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.


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 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 and in vivo, topical and systemic. Both JAK's have also shown to be effective in academic studies with humans. Thank you for reading. 


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.  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 HAMD 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.


Thursday, July 7, 2016

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.


Friday, June 24, 2016

Agitation in Alzheimer's Disease - An Unmet Need

This is an indication that has seen an increase in clinical trials that past few years.  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  (AVP-923)
Avanir (owned by Otsuka) is running three phase 3 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 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.

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, with a completion date around October 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!

Is being studied by the University Rochester School of Medicine.  The FDA put a dose limit of 20mg per day into the study.  The clinical trial is here NCT00898807.  The JAMA write up is here JAMA.  An important quote from the article relates to "cognitive worsening and QT interval prolongation observed in the citalopram group raised concern about the 30 mg per day dose used in this study and may limit the clinical utility of the findings".

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.


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 is planning a phase 2 clinical trial by the end of 2016 for agitation associated with Alzheimer's disease. 

Bottom Line:  AVP-786 (AVP-923) and Celexa, are the only drugs that have been through a clinical trial for Alzheimer's Agitation.  AVP-786 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.    



Tuesday, June 21, 2016

Inter Partes Review - The Verdict Is In

We originally wrote about this here Inter-Partes-Review-and-Patents.  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. 


Friday, June 17, 2016

Galapagos Updates Cystic Fibrosis Program

In their most recent press release, 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. 


Friday, June 10, 2016

CTP-656 ECFS Presentation

Concert presented at the European Cystic Fibrosis Society today, and presented phase 1 multiple dosing 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.

CTP-656 to M1 Ratios
Single dose CTP-656 to M1 ratio = 1.5
7th day dose CTP-656 to M1 ratio = 1.7

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.


Monday, June 6, 2016

D-Ivacaftor US Patent 9,181,192 B2

This is a new d-ivacaftor patent listed on Concerts website.  This looks like an add on to the original US patent regarding d-ivacaftor for Cystic Fibrosis, except that it has a section that relates to COPD (chronic obstruction pulmonary disease).  The added section of the patent is below.

15. A method of treating COPD in a subject comprising administering to the subject a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, wherein the compound of Formula I has the following structural formula:

Concert is currently assessing the possibility of entering clinical trials for COPD, which would be an extremely large potential market to pursue.  The patent runs to 2032.  Thank you for reading.