-217 has a pharmacokinetic profile to potentially support once-daily oral dosing and a selectivity profile that minimizes potential off-target side effects."
SAGE-547 and SAGE-217 have a unique mechanism of action (MOA), and has been found to act very rapidly, with a mild safety profile.  The company has recently completed a secondary offering.  The profile is below. 

Quick Facts:
Shares Out:  37M
Market cap:  $1.6B
Cash:  $272M
Patents:  Range from 2032 to 2036

Bottom Line:
Sage Therapeutics is an interesting company with plenty of cash and a very successful phase 2 clinical trial completed.  The future will be focused on their oral, once daily SAGE-217.  We will keep you posted with further updates on SAGE.  Thank you for reading.

Contact:  portfoliomgt1@gmail.com
 

Saturday, October 15, 2016

2016 NACFC Conference October 27-29th

This years North American Cystic Fibrosis Conference (NACFC), will be held in Orlando from October 27th through the 29th.  Below are some abstracts to look for during that conference. 
ConcertAbstract 224CTP-656  Multiple Dose Pharmacokinetic Profile Continues to Support a Once-Daily Potentiator for Cystic Fibrosis Patients with Gating Mutations.  The trial showed a superior PK profile compared to ivacaftor. 

GalapagosAbstract 252Safety, tolerability, and pharmacokinetics of a novel CFTR corrector molecule GLPG2222 in healthy volunteers.  Full safety and PK data will be presented at the conference. 
Galapagos: Abstract 253GLPG1837 in subjects with cystic fibrosis (CF) and the S1251N mutation:  Results from a phase IIA study (SAPHIRA2).  Pending results September.

Proteostasis Therapeutics: Abstract 187:  Phase 1 initial results evaluating safety, tolerability, PK and biomarker data using PTI-428, a novel CFTR modulator, in patients with cystic fibrosis.  PTI-428 is an amplifier designed for any mutation. 

 Vertex:  Abstract 188:  Discovery and biological profile of next-generation CFTR Correctors.  VX-152 and VX-440 are highlighted in this abstract.  Vertex has other abstracts listed, that have been previously presented.

The link to the NACFC abstracts can be found here, 2016 NACFC Abstracts.            
Thank you for reading.

