Elcelyx Therapeutics raises $40 million to develop delayed-release metformin

Metformin is the most widely prescribed diabetes drug in the world. Many diabetics couldn’t take the drug because of adverse side effects or impaired kidney function. Metformin could accumulate in the plasma, resulting in lactic acidosis, a fatal adverse event.

Elcelyx Therapeutics is developing a delayed-release formulation of metformin (Met DR) which limits the absorption of metformin into the blood, avoiding the risk of lactic acidosis. The company just closed a $40 million Series E financing to advance the program.

The mechanism of action of metformin remains incompletely understood. A decade ago, scientists suggested that metformin reduces glucose synthesis via activation of AMPK[1]. Researchers from the University of Pennsylvania challenged the AMPK hypothesis and provided a novel mechanism by which metformin suppresses the glucagon signaling[2].

Elcelyx researchers have their own thoughts. They believe the gastrointestinal tract is the principal site of action of metformin[3]. The drug can enhance the secretion of GLP-1 in the intestines. Thus metformin is not necessary to be absorbed into the blood.

Currently existing formulations of metformin (Met IR/XR) dissolve in the stomach, where the drug is absorbed into the blood. In contrast, Elcelyx’s delayed-release formulation passes through the stomach, and release metformin in the intestines. The metformin concentrations in the plasma were reduced by 75%.

Elcelyx has completed a 12-week, 240-patient trial[4]. The mean 4 week FPG reductions were -13 mg/dl and -18 mg/dl for 600 mg and 1000 mg Met DR. As a non-blinded reference, Met XR 1000 mg and 2000 mg resulted in FPG reductions of -12 mg/dl and -25 mg/dl. In other words, 600 mg Met DR produced a reduction in FPG similar to 1000 mg Met XR, while 2000 mg Met XR resulted in additional reductions in FPG compared to 1000 mg Met DR.

Elcelyx intends to develop Met DR for patients with kidney impairment. The Phase III trials would cost $100 million or more, which means the company may need to raise more money. I am not so optimistic about the gut-based pharmacology of metformin. It was published in PLoS One that was filled with lower quality papers.

[1] J Clin Invest. 2001, 108(8), 1167-1174.
[2] Nature. 2013, 494(7436), 256-260.
[3] PLoS One. 2014, 9(7), e100778.
[4] Diabetes Care. 2015, pii: dc150488.

Former Pharmacyclics CEO raises $75 million to develop oral checkpoint inhibitor

Corvus Pharmaceuticals closed a $75 million Series B financing yesterday. Just ten months ago, the company raised a $33.5 million Series A round. The proceeds will be used to develop its oral checkpoint inhibitor.

The company was launched by former Pharmacyclics (NASDAQ: PCYC) CEO Richard Miller last year. In Pharmacyclics, Miller established the ibrutinib program. Imbruvica (ibrutinib) is estimated to generate peak sales of $6-$9 billion. With the new company, Miller turns his attention to checkpoint inhibitors, a red hot field.

Checkpoint inhibitors such as anti-PD1 and anti-CTLA4 have been a revolution for the treatment of cancer. Many companies are developing candidates targeting other checkpoints (e.g., CD40, OX40, 4-1BB, TIM3, LAG3, GITR, KIR).

All approved checkpoint inhibitors including nivolumab, pembrolizumab and ipilimumab are monoclonal antibodies. Corvus’s lead product candidate is a small-molecule drug which could be taken orally. It also targets a different checkpoint protein, but the company didn’t disclose which one.

Small-molecule immunotherapies such as IDO inhibitors and Aduro Biotech’s (NASDAQ: ADRO) cyclic dinucleotides (CDNs) have caught the eyes of scientists and investors worldwide. Corvus could be the next big thing.

Tyrogenex presents Phase I results of oral therapy for AMD

Anti-VEGF therapies including Avastin (bevacizumab), Lucentis (ranibizumab), Eylea (aflibercept) and conbercept have reformed the treatment of wet age-related macular degeneration (AMD). Both Lucentis and Eylea sold billions of dollars per year. Conbercept, developed by Kanghong Pharmaceutical (SZSE: 002773), also sells well in China, generating CNY 110 million in the first half of 2015.

Currently approved anti-VEGF products for AMD are monoclonal antibodies and fusion proteins. Patients require repeated eye injections of anti-VEGF biologics to control their disease. An oral treatment with similar efficacy and safety will be welcomed by many patients. That is what Tyrogenex is doing right now.

Tyrogenex’s lead compound is called X-82, which inhibits VEGFR, PDGFR, FLT3 and KIT. The compound is currently in Phase II trials for wet AMD and solid tumors. In June 2014, the company received $15 million in Series D financing from Brace Pharma. The funding is used to support the Phase II trials.

