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Friday, June 24, 2016

Putting A Value On BioSig's PURE EP

BioSig Technologies, Inc. (BSGM) is a Minnesota-based medical device company developing a proprietary technology platform designed to improve the rapidly growing multi-billion dollar electrophysiology (EP) marketplace. The system is called PURE EP, and it marries together proprietary hardware and advanced signal processing software that improves the signal clarity of cardiac data during an electrophysiology study. PURE EP provides information unobtainable from existing EP devices on the market today. The enhanced real-time information provides the electrophysiologists with a better diagnostic tool, leading to improved clinical outcomes through maximized ablation efficacy, shorter surgery times, and minimized need for repeat procedures.

PURE EP is a Class II medical device designated by the U.S. FDA. As such, FDA approval is possible through a 510(k) application. This means BioSig should not need human clinical data as part of the application to the agency. Proof-of-concept and pre-clinical data exist through the company’s collaboration with UCLA Labs and The Mayo Clinic. In my last article on BioSig, I reviewed very important data presented at the International Dead Sea Symposium (IDSS) by researchers at the Mayo Clinic in March 2016. Investors can view that article here >> LINK

In this article, I thought I would take a look at what BioSig Technologies is worth based on some conservative assumptions of success.

Tuesday, June 21, 2016

RedHill Reports Positive Phase 1 For YELIVA™

On June 21, 2016, RedHill Biopharma (NASDAQ: RDHL) released full results from the company's Phase 1 clinical trial with YELIVA™ (ABC294640) for the treatment of patients with advanced solid tumors. The full clinical study report is consistent with the positive top-line data reported by the company in October 2015. Primary and secondary endpoints were successfully met demonstrating the drug is well tolerated and can be safely administered to cancer patients at predicted therapeutic levels.

Successful Phase 1 Study In The Books

A total of 21 patients with advanced solid tumors were enrolled in the Phase 1 trial. The majority of the subjects had gastrointestinal cancers, including pancreatic, colorectal, and cholangiocarcinoma. The study took place at the Medical University of South Carolina (MUSC) and was supported by grants from the U.S. National Cancer Institute (NCI) awarded to MUSC and from the U.S. FDA's Office of Orphan Products Development (OOPD) awarded to Apogee Biotechnology Corp., the original inventor of the drug. 

RECIST 1.1 data was available for 16 of the 21 subjects. Results show one subject with partial response and six with stable disease. Of the three patients with cholangiocarcinoma, one had a partial response, and the other two had stable disease, one for over a year. The most common side effects were grade 1-2 fatigue and nausea. PK/PD data showed administration of YELIVA™ resulted in a rapid and pronounced decrease in sphingosine 1-phosphate (S1P) levels over the first 12 hours, with a return to baseline at 24 hours, which is consistent with the clearance of the drug. 

A Validated Approach

I just wrote a very detailed article on YELIVA™ last week, so I will not delve into the science or the history of the drug here. However, investors should know that the mechanism of action - downregulation of aberrant sphingosine 1-phosphate (S1P) - is a clinically and commercially validated approach to targeting inflammatory and autoimmune diseases (1). 

In September 2010, Novartis gained U.S. approval for Gilenya® (fingolimod) for the treatment of multiple sclerosis. Fingolimod-phosphate, the active metabolite of Gilenya®, is an S1P receptor modulator that affects immune cell trafficking and activation of innate and adaptive immune response. Gilenya® is thought to arrests lymphocyte egress from secondary lymphoid tissues and reduces neuroinflammation in the nervous system (2). The reduction of inflammation on both the central and peripheral nervous system propagates nerve regeneration via elevation of axonal cAMP and reduction of lysophosphatidic acid (LPA) (3).

In July 2015, Celgene acquired Receptos for $7.2 billion, primarily to add ozanimod, a novel S1P receptor modulator to its pipeline. Ozanimod is currently under late-stage clinical development for the treatment of ulcerative colitis, Crohn's disease, and multiple sclerosis. The ability of ozanimod to sequester lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, contributes to the drug's potential utility in autoimmune and inflammatory diseases (4).

However, both fingolimod and ozanimod convey the risk of serious infection, likely due to the drugs' sequestering of lymphocytes. The label for Gilenya® includes warnings for risk of serious infections, including progressive multifocal leukoencephalopathy (PML). YELIVA™, on the other hand, does not sequester lymphocytes. The mechanism to downregulate S1P is through inhibition of sphingosine kinase-2 (SK2), a conserved lipid kinase that catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate. RedHill is currently targeting cancer indications with YELIVA™, including both solid tumor and hematological cancers, but the mechanism is one that certainly warrants exploration of inflammatory and autoimmune diseases as well (5).