Contact:  portfoliomgt1@gmail.com                              

Thursday, October 6, 2016

Ruxolitinib For Alopecia Areata

This academic Alopecia Areata clinical study by Columbia University, has finally been released in full to the public.  I highlighted what I believe are the important points to consider regarding this study.  The complete study can be found here JCI. 
Abstract
BACKGROUND. Alopecia areata (AA) is a common autoimmune disease with a lifetime risk of 1.7%; there are no FDA-approved treatments for AA. We previously identified a dominant IFN-γ transcriptional signature in cytotoxic T lymphocytes (CTLs) in human and mouse AA skin and showed that treatment with JAK inhibitors induced durable hair regrowth in mice by targeting this pathway. Here, we investigated the use of the oral JAK1/2 inhibitor ruxolitinib in the treatment of patients with moderate-to-severe AA.
METHODS. We initiated an open-label clinical trial of 12 patients with moderate-to-severe AA, using oral ruxolitinib, 20 mg twice per day, for 3–6 months of treatment followed by 3 months follow-up off drug. The primary endpoint was the proportion of subjects with 50% or greater hair regrowth from baseline to end of treatment.
RESULTS. Nine of twelve patients (75%) demonstrated a remarkable response to treatment, with average hair regrowth of 92% at the end of treatment. Safety parameters remained largely within normal limits, and no serious adverse effects were reported. Gene expression profiling revealed treatment-related downregulation of inflammatory markers, including signatures for CTLs and IFN response genes and upregulation of hair-specific markers.
CONCLUSION. In this pilot study, 9 of 12 patients (75%) treated with ruxolitinib showed significant scalp hair regrowth and improvement of AA. Larger randomized controlled trials are needed to further assess the safety and efficacy of ruxolitinib in the treatment of AA.
TRIAL REGISTRATION. Clinicaltrials.gov NCT01950780.
FUNDING. Locks of Love Foundation, the Alopecia Areata Initiative, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the Irving Institute for Clinical and Translational Research/Columbia University Medical Center Clinical and Translational Science Award (CUMC CTSA).
Introduction
Alopecia areata (AA) is a major medical problem and is among the most prevalent autoimmune disease in the US, with a lifetime risk of 1.7% (1). AA affects both sexes across all ethnicities and represents the second most common form of human hair loss, second only to androgenetic alopecia (2). AA usually presents with patchy hair loss. One-third of these patients will experience spontaneous remissions within the first year. However, many patients’ disease will progress to alopecia totalis (AT, total scalp hair loss) or alopecia universalis (AU, loss of all body hair). Persistent moderate-to-severe AA causes significant disfigurement and psychological distress in affected individuals (3). In clinical practice, there are no evidence-based treatments for AA (4), yet various treatments are offered, most commonly topical and intralesional steroids, which have limited efficacy.
Our recent mechanistic studies demonstrated a dominant role for type I cellular immunity in AA pathogenesis, mediated by IFN-γ–producing NKG2D-bearing CD8+ cytotoxic T lymphocytes (CTLs) (5). The central role of type I cellular immunity is also reflected in the transcriptional landscape of AA lesional skin in humans and mice, which is dominated by IFN response genes and a CTL signature. These findings provided the rationale for therapeutically targeting JAK1/2 kinases in AA, and, indeed, we showed that treatment with JAK inhibitors reversed AA in C3H/HeJ mice and eliminated the type I inflammatory response in the skin (6).
On the basis of our preclinical findings, we initiated a phase II efficacy signal-seeking clinical trial in moderate-to-severe AA, assessing the clinical and immunopathological response to treatment with oral ruxolitinib, a JAK1/2 inhibitor currently FDA approved for the treatment of myeloproliferative disorders.
Results
Efficacy. This study was an open-label clinical trial to investigate ruxolitinib (Jakafi, Incyte Pharmaceuticals), 20 mg orally twice daily, in the treatment of moderate-to-severe AA (Table 1 and Figure 1A). All patients received ruxolitinib for 3–6 months, followed by a 3-month observational phase to assess treatment response durability.
Hair regrowth during and following discontinuation of ruxolitinib treatmentFigure 1
Hair regrowth during and following discontinuation of ruxolitinib treatment. (A) Patient enrollment flow chart. (B) Severity of alopecia tool (SALT) scores for individual patients during (solid lines) and following cessation of (dashed lines) ruxolitinib treatment. (C) Percentage regrowth for individual patients during and following cessation of ruxolitinib treatment. (D) Predicted (black lines) and actual patient regrowth trajectories (blue lines) from regression models presented in Supplemental Table 1.

Table 1
Demographic and treatment time variables overall and by responder status
Nine of twelve patients (75%) had significant hair regrowth and achieved the primary outcome of at least 50% regrowth (Table 2). The mean baseline severity of alopecia tool (SALT) score of 65.8% ± 28.0% decreased to a score of 24.8% ± 22.9% at 3 months and to a score of 7.3% ± 13.5% at the end of 6 months of treatment (P < 0.005, Table 2). As a group, the responders exhibited a 92% reduction in hair loss from baseline (Figure 1, B–D;Figure 2; and Supplemental Table 1; supplemental material available online with this article; doi:10.1172/jci.insight.89790DS1), with 7 of the 9 responders achieving over 95% regrowth by end of treatment.
Clinical photographs of responder AA patients on ruxolitinib.Figure 2
Clinical photographs of responder AA patients on ruxolitinib. Pairs of photographs for subjects 1, 2, 3, 4, 8, 9, 10, 11, and 12 are shown as labeled. Photographs labeled “a” in each pair were taken at baseline, and those labeled “b” were taken at the end of treatment with ruxolitinib.

