CAR-T treated leukemia patients survive for 4.5 years

In the summer of 2010, Novartis and the University of Pennsylvania began testing their anti-CD19 CAR-T therapy, CTL019, in patients with relapsed and refractory chronic lymphocytic leukemia (CLL). The mature results from the trial were published in Science Translational Medicine[1]. Dr. Carl June led the study.

The trial enrolled 14 heavily pretreated CLL patients. These patients were treated with CTL019 at doses of 1.4 × 10^7 to 11 × 10^8 cells. Four patients had a complete response (CR), and additional four patients had a partial response (PR). Six patients did not respond to the therapy and progressed soon.

One of the CR patients died at 21 months due to infections after removal of the skin cancer on his leg. The three other patients are still alive with no signs of recurrence. At the time of the report, they have survived for 28, 52, and 53 months after receiving CTL019.

Two of the PR patients died of disease progression at 10 and 27 months. One of the PR patients died from a pulmonary embolism (肺动脉栓塞) at 6 months. The other patient was switched to other therapies due to the disease progressed at 13 months.

The CR rate in CLL was much lower than that in ALL (acute lymphocytic leukemia). No CLL patient with CR has relapsed, while in a previous ALL trial, 37% of CR patients have subsequently relapsed[2]. The CAR-T cells remain in CLL patients’ blood and retain their ability to hunt for cancer cells beyond four years.

[1] Sci Transl Med. 2015, 7(303), 303ra139.
[2] ASH2014,


CAR-T with low-affinity shows promising results in mice with solid tumor

Anti-CD19 CAR-T therapy has demonstrated potent clinical efficacy in patients with B-cell leukemia and lymphoma. However, this therapy faces many challenges in the context of solid tumors. Most proteins overexpressed on cancer cells may also be expressed on normal cells. CAR-T cells cannot distinguish cancer cells from normal cells. Five years ago, one patient died after the treatment with anti-HER2 CAR-T due to the expression of HER2 in lung tissues[1].

CD19 is not known to be expressed on any healthy tissue other than B cells. Even though such CAR-T cells attack cancer cells and normal B cells, patients can live without B cell for a long time. Further, CD19 is not expressed on hematopoietic stem cells, and therefore B cells should return when the CAR-T cell is no longer present. This may not be the case with solid tumors.

To make CAR-T therapy applicable to solid tumors, Dr. Laurence Cooper of ZIOPHARM Oncology (NASDAQ: ZIOP) developed CAR-T with reduced affinity, and showed that these CAR-T cells could distinguish cancer from normal cells[2]. In other words, Cooper’s CAR-T cells could minimize the “on target off tumor” toxicity in mice.

The researchers chose wild-type EGFR as a target. The protein is overexpressed glioblastoma but is also found at low levels on certain normal cells. Two CARs were generated from cetuximab (cetux) and nimotuzumab (nimo), respectively. Cetux has higher affinity for EGFR, while nimo has low lower affinity.

The researchers then tested the anti-EGFR CAR-T cells in NSG mice with glioma. Cetux-CAR-T cells and nimo-CAR-T cells both significantly inhibited tumor growth. However, the cetux-CAR-T cells caused significant toxicity, resulting in significant death of mice within 7 days of T-cell infusion. The nimo-CAR-T cells have no apparent toxicity.

EGFR CAR T cells

NSG mice lack mature T cells, B cells, and NK cells, and are also deficient in multiple cytokine signaling pathways. It is unclear whether CAR-T with low-affinity could reduce cytokine storm, a common life threatening side effect associated with CAR-T therapy. The researchers used cancer cells that express a median density of 240,000 molecules of EGFR/cell to establish mouse model. In patients, it should be far more complicated.

[1] Mol Ther. 2010, 18(4), 843-851.
[2] Cancer Res. 2015, doi: 10.1158/0008-5472.CAN-15-0139.

What are the differences between biosimilar and interchangeable?

When biologics’ patents expire, other companies can launch similar products and lower costs. However, most biologics are more complex than small molecule drugs in structure, and are more difficult to characterize. Of course, the clinical uses of similar biologics are more complex.

The FDA divides similar products into biosimilar and interchangeable. Biosimilars are highly similar to the reference product, and have no clinically meaningful differences from the reference product. An interchangeable product, in addition to meeting the biosimilar standard, is expected to produce the same clinical result as the reference product in any given patient.

In other words, both biosimilars and interchangeable products have allowable differences from the reference product because they are made from living organisms, but have no clinically meaningful differences. The interchangeable standard is stricter. In addition to demonstrating clinical similarity, interchangeable product manufacturers have to demonstrate that product switching doesn’t increase risk.

According to the latest draft guidance, titled “Nonproprietary Naming of Biological Products”, the reference product and biosimilars would share a “core drug substance” name and would also carry a distinct four-letter suffix for each product (e.g., replicamab-cznm, replicamab-hixf). Interchangeable products may share the same suffix as the reference product.

That approach would restrict easy substitution of biosimilars for the reference product. An interchangeable product can be substituted for the reference product by a pharmacist, even if the physician writes the prescription for the reference product. However, a biosimilar should be prescribed by a physician (the physician has to write the specific name of the biosimilar).

Chipscreen BioSciences surpasses Eddingpharm in breast cancer

In July 2015, Chipscreen BioSciences initiated a Phase III trial of chidamide in hormone receptor (HR) positive breast cancer (CTR20150456). It is the first Phase III trial to evaluate the efficacy and safety of HDAC inhibitor in Chinese patients with breast cancer.

