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.

Why Aquinox Pharmaceuticals stock rockets 1000% on Phase II results

Aquinox Pharmaceuticals (NASDAQ: AQXP) stock surges 1000% on positive Phase II results for AQX-1125 in patients with bladder pain syndrome, or interstitial cystitis (BPS/IC). The stock hit a 52-week high of $55.75 on Monday morning, which was 3,000% above Thursday’s lows.

Interestingly, the stock plunged 67.48% on July 09, just one month ago, when the company announced AQX-1125 failed to demonstrate efficacy in chronic obstructive pulmonary disease (COPD).

Aquinox’s lead product candidate, AQX-1125, is a SHIP1 activator. SHIP1 functions as a negative regulator of immune cells. SHIP1 activators have an anti-inflammatory effect. AQX-1125 is the only SHIP1 activator currently in clinical trials. Aquinox is investigating AQX-1125 in three Phase II trials, known as FLAGSHIP trial in COPD, LEADERSHIP trial in BPS/IC, and KINSHIP trial in atopic dermatitis.

As mentioned before, the FLAGSHIP trial has failed. The company has no further development plans for COPD. The ongoing KINSHIP trial is expected to read out 2015Q4. Let’s turn our attention to bladder pain. Actually, AQX-1125 missed the primary endpoint in the LEADERSHIP trial. AQX-1125 demonstrated a positive trend in reduction of pain compared to placebo, but the difference was not statistically significant (p=0.061).

The primary endpoint was based on an 11-point numeric rating scale (NRS). AQX-1125 demonstrated an average 2.4-point reduction in pain score, while placebo led to a mean 1.3-point reduction. Investors didn’t buy the disappointed top line data. The miss sent Aquinox shares down 7.74% on June 25.

On August 07, the company announced that the LEADERSHIP trial met multiple secondary endpoints. The additional positive results suggest that a longer or larger trial may have achieved the statistical goal. A loss of treatment effect was observed during an additional four-week follow up period, which validates the efficacy of AQX-1125.

AQX-1125

BPS/IC is a chronic bladder disease characterized by pelvic pain and increased urinary frequency. The disease currently affects 5-12 million people in the U.S. There is no known cure for BPS/IC. The only oral therapy, Elmiron, was first approved in 1996. However, in two Phase IV trials, Elmiron showed no benefit over placebo.

Elmiron is priced at $625 per month, and generated annual sales of $279 million in 2014. The drug requires taking three times per day, while AQX-1125 is a once-daily therapy. Aquinox believes the opportunity for AQX-1125 could exceed $1 billion in the U.S. alone. Investors should be more cautious. IC/BPS is still very challenging to diagnose and treat due to a lack of specific biomarker and definitive diagnostic test.

Allergan (NYSE: AGN) acquired worldwide rights to TARIS Biomedical’s lead program, LiRIS, in August 2014. The company paid $67.5 million upfront and agreed to pay $520 million milestones. The program is now in Phase II trials (NCT02411110, NCT02395042).

By the way, Aquinox is a spin-off from the University of British Columbia. The company is backed by leading VCs including Ventures West, Baker Brothers, Pfizer Venture and J&J. Baker Brothers purchased 548,534 shares on July 09 and additional 2.5 million shares on August 07.