Table 2
Description of variables at baseline and end of treatment, among all subjects, responders only, or nonresponders only
Regrowth was seen in responders as soon as 4 weeks after study medication was initiated and initially presented as variably subtle patchy areas of regrowth, consisting of pigmented terminal hairs, with the exception of one patient (subject 4) with concurrent vitiligo, who exhibited primarily gray hair regrowth. Of note, the areas of vitiligo in this patient were also noted to improve with ruxolitinib treatment (7). Hair regrowth for all responders increased steadily, with substantial increases each month, resulting in the majority (8 of 9) of responders achieving at least 50% regrowth by the week 12 visit. Responding patients with evidence of regrowth at 3 months continued treatment until they had either achieved 95%–100% regrowth or completed 6 months of treatment.
Durability of responses was assessed in the 3-month follow-up period off treatment. Three of nine responders noted shedding, beginning at week 3 following ruxolitinib discontinuation, and had marked hair loss at week 12 off drug (Supplemental Figure 1); however, hair loss did not reach baseline levels (Figure 1, B and C). Six of nine responders reported increased shedding without major hair loss.
Biomarker and clinical correlative studies. Gene expression profiling was performed on skin biopsies taken at baseline and following 12 weeks of treatment, with additional optional biopsies performed earlier in the treatment course. Baseline scalp samples exhibited a distinct gene expression profile when compared with samples taken from unaffected patients (Figure 3Aand Supplemental Table 2). Following ruxolitinib treatment, gene expression profiles of AA patient scalp samples clustered more closely with healthy control scalp samples than with baseline AA samples (Figure 3B), indicating global normalization of the AA pathogenic response. Gene expression profiles attributed to the IFN, CTL, and hair keratin (KRT) signatures were assessed in the trivariate AA disease activity index (ALADIN, Figure 3C), a summary index of the AA pathogenic inflammatory response and hair regrowth (8). Importantly, eventual AA responders clustered together on the ALADIN matrix at baseline, sharing high IFN and CTL scores (Figure 3, C and D).
Biomarkers based on skin gene expression correlate with clinical response.Figure 3
Biomarkers based on skin gene expression correlate with clinical response. (A) Heatmap and clustering dendrogram of samples from patients at baseline (nresponders = 9,nnonresponders = 2) and week 12 of treatment (nresponders = 9, nnonresponders = 1) and healthy controls (n = 6) using differentially expressed genes between baseline responder and healthy control samples (Supplemental Table 2). Black, normal subjects; red, AA responder patient at baseline; purple, AA responder patient after 12 weeks treatment; yellow, AA nonresponder patient at baseline; blue, AA nonresponder patient after 12 weeks treatment. (B) Principal components plots of samples taken from subjects at 12 weeks after treatment and at baseline. Principal components are labeled PC1, PC2, and PC3. (C) Heatmap of AA disease activity index (ALADIN) genes. (D) Three-dimensional plot of ALADIN signatures. (E) ALADIN component signature scores. Left panel, cytotoxic T lymphocyte (CTL) signature scores; middle panel, IFN signature scores; right panel, hair keratin (KRT) signature scores. R, responders; NR, nonresponders; HC, healthy controls. *P < 0.05, **P < 0.01, ***P <0 .001.="" 0="" 12="" and="" by="" compare="" compared="" followed="" kruskal-wallis="" ranked-sum="" samples.="" samples="" signed-rank="" strong="" style="box-sizing: inherit;" test.="" test="" the="" to="" used="" using="" was="" week="" were="" wilcoxon="">F
Adverse events. Ruxolitinib was well tolerated and safely administered in all 12 patients. There were no serious adverse effects, and no patients required discontinuation of therapy. Observed adverse effects were infrequent and included 3 minor bacterial skin infections (in the same patient), 9 episodes of upper respiratory tract infection/allergy symptoms in 7 patients, 1 urinary tract infection, 1 case of mild pneumonia, 1 conjunctival hemorrhage following a surgical procedure, and mild gastrointestinal symptoms. One patient developed lowered hemoglobin, which resolved with dose modification.  Thank you for reading.

Contact:  portfoliomgt1@gmail.com