The Phase I results of X-82 for AMD were presented at the 15th EURETINA Congress. The trial enrolled 35 previously treated patients with wet AMD. Four dose levels, ranging from 50 mg to 200 mg, were evaluated. Of the 25 patients completing the full 24-week treatment, 15 required no intravitreal injections of Lucentis, and had a mean visual acuity improvement of +5.3 letters.

The Phase I results were clinical meaningful. 43% (15/35) of patients maintained or improved their visual acuity scores, and did not require any injections of Lucentis. What really concerns me is the safety profile of X-82. As we know, multikinase inhibitors (e.g., sorafenib, sunitinib) could result in various adverse events. Lucentis and Eylea are well tolerated because of their high selectivity and local injection.

X-82 is derived from sunitinib, but X-82 has a shorter half-life than sunitinib, resulting in less tissue accumulation. Indeed, X-82 caused fewer side effects than sunitinib. There were still three patients experiencing transaminase elevations within the first month of starting treatment. Only 71% (25/35) of patients completed the full 24-week treatment.

Tyrogenex and its sister company, Xcovery, were founded by Dr. Chris Liang (梁从新) who emigrated from China in 1984. Liang is credited as the co-inventor of sunitinib. In 2007, Xcovery was one of the most promising biotech companies in the world, but it looks just so-so today. In October 2014, Beta Pharma invested $20 million into Xcovery while gained China rights to X-396, an ALK inhibitor. AnewPharma, a Shanghai-based company, is responsible for developing X-82 (CM082) in China.

CytomX Therapeutics graduates from Third Rock academy with Probody platform

Prodrug is an important concept in drug design. A prodrug is administered in an inactive form, and is then converted to an active metabolite in vivo. Prodrugs are often designed to selectively release the parent drugs in the diseased tissues.

Prodrug strategy is always used in the design of small molecule drugs. CytomX Therapeutics (NASDAQ: CTMX) applied the concept to create antibody prodrugs that remains inactive until it reaches the tumor. The antibody prodrugs are called probody for short.

The probody concept was proposed by Prof. Patrick Daugherty who co-founded CytomX in February 2008. The design and preclinical data of anti-EGFR probody CTX-023 have been disclosed in the journal Science Translational Medicine[1].

The probody consists of an authentic IgG heavy chain and a modified light chain. A masking peptide is fused to the light chain through a peptide linker that is cleavable by tumor-specific proteases. The masking peptide prevents the probody binding to healthy tissues, thereby minimizing toxic side effects.

CytomX’s lead candidate is an anti-PDL1 probody called CX-072. The drug is expected to be better than other anti-PDL1 antibodies because the probody does not significantly inhibit the PDL1 pathway outside of the tumor. The company anticipates filing an IND in 2016H2.

CytomX was named as a Fierce 15 biotech company by FierceBiotech in 2013. The company has filed Form S-1 for a $100 million IPO. Third Rock is the biggest investor, with 31% of the stock. Strategic partners include Bristol-Myers Squibb, Pfizer and ImmunoGen (NASDAQ: IMGN).

[1] Sci Transl Med. 2013, 5(207), 207ra144.

Checkmate Pharmaceuticals raises $20 million Series A financing for development of TLR9 agonist

Checkmate Pharmaceuticals raised $20 million Series A financing from Sofinnova Ventures and venBio. The company has licensed a virus-like particle platform including a clinical TLR9 agonist known as CYT003 from Cytos Biotechnology.

Checkmate is led by CEO Arthur Krieg, former CSO of Sarepta Therapeutics (SRPT). Krieg only worked at Sarepta for six months. Sarepta never explained the reasons for the abrupt departure of Krieg. Here is the speculation from stockerjocker (@np32817):

It was a failed bid to replace CG (Chris Garabedian) and become CEO. Board stuck with CG. AK (Arthur Krieg) then immediately terminated.

CYT003 is an immune modulator derived from CpG oligonucleotides. Krieg demonstrated that the CpG motifs in bacterial DNA was responsible for B-cell activation in 1995[1]. He led the R&D of agatolimod (PF-3512676, CPG 7909), a TLR9 agonist. However, Pfizer discontinued the Phase III trials of agatolimod in NSCLC[2] and melanoma[3] due to a lack of clinical efficacy.

Cytos has tested CYT003 in hundreds of asthma patients, and it failed to demonstrate clinical efficacy. Krieg believes the drug will enhance the efficacy of checkpoint inhibitors. Checkpoint inhibitors have shown remarkable results in cancers, but they work for only a limited number of patients (about 20%).