Next Steps For YELIVA™

RedHill is currently recruiting patients for a Phase 1/2 clinical study (NCT02229981) with YELIVA™ for refractory or relapsed Diffuse Large B-cell Lymphoma (DLBCL). Funding from this program is being supported by a $1.5 million grant awarded by the NCI under the NIH SBIR/STTR program to Apogee in conjunction with the Louisiana State University Health Science Center (LSUHSC). Estimated target enrollment is 33 patients with DLBCL, with the primary analysis focusing on the tolerability of the drug. Secondary evaluations will focus on the preliminary signs of efficacy. The trial is expected to complete in 2017.

Over-expression of S1P is quite common in patients with DLBCL. A team of researchers out of Japan found S1PR1 over-expression in 15.7% of all cases with DLBCL and over half of the cases with primary testicular (PT)-DLBCL (6). The potential to improve response to Rituxan® represents an exciting path forward for YELIVA™ in this indication.

A Phase 1/2 study of YELIVA™ for the treatment of refractory or relapsed Multiple Myeloma (rrMM) will initiate in the coming weeks. The study will take place at Duke University Medical Center and is supported by a $2 million grant awarded to Apogee, in conjunction with Duke University, from the NCI SBIR Program. SK2 is over-expressed in myeloma cells and contributes to myeloma cell survival and proliferation. Data published by MUSC in Blood in 2014 shows that inhibition of SK2 by YELIVA™ effectively inhibited myeloma cell proliferation and induced caspase 3–mediated apoptosis (7). The mechanism of action is down-regulation of c-Myc and Mcl-1, and that there may be a synergistic benefit to combination with a Bcl-2 inhibitor, such as venetoclax (Venclextra™).

Finally, a Phase 2 study with YELIVA™ for the treatment of advanced Hepatocellular Carcinoma (HCC) should be initiated in the third quarter of 2016. The study will take place at the MUSC Hollings Cancer Center, with additional clinical centers in the U.S. The study is supported in part by a $1.8 million grant from the U.S. NCI awarded to MUSC, with additional funding from RedHill. 

The initiation of the Phase 2 HCC study is quite interesting because researchers out of MUSC published data in 2011 showing the antitumor effects of YELIVA™ combined with the multikinase inhibitor, Nexavar® (sorafenib), in mouse models of hepatocellular carcinoma xenografts (8). New data just recently published in Oncotarget show synergistic effects between YELIVA™ and sorafenib in preclinical models of Cholangiocarcinoma (9). Positive Phase 2 data in HCC could spark significant partnering interest in YELIVA™ from big pharma.

Conclusion

Initial clinical funding to date for YELIVA™ has been through non-dilutive grants and awards to partners and universities. I found over a dozen proof-of-concept results in numerous solid tumor and hematological indications. RedHill exited the first quarter with $53.4 million in cash, so management can pursue multiple paths forward with YELIVA™ development. I'm not aware of any other company working on an SK2 inhibitor (per FactSet, June 2016), a mechanism that seems to offer potential synergy with chemotherapies paclitaxel, docetaxel, 5-FU, and cisplatin, along with targeted therapies, including Rituxan® and Nexavar®. I'm particularly interested in the upcoming trials in DLBCL, MM, and HCC.

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Related:

Why Big Pharma Should Be Interested In RedHill's YELIVA™>> LINK

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BioNap is party to a services agreement with the company that is the subject of this report pursuant to which BioNap is paid five thousand dollars per month by the company in exchange for the provision of research reports, investor relations services, and general consulting services. Please see additional information on our Disclaimer.

Wednesday, June 15, 2016

Why Big Pharma Should Be Interested In RedHill's YELIVA™

In October 2015, RedHill Biopharma (RDHL) announced positive top-line results from a Phase 1 clinical study with YELIVA™ (ABC294640) in patients with advanced solid tumors (see release). The primary endpoint of the study was to identify the maximum tolerated dose (MTD) and any dose-limiting toxicities that would inhibit use of the drug in the next stage of clinical trials. Secondary endpoints included safety, toxicity, pharmacokinetics (PK), and pharmacodynamics (PD), all of which were met successfully in the Phase 1 study.

