Youyou Tu wins 2015 Nobel Prize in Physiology or Medicine

Youyou Tu received the 2015 Nobel Prize in Physiology or Medicine. She became the first Chinese scientist who won the prize. In 1970s, Tu successfully extracted artemisinin from Artemisia annua with ether. At first, they failed to extract the compound with boiling water, because hot water had already damaged the compound.

Chinese investors may hype the concept as they always did in the past, though artemisinin suppliers such as Fosun Pharma (SSE: 600196) and KPC Pharmaceuticals (SSE: 600422) didn’t and will not earn much from the drug because of its low price. Chinese stock markets are filled with speculators and retail investors. We will see.


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.

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.


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.

29-year-old creates biggest biotech IPO in history with GlaxoSmithKline abandoned drug

Axovant Sciences (NASDAQ: AXON) just raised $315 million by offering 21 million shares at $15. The stock closed at $29.90, which valued the company at $2.8 billion. In my opinion, the company doesn’t seem worth the investment. The craziness in the market reflects that we are really in a biotech bubble.

Axovant was created by Vivek Ramaswamy, a 29-year-old former hedge fund manager. He is also the chairman of Tekmira Pharmaceuticals (NASDAQ: TKMR). In December 2014, Ramaswamy picked up an abandoned Alzheimer’s drug called SB742457 (now known as RVT-101) from GlaxoSmithKline for €4.5 million. This is Axovant’s sole asset.

RVT-101 is a selective 5-HT6 receptor antagonist and has been evaluated in 13 clinical trials. RVT-101 alone is ineffective when compared to placebo. But RVT-101 plus donepezil did demonstrate an improvement in cognition in the AZ3110866 trial (Phase IIb).

Both RVT-101 and donepezil don’t treat the underlying cause of Alzheimer’s disease. The benefit of RVT-101 in combination with donepezil was only 12 weeks compared to donepezil alone. There was good reason why GlaxoSmithKline gave up the compound.


Axovant isn’t alone in this field. Lundbeck and Otsuka Pharmaceutical are testing a similar drug known as idalopirdine (Lu AE58054) in Phase III trials. In March 2013, Otsuka acquired the rights to idalopirdine in the U.S., Canada, and East Asia for $675 million.

Addition of idalopirdine (90 mg/day) to donepezil treatment resulted in improved cognitive performance as measured by ADAS-Cog at Week 24. Idalopirdine seemed to be more effective than RVT-101 (mean difference in ADAS-Cog: -2.16 vs. -1.66).

After the acquisition last December, Axovant didn’t conduct any clinical trial at all. But Ramaswamy got two trump cards: (1) Lawrence Friedhoff, the developer of donepezil; (2) Lawrence Olanoff, the developer of memantine. Axovant intends to begin a Phase III pivotal trial in 2015Q4 and to submit an NDA to the FDA by the end of 2017.

Two other hedge funds, RA Capital Management and Visium Asset Management indicated an interest in purchasing up to $150 million of Axovant shares at the IPO price. However, they are allowed to sell their shares (if they buy) after 90 days, half the standard lock-up time.

Gain-of-function p53 mutations are important biomarkers for Hsp90 inhibitors

p53 is a well-known tumor suppressor that prevents cancer formation. More than 50% of human tumors contain a mutation or deletion of p53. Li-Fraumeni syndrome, a rare inherited disorder that greatly increases the risk of developing cancers, is caused by heterozygous mutations of p53.

Mutant p53 (mutp53) proteins not only lose their tumor suppressor functions, but also gain oncogenic functions that promote cancer cell survival. Li-Fraumeni patients with gain-of-function p53 mutations have shorter tumor-free survival than those with loss of p53 expression (p53-null).

Cancer researchers at Stony Brook University and Synta Pharmaceuticals (NASDAQ: SNTA) showed that tumors with gain-of-function p53 mutations depend on sustained mutp53 expression[1]. The Hsp90/HDAC6 chaperone machinery is a major determinant of mutp53 stabilization.

The researchers treated Q/- (R248Q mutation), H/H (R172H mutation) and p53-null mice with weekly doses of Hsp90 inhibitor ganetespib. The drug benefited only mutp53 mice but not p53-null mice, extending the survival of Q/- mice and H/H mice by 59% and 48%, respectively.


Synta is testing ganetespib in patients with second-line NSCLC in a Phase III trial (GALAXY-2).

In the previous Phase II/III trial (GALAXY-1), median overall survival for ganetespib/docetaxel was 9.8 months compared to 7.4 months for docetaxel. The result was not statistically significant.

Subgroup analysis showed that ganetespib/docetaxel significantly improved overall survival (10.7 vs. 6.4 months) in patients with diagnosis of advanced disease greater than 6 months. The GALAXY-2 trial excludes rapid progressors.

Investors don’t buy the subgroup analysis, as usual. Synta shares have plummeted more than 70% since 2013. I have no confidence in the GALAXY-2 trial as well. Anyhow, the study of p53 mutations will help Synta select right patients.

[1] Nature. 2015, doi: 10.1038/nature14430.

