Saturday, October 22, 2016


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.  Their profile now looks like this 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.


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 some 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.


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
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.
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).
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.
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.


Wednesday, September 28, 2016

ITI-007 Phase 3 Results

This is the second phase 3 clinical trial for patients with schizophrenia and Intra-Cellular drug ITI-007.  This trial had Risperidone as an active comparator and a placebo arm, the clinical trial is here NCT02469155.  I am including our write up on the first phase 3 clinical trial (Study '301) here ITI-007 Phase 3 Results, for the specific reason of attempting to uncover how ITI-007 has performed on the PANSS Negative Symptoms subscale.  The first phase 3 clinical trial did not show statistically significant improvement in the PANSS Negative Symptoms subscale from the company PR in September of 2015. 
Today (Study '302) the company released phase 3 clinical trial top line results, that did not mention any significance to the Negative Symptoms in the Intra-Cellular press release here, Intra-Cellular Therapies Announces Top-Line Results from the Second Phase 3 Trial of ITI-007 in Patients with Schizophrenia (Study ‘302)

Bottom Line:  Intra-Cellular's ITI-007 results today should create plenty of skepticism regarding the drug as a viable CNS candidate for schizophrenia, bi-polar, and Alzheimer's agitation. The company is currently in phase 3 for both of the two later indications with ITI-007.  The PANSS Negative Symptom subscale had zero mention from today's top-line press release. Based on the two phase 3 clinical trials, ITI-007 does not have a strong effect on the PANSS Negative Symptoms subscale.  AVP-786 is currently in clinical trials being tested for negative symptoms associated with schizophrenia.  Thank you for reading. 


Friday, September 16, 2016

Deuterated Drugs

Giving credit where due.  Below are two well written articles on the deuteration of drugs.  I have taken parts of the articles that seem pertinent to us, for investment purposes.  The complete articles can be accessed from the Concert Pharmaceuticals website below.

From:  "A decades-old drug technology finally nears it's big breakthrough"

Should Teva get regulatory approval, it would open a market in the “many tens of billions of dollars,” said Roger Tung, whose company Concert Pharmaceuticals Inc. is also developing treatments with deuterium.  “It would show the breadth of possibilities,” Tung, the chief executive officer of Lexington, Massachusetts-based Concert, said in an interview. “Deuterium provides unique properties that cannot be attained in any other way.”

From:  "Deuterium switcheroo breathes life into old drugs"

Even champions of deuterated drugs note there are plenty of pitfalls. Thomas Gant, scientific founder of the deuterated drug maker Auspex (he’s no longer with the company) and inventor of many deuterated drug candidates, including SD-809, says most synthetic chemists don’t have a good grasp of how chemical reactions operate in the presence of deuterated reagents or substrates.
“It is actually pretty surprising how many reactions that most chemists wouldn’t think would have an effect on the positions of hydrogens will actually cause quite a bit of randomization and dancing around of hydrogen radicals,” he says. “So you run these reactions expecting it to have no effect on your deuterated drug, and in fact, you can see a pretty dramatic effect in some instances. It’ll essentially spread the deuterium around the molecule” so you don’t have the original compound anymore.
As far as intellectual property is concerned, Gant says, it’s important to know the law. Deuterated compounds are considered new chemical entities and can be patented. But to get a patent, he explains, “you have to have actually done the chemistry, produced the deuterated compound, shown the spectra, shown deuterium incorporation rates, and shown biology to demonstrate a perceived benefit.”
It’s not unusual for pharmaceutical companies to include deuterated versions of original drugs in their boilerplate wording for patents. “This is something that companies routinely do to scare off people who don’t understand patents,” Gant says. “People think that the deuterated compounds have been covered. But they haven’t been covered because they haven’t been made and they haven’t been tested. So it might be written in the general description, but it doesn’t actually cover the application of deuterated compounds. 
Thank you for reading.


Saturday, September 10, 2016

Nuplazid Launch Progression

The launch of Acadia Pharmaceuticals Nuplazid for Parkinson's Disease Psychosis (PDP), so far has been successful based on management conference call discussions. We previously wrote about the commercialization opportunity here, Nuplazid Priced at $23,400 / Year

 Chief commercial officer Terry Moore had this to say regarding the launch of Nuplazid, "One of the things I find interesting is we do have physicians report back to us that they are very pleased with what they are seeing in terms of efficacy. But what I find interesting is that they are reporting that the caregiver is reporting that they see the difference at home and that they are reporting that to the physician." 
Medicare Part D has it covered as 34/mg, taken as two 17/mg pills a day, for around $2,000 for a 30 day supply.  The annual price is similar to company guidance of $24K per year Nuplazid, for Parkinson's Disease Psychosis, which is the only approved drug for this unmet need.

Bottom Line:  This market pullback may create a decent entry price for ACAD investors that have been waiting to go long the stock.  No positions in Acadia.  Thank you for reading. 


Friday, September 2, 2016


A new patent for Concert Pharmaceuticals here, Deuterated Ibrutinib.  Ibrutinib is sold commercially under the name Imbruvica, and has a 50% - 50% sales sharing agreement by AbbVie and JNJ.  Imbruvica is a Bruton's tyrosine kinase (BTK) inhibitor for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, and is dosed once daily.  The patent expiration date is July 2032, for d-ibrutinib, and 2026 at the earliest for the non-deuterated ibrutinib. 

The drug is going head to head against Astra Zeneca's ACP-196, in a clinical trial below for previously treated subjects, with high risk chronic lymphocytic leukemia.

Estimated Enrollment:500
Study Start Date:June 2015
Estimated Primary Completion Date:June 2019 (Final data collection date for primary outcome measure)
ArmsAssigned Interventions
Experimental: ACP-196
ACP-196 will be orally administered until disease progression or unacceptable toxicity.
Drug: ACP-196
Active Comparator: ibrutinib
Ibrutinib will be orally administered until disease progression or unacceptable toxicity.
Drug: ibrutinib

Bottom Line:  Analyst have projected up to 6 billion in annual revenue for Imbruvica, for various cancer indications.  The 500 patient head to head clinical trial against ACP-196 above will not readout until 2019, but more importantly when complete, will display a safety and efficacy comparison for these two drugs.  Thank you for reading.   


Wednesday, August 31, 2016


CRISPR-Cas9 is the hottest new gene-editing technology that has gained enormous press the last few years for it's accuracy.  The science is being used to address the underlying genetic causes of human disease.  The advantages seen thus far, is that it is faster, less expensive, and more accurate than prior gene-editing technology.  CRISPR-cas9 enables geneticists and medical researchers to edit parts of the genome, by cutting out, replacing or adding parts to the DNA sequence.  There are a few publicly traded companies, and one private.  The companies include the following. 

Intellia Therapeutics:  NTLA
Editas Medicine:  EDIT
Cellectis:  CLLS
Crispr Therapeutics:  Private

Bottom Line:  The above names are worth following, and learning more about the science of CRISPR-cas9 gene-editing.   Thank you for reading.


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.
click to enlarge
click to enlarge
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. 

Wednesday, August 17, 2016

Vertex VX-661 Corrector Phase 3 Clinical Trial Update

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.