In the next few weeks, I'm expecting management to provide the final data from the Phase 1 study. For the purpose of this article, I thought I'd focus on the available data with YELIVA and where RedHill might take the drug in the next stage of studies. I think YELIVA represents a very interested asset that a larger pharmaceutical company might like to acquire. The drug offers a novel mechanism of action, can be dosed orally, and has synergistic benefits with some large blockbuster oncology drugs, including Avastin®, Erbitux®, Rituxan®, and Nevaxar®.

RedHill's corporate strategy is to advance novel assets for gastrointestinal, inflammatory, and oncology indications into late-stage clinical studies and then partner for commercialization. The company has three Phase 3 GI-related assets, RHB-104 for Crohn's disease, RHB-105 for H. pylori infection, and Bekinda™ for gastroenteritis / irritable bowel. Partnering opportunities exist with all three, but YELIVA might represent the most interesting overall opportunity for the company.

Tuesday, June 14, 2016

Relmada's LevoCap ER Is A Target For Specialty Pharma

As most investors that have followed my work know, I've been a big fan of Depomed, Inc. for the past several years. Depomed, along with fellow specialty pharmaceuticals players including Purdue, Horizon, Endo, and Mallinckrodt, has shown that it is possible to build a successful commercial business focusing on the pain market. I say that because developing new drugs in the pain and neurology space is notoriously one of the most challenging areas of pharmaceutical development. The challenge is likely due to the diverse nature of the affliction, the vastly different ways in which individuals respond to pain medications, compliance, and pesky placebo response.

My article today will focus on a new potential player in the pain and neurology market, Relmada Therapeutics (RLMD). I'm intrigued by Relmada because the company has a diverse pipeline of pain medications in various stages of clinical development. The lead candidate, d-methadone, has characteristics that make the drug look very intriguing for neuropathic or psychiatric pain and depression, an enormous market opportunity validated by the success of some blockbuster drugs, including Pfizer's Lyrica® and Eli Lilly's Cymbalta®. I've already written about d-methadone, so I encourage investors to view that article >> HERE.

For this article, I focus on LevoCap ER, an extended release, abuse deterrent formulation of levorphanol. Relmada will request a Type-B meeting with the U.S. FDA for late summer 2016, after which time management would like to partner the asset for the initiation of a Phase 3 trial in 2017. Depomed's acquisition of the Nucynta® franchise and cebranopadol proves the market for novel pain drugs remains hot, and with companies like Purdue, Endo, and Mallinckrodt struggling to find growth and protect their core business, Relmada Therapeutics might be an excellent acquisition target as its pipeline matures. 

Monday, June 13, 2016

Revive Therapeutics Targets Cystinuria With Bucillamine

Focus On Rare Diseases Could Results In Substantial Returns

Targeting rare and orphan diseases is a business model validated by many smaller biopharmaceutical companies. Although the patient populations are modest, they are highly specific and can be efficiently targeted with a focused sales effort. Limited competition and agency-backed intellectual property protection make this strategy incredible profitable, and one that has gained in popularity over the past decade. Cystinuria is one such orphan disease, the success of which targeting has been substantiated by Retrophin, Inc (NASDAQ: RTRX).

In late May 2016, Revive Therapeutics (TSXV: RVV) (OTC: RVVTF) announced it intends to raise $1.5 million through a best-efforts non-brokered private placement. Raising such a small amount of $1.5 million usually would not excite biopharma investors, but I find this case quite intriguing given the current market value of Revive at only $2.5 million as of today. I also find management's comments in the release interesting. The proceeds will be used to advance the development of bucillamine into a Phase 2 clinical study during the second half of 2016 for the treatment of cystinuria.

Bucillamine is a drug that has been approved and used in Japan for over three decades, mostly for the treatment of rheumatoid arthritis (RA). Ayumi Pharma reports 57 million tablets sold in 2015. Recent data confirm the efficacy of bucillamine in RA (1), as well as other oxidative conditions such as cisplatin-induced ototoxicity (2) and transplantation-associated reperfusion injury (3). Revive has previously studied bucillamine in a Phase 2a study in patients with gout, demonstrating efficacy comparable to Takeda's Colcrys® (4).

The opportunity in gout is real, although further advancement is something that is beyond the current capabilities of Revive. As such, Revive will seek to partner bucillamine for the next steps in gout and instead focus on cystinuria, a smaller patient population but one that offers potential peak sales in the $500 million range given the success of Retrophin's Thiola® and the conceptual superiority of bucillamine to monothiol drugs like tiopronin and d-penicillamine.