Syndax Pharmaceuticals (NASDAQ: SNDX) is evaluating another HDAC inhibitor, entinostat, in breast cancer in a pivotal Phase III trial in breast cancer. Two years ago, the FDA granted Breakthrough Therapy Designation to the drug based on Phase IIb (ENCORE 301) results.

In September 2013, Eddingpharm licensed China rights to entinostat. Eddingpharm originally intended to participate in Syndax’s global Phase III trial. However, the IND wasn’t submitted to the CFDA until February 2015. If all goes well, Eddingpharm will commence clinical study of entinostat in 2016.

Syndax’s Phase IIb trial (NCT00676663) assigned 130 patients with HR positive breast cancer progressing on first-line therapies[1]. Patients were randomly assigned to exemestane + entinostat (EE) or exemestane + placebo (EP). Median overall survival was improved to 28.1 months with EE versus 19.8 months with EP (p=0.036).

The Phase IIb results appear encouraging, but I still have some doubts. There is no difference in response rate (6.3% vs. 4.6%). The median progression-free survival (mPFS) of 2.3 months in the EP group was lower than the 3.8-4.1 months observed in other similar trials[2,3]. The EE group had more Grade 3/4 adverse events (50% vs. 26%).

The FDA has approved everolimus plus exemestane for the second-line treatment of HR positive breast cancer. The combination of palbociclib with fulvestrant has also shown a marked benefit in second-line treatment in a Phase III trial. Entinostat, if approved, will have to compete with everolimus and palbociclib in the second-line settings.

Entinostat (MS-275) was discovered by Japanese scientists in Mitsui Pharmaceuticals in 1990s. European Patent EP0847992 which covers entinostat expires in 2017. The patent protection for the compound relies on WO2010022988 which covers a crystalline polymorph.

Syndax licensed the program from Bayer with an upfront fee of $2 million in April 2007. The company conducted a Phase II trial of entinostat plus erlotinib in non-small cell lung cancer, but failed. Fortunately, the Phase II trial in breast cancer succeeded.

Chipscreen’s chidamide is an anolog derived from entinostat. The CFDA has approved chidamide for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) in December 2014. Chipscreen is likely to complete the breast cancer study in advance of Eddingpharm.


[1] J Clin Oncol. 2013, 31(17), 2128-2135.
[2] N Engl J Med. 2015, 373(3), 209-219.
[3] N Engl J Med. 2012, 366(6), 520-529.
[4] J Med Chem. 1999, 42(15), 3001-3003.

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Chipscreen grabs CFDA approval for chidamide

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.

Oral GLP-1 to enter Phase III clinical trial

Novo Nordisk decided to initiate a global Phase III trial, named PIONEER, to evaluate the efficacy and safety of OG217SC, a once-daily oral formulation of semaglutide, in 8,000 people with type 2 diabetes. The drug is said to be one of the company’s most promising candidates.

Semaglutide is a follow-up to Victoza/Saxenda (liraglutide)[1]. The GLP-1 affinity of semaglutide was 3-fold decreased compared to liraglutide, whereas the albumin affinity was increased. An increased affinity to albumin could extend the circulating half-life.

Novo Nordisk originally developed semaglutide as a once-weekly injectable therapy. The first phase IIIa trial (SUSTAIN1) demonstrated that 1.0 mg semaglutide led to a HbA1c reduction of 1.9% and a weight loss of 4.6 kg. If the injectable version is approved, it will have to compete with other long-acting GLP-1 products (e.g., Bydureon, albiglutide, dulaglutide) on the market.

Novo Nordisk has partnered with two biotech companies, Emisphere Technologies (EMIS) and Merrion Pharmaceuticals (MERR), to overcome the barriers to oral GLP-1 and insulin delivery. Emisphere’s Eligen technology uses SNAC (salcaprozate sodium) as an oral absorption promoter. This technology was originally used for oral delivery of insulin. In October 2006, Emisphere announced the Phase II results of their oral insulin tablet. Eligen insulin plus metformin failed to achieve significant superior glycemic control over metformin alone. Merrion’s GIPET technology consists of enteric-coated tablets targeting the duodenum, with peptide and absorption enhancers (medium-chain fatty acid) inside.

Novo Nordisk’s decision to advance oral semaglutide into Phase III trial follows positive Phase II proof of concept results. Patients treated with oral semaglutide in five different doses ranging from 2.5 mg to 40 mg once daily achieved dose-dependent reduction in HbA1c of 0.7% to 1.9% after 26 weeks. The first phase III trial is designed to compare semaglutide at three doses (3mg, 7mg and 14mg) with sitagliptin. The trial will start in 2016Q1.

Victoza/Saxenda (liraglutide) is the best-in-class once-daily GLP-1. This product is forecast to reach $4.4 billion peak sales. OG217SC could be the first of oral GLP-1, which means the drug could change the GLP-1 market.

The dosage of oral semaglutide is 100 fold higher than the injectable version. So the oral GLP-1 will cost much more than injectable GLP-1 and other oral therapies. The advantages of once-daily oral GLP-1 over once-weekly injectable GLP-1 may not be very significant.

Oramed Pharmaceuticals (NASDAQ: ORMP) is developing oral insulin ORMD-0801 and oral GLP-1 ORMD-0901. The company also uses SNAC as an oral absorption promoter, but I doubt Oramed would ever initiate a Phase III trial.

[1] J Med Chem. 2015, doi: 10.1021/acs.jmedchem.5b00726.

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.