Why do so few patients respond to checkpoint inhibitors?
In a patient whose immune system is already activated and poised to kill their tumor, treatment with a checkpoint inhibitor can free the immune system to destroy the tumor. Unfortunately, most patients’ immune systems are not already activated so treatment with a checkpoint inhibitor does not provide any therapeutic benefit and may actually worsen the patient’s condition by causing significant toxicity.
Source: Checkmate Pharmaceuticals website.

Checkmate believes that there is tremendous promise to the combination of CpG DNA and checkpoint inhibitors. CpG DNA activates the anti-tumor T cells, while checkpoint inhibitors block immunoinhibitory signals.

Dynavax Technologies (NASDAQ: DVAX) is combining its TLR9 agonist SD-101 with Merck’s pembrolizumab in Phase I/II trials. In a 21-patient phase I study of tremelimumab plus PF-3512676, two melanoma patients achieved durable partial response[4].

[1] Nature. 1995, 374(6522), 546-549.
[2] J Clin Oncol. 2011, 29(19), 2667-2674.
[3] Cancer. 2009, 115(17), 3944-3954.
[4] Br J Cancer. 2013, 108(10), 1998-2004.

The role of CD95 in cancer: promoter or suppressor?

CANbridge Life Sciences, a Beijing-based biotech company, in-licensed China rights to Apogenix’s lead candidate, APG101. The drug is a fusion protein that consists of the extracellular domain of CD95 and the Fc domain of IgG1 and blocks the interaction between CD95 and its ligand. Apogenix has completed a Phase II trial in patients with recurrent glioblastoma[1].

What interests me is the exact function of CD95 in cancer. CD95 (also known as Fas receptor) is a death receptor on the surface of cells that mediates apoptosis. Cancer cells often downregulate CD95 to evade apoptosis. Thus CD95 agonists were considered to kill cancer cells[2]. However, severe liver toxicity was observed in mice due to CD95-mediated apoptosis of hepatocytes.

In 2010, scientists from the University of Chicago speculated that CD95 could actually promote the growth of tumors[3]. The discovery seems unbelievable because CD95 had previously been defined as a tumor suppressor.

APG101 indeed showed a clinical benefit in patients with relapsed glioblastoma in the Phase II trial. PFS rates at 6 months were 20.7% for reirradiation + APG101 and 3.8% for reirradiation alone (p=0.048). Median PFS was 4.5 months vs. 2.5 months (p=0.0162). Median OS for both two arms were 11.5 months.

In the Phase II trial, there was no difference  in median OS. Many scientists still believe CD95 is a tumor suppressor[4,5]. Apogenix announced Phase II results in March 2012, but Phase III study hasn’t been initiated until now. The median OS of 11.5 months in second-line setting is not that attractive.

[1] Clin Cancer Res. 2014, 20(24), 6304-6313.
[2] Brain Pathol. 1998, 8(2), 285-293.
[3] Nature. 2010, 465(7297), 492-496.
[4] J Immunol. 2012, 188(9), 4441-4449.
[5] J Biol Chem. 2012, 287(30), 25530-25540.

Afferent Pharmaceuticals raises $55 million to develop cough and pain killer

Afferent Pharmaceuticals completed a $55m Series C financing. The round was led by Fidelity Management & Research Company, with participation from other crossover funds. The company was founded by the biotech foundry Third Rock Ventures in December 2009.

Dr. Anthony Ford, the founder and chief scientific officer of Afferent, was previously a scientist at Roche Bioscience. About 15 years ago, Ford found that the ATP receptor P2X3 is critical for peripheral pain responses[1]. P2X3 knock-out mice have reduced pain-related behavior in response to injection of ATP.

Abbott Laboratories reported a non-nucleotide antagonist of P2X3 receptor called A-317491 in 2002[2]. At that time Ford led the P2X3 discovery program at Roche. Afferent in-licensed the P2X3 program form Roche.

Afferent is developing its lead candidate, AF-219, for the treatment of cough and bladder pain. Results from a proof-of-concept study in chronic cough patients have been published in The Lancet[3]. The drug reduced cough frequency by 75% compared to placebo.

Kathleen Glaub joined the company as CEO in August 2014. She was one of the Top 10 Women in Biotech[4] in 2011 when her company Plexxikon was sold to Daiichi Sankyo in a $935 million deal. Plexxikon’s Zelboraf (vemurafenib) gained an FDA green light for treating melanoma that year.