I'm eagerly watching the success of Revive's planned private placement. I think if the deal closes investors could see a substantial recovery in the shares. I expect Revive to file a U.S. investigational new drug (IND) application for bucillamine in the treatment of cystinuria shortly, which should allow the initiation of a Phase 2 study in the coming months.

Below is an introduction to cystinuria and the market opportunity that Revive has with bucillamine. I believe the shares are vastly under-valued as of today, artificially depressed by the announced best-efforts private placement - a quandary unique to the backward way in which Canadian companies must raise cash. With limited investment and a rather quick turnaround, Revive should be able to demonstrate proof-of-concept with bucillamine in cystinuria and set the stage for a major re-valuation of the shares in 2017.

Wednesday, June 8, 2016

Can-Fite Takes Aim At Celgene's Otezla

On June 7, 2016, Can-Fite BioPharma Ltd. (CANF) announced it had submitted a protocol design to the European Medicines Agency (EMA) for a Phase 3 trial and Registration Plan for piclidenoson (CF101) in the treatment of psoriasis. The filing of the protocol design follows a pre-submission meeting held between the company and the EMA earlier in the year. In the planned Phase 3 trial, Can-Fite will study piclidenoson's efficacy and safety in treating psoriasis, head-to-head, versus Celgene's Otezla® (apremilast). In 2015, Celgene reported global Otezla® sales of $472 million. By 2022, Evaluatepharma believes Otezla® will generate $2.9 billion in sales.

Taking on biotech behemoth Celgene head-to-head is a ballsy move by Can-Fite. I love it! Finally, a biopharma company is willing to run a Phase 3 trial that means something. Otezla® sales are soaring at Celgene, and given the similar mechanism of action among the two drugs, this is the type of real data that patients, physicians, and payers want to see. 

Which drug is better? We will have to wait for the results of the Phase 3 trial to be certain, but the best place to start today is by comparing Can-Fite's previous results with the published data for Otezla®.

Tuesday, June 7, 2016

What Is Immune Pharma Doing With Ceplene?

Last week, shares of Immune Pharmaceuticals (IMNP) spiked in response to Jazz Pharma's acquisition of Celator Pharma for $1.5 billion. Celator is developing VYXEOS™, a liposome injection of cytarabine + daunorubicin for patients with high-risk (secondary) acute myeloid leukemia (AML). Back in March 2016, Celator announced Phase 3 data showing its formulation to be vastly superior to the standard of care regimen of cytarabine + daunorubicin, known as "7+3". In my opinion, VYXEOS will become the new standard of care for induction therapy in patients with high-risk AML. Jazz's take-out of Celator at nearly 100% premium has brought significant investor interest to the AML space.

Over the past few months, Immune has been highlighting new analyses of data with Ceplene® hinting at a potential path forward for the drug. Ceplene (histamine dihydrochloride) is administered in conjunction with low dose interleukin-2 (IL-2) for maintenance of remission in patients with AML following successful induction therapy. In theory, these are patients (or future patients) that achieve complete remission (CR) using VYXEOS but are ineligible for a "curative" bone marrow transplant (BMT) or still considered high-risk for relapse post-consolidation or post-BMT.

Investors briefly turned their enthusiasm for AML stocks to Immune early last week. Whether or not the spike in Immune Pharma shares was warranted is the subject of an article on Seeking-Alpha by Tom Mathies (see article HERE). In short, the author does not believe Ceplene has a viable future. However, I've studied some of the recent data that Immune has presented, including a new post hoc analysis from the Phase 3 trial and new data biomarker response analysis presented at the American Association for Cancer Research (AACR) Annual Meeting in April 2016, and I think there are some key points worth mentioning about Immune's Ceplene strategy.

Monday, June 6, 2016

Target Validation Enhances Potential For Pieris’ Inhaled Asthma Drug

Pieris Pharmaceuticals (NASDAQ: PIRS) is a biopharmaceutical company developing a novel class of drugs called Anticalins®, which are similar to monoclonal antibodies (mAbs) in that they are target-specific binding proteins, but have a number of differentiating characteristics that potentially make them superior to mAbs, such as novel routes of administration including inhalation. Below is a brief review of Pieris and the company’s Anticalin® platform. For purposes of this article, I focus on PRS-060, an Anticalin® that the company is developing as an inhaled treatment for asthma.