[1] Nature. 2000, 407(6807), 1011-1015.
[2] Proc Natl Acad Sci USA. 2002, 99(26), 17179-17184.
[3] Lancet. 2015, 385(9974), 1198-1205.
[4] http://www.fiercebiotech.com/special-reports/fiercebiotechs-2011-women-biotech

Unum Therapeutics raises $65 million to develop next-gen CAR-T

Unum Therapeutics has completed a $65 million Series B financing. New investor New Leaf Venture Partners led the round. The company was launched by Fidelity Biosciences, Atlas Venture and Sanofi-Genzyme BioVentures with a $12 million Series A financing in October 2014.

Unum is developing the antibody-coupled T-cell receptor (ACTR) technology developed by Dr. Dario Campana. At St. Jude Children’s Research Hospital, Campana previously created the anti-CD19 CAR-T that Dr. Carl June at the University of Pennsylvania took into clinical trials.

ACTR is a chimeric protein that combines the Fc receptor (CD16) with the signal transduction domains (4-1BB/CD3ζ). Engineered T cells bearing the ACTR can bind to a monoclonal antibody which then acts as a bridge to the tumor cells.

In contrast to other CAR-T therapies that hit a single target, Unum’s approach is not restricted by antigens. In other words, one ACTR therapy can be used in combination with a variety of antibodies like Rituxan or Herceptin to attack many different cancers.

In addition, the activity of CAR-T therapy can be turned up or down by adjusting antibody dose. Furthermore, Unum uses mRNA instead of a virus to modify T cells. The modified cells are disarmed in about a week. These features may avoid safety problems that were commonly reported in CAR-T trials.

Unum is testing its lead ACTR therapy, ATTCK20, in combination with Rituxan in a Phase I trial. The new money gives the company enough fuel to complete a series of proof-of-concept studies.

Pill with needles may replace injections

Most patients prefer to take a drug orally instead of getting an injection. However, a large majority of biologic cannot be given as a pill. Carl Schoellhammer, a MIT graduate student, invented a microneedle pill that may replace injections. On May 21, Schoellhammer won a $15,000 Lemelson-MIT National Collegiate Student Prize for his invention.

The system uses a capsule coated with tiny needles in order to inject drugs directly into the lining of the intestine. The capsule is 2 cm in length and 1 cm in diameter. It is coated with a series of stainless steel needles about 5 mm in length and 0.5 mm in outer diameter (25G). The needles are protected by a pH-responsive coating that dissolves upon reaching the intestine.

Fig 1. Carl Schoellhammer’s microneedle pill[1].

Because there are no pain receptors in the lining of the gastrointestinal tract, patients would not be aware of the microneedles injecting the drug. Schoellhammer has tested the capsule in pigs with success in both safety and results. The capsule could be used to deliver a broad range of drugs currently limited to injection.

Rani Therapeutics, a spinoff of InCube Labs, is developing a similar microneedle pill. The company is funded by Google Ventures, InCube Ventures, and VentureHealth. Rani’s capsule uses degradable sugar needles instead of stainless steel needles. The drug filled needles could be pushed into the wall of the intestine by carbon dioxide produced by citric acid and sodium bicarbonate.

Fig 2. Rani Therapeutics’ robotic pill[2].

[1] J Pharm Sci. 2015, 104(2), 362-367.
[2] Timothy Hay. Can ‘Robotic’ Pills Replace Injections? Wall Street Journal. February 18, 2014.

Mirna Therapeutics raises $41.8 million to develop microRNA therapy for liver cancer

Mirna Therapeutics has completed a $41.8 million Series D financing led by Baxter Ventures, Celgene Corporation, Pfizer Ventures, etc. The funding will enable Mirna to advance its lead microRNA product candidate, MRX34, into Phase Ib and Phase II trials in 2016.

MicroRNAs (miRNA) are short naturally occurring non-coding RNAs that regulate the translation of target mRNA. MicroRNAs offer greater ability to target the root causes of many diseases than conventional small molecules or proteins.

Source: miRagen Therapeutics

Several biotech companies have sprouted up to prove the miRNA concept, including Santaris Pharma, Regulus Therapeutics (NASDAQ: RGLS), miRagen Therapeutics, and Mirna Therapeutics. In 2008, Santaris Pharma pushed the first anti-miRNA therapy, miravirsen (SPC3649), into Phase I trial. In August 2014, Roche acquired Santaris for $450 million.

Mirna’s MRX34 is a first-in-class miR-34 liposome for the treatment of liver cancer. Natural miR-34 is a p53-induced miRNA which is lost or under expressed in tumors[1]. The p53 protein is a well-known tumor suppressor. In the preclinical studies, intravenous delivery of MRX34 resulted in a greater than 100-fold increase of miR-34 levels in liver cancer cells.

[1] Nature. 2007, 447(7148), 1130-1134.