Orexigen Therapeutics’ data leaks deeply hurt patients and investors

Orexigen Therapeutics (NASDAQ: OREX) shares have dropped 27% to $5.01 since Tuesday, when the company announced termination of the cardiovascular outcomes trial (CVOT) of the obesity drug Contrave. To make matters worse, new data showed the drug doesn’t reduce cardiovascular risks.

Contrave is a sustained release formulation of two old drugs: bupropion and naltrexone. In September 2014, the FDA approved Contrave as a weight-loss drug but required a post-marketing CVOT because bupropion can raise blood pressure and heart rate.

Before the FDA approval, Orexigen had initiated a 9,000-patient CVOT, called LIGHT, to prove that Contrave caused no more than a 40% increase in cardiovascular risks. If all had gone well, the LIGHT trial would be completed in 2017.

However, during the review of Contrave, the FDA learned that more than 100 people saw the interim, unblinded results from the Light trial. (Orexigen only has 47 employees, which means people outside of the company got the data.) Leaking interim results to more unnecessary people could negatively impact the conduct of the remaining portion of the trial. Patients may opt to drop out of the trial and take Contrave rather than have a 50% chance of taking placebo. The FDA required Orexigen to do a second CVOT.

In March 2015, Orexigen disclosed the first 25% interim results from the LIGHT trial. Going against the longtime concerns that Contrave can increase major adverse cardiac events (MACE), the first 25% interim analysis suggested the drug not only helped patients lose weight but also prevented MACE. At the first 25% interim analysis, 59 patients in the placebo group recorded MACE compared to 35 in the Contrave group.

However, the next 25% of data showed that 43 patients in the placebo group had MACE compared to 55 on Contrave. Combining all the data, Contrave showed only a 12% decreased risk from placebo (90 vs. 102), which is not statistically significant. Moreover, 26 patients died of non-cardiovascular causes in the Contrave group, compared to 17 in the placebo group.

Orexigen has made two mistakes: (1) leaking interim results to more unnecessary people; (2) publicly releasing the first 25% interim analysis which might mislead patients and investors. Interim data are interim. The second 25% of data even suggested the drug could increase cardiovascular risks. Who knows what would have happened if the study went to completion.

Orexigen says that a new CVOT will begin later this year. The target completion date is 2022. Contrave’s approval was based on the FDA getting the LIGHT results by 2017, now it will be 2022 at the earliest. George Budwell at The Motley Fool concerns whether the FDA should pull Contrave from the market. Orexigen’s partner, Takeda, is seeking Orexigen to pay for the entire $200 million estimated cost of the new clinical trial.

Catalyst Pharmaceutical shares plummet on competitor’s positive results

Catalyst Pharmaceutical (NASDAQ: CPRX) shares tumbled as much as 42% after Jacobus Pharmaceuticals, a competitor, disclosed positive results of 3,4-diaminopyridine (3,4-DAP, amifampridine) in patients with Lambert-Eaton myasthenic syndrome (LEMS) at the AAN2015 Annual Meeting.

LEMS is a rare autoimmune disease with a prevalence of 3000 patients in the U.S. and Canada. In LEMS patients, autoantibodies are formed against calcium channels, resulting in muscle weakness. Approximately 50% of LEMS patients have small cell lung cancer (SCLC) and will not survive for long.

3,4-DAP is recommended to improve LEMS symptoms. The compound blocks potassium channel efflux in nerve terminals so that calcium channels can be open for a longer time. In 2010 BioMarin Pharmaceutical (NASDAQ: BMRN) launched Firdapse (3,4-DAP phosphate) in the EU. Firdapse is the first and only approved drug for this indication.

In October 2012, BioMarin out-licensed North American rights of Firdapse to Catalyst. In August 2013, Firdapse received Breakthrough Therapy Designation from the FDA. In September 2014, Catalyst announced positive Phase III results. Catalyst expects an NDA submission to the FDA by 2015Q3. If approved, Firdapse may cost $60,000-80,000 per year, which would yield sales of $200 million.

For the past 20 years, Jacobus Pharmaceuticals, a family-owned pharmaceutical company has provided LEMS patients with 3,4-DAP for free in the U.S. under an FDA-approved compassionate use program. Compassionate use, also called expanded access, provides a pathway for patients to use investigational drugs that have not yet been approved by the FDA.

The company was founded by David Jacobus in 1977. About 20 years ago, Jacobus began to manufacture 3,4-DAP at the request of the Muscular Dystrophy Association. Jacobus sends 3,4-DAP to patients or their doctors every three months. The only thing Jacobus asks in return is that patients should mail back the ice packs used to protect 3,4-DAP.

Why supply 3,4-Dap for free? “Because supplying the drug for free is the right thing to do,” said Laura Jacobus. She also charged Catalyst with greed and indifference to LEMS patients. “They don’t want to help LEMS patients; they just want to make money.” Jacobus are conducting its own clinical trial to win FDA approval.

However, no one is perfect. The Jacobus compassionate use program can only reach 100-200 patients, which means most patients do not have access to treatment. Even more serious is the cGMP defects of Jacobus in the past. The FDA issued 483 inspection reports for the Jacobus facility in 2011 and again in 2012 (read them here and here).

Catalyst’s Firdapse contains the phosphate salt of 3,4-DAP. The phosphate salt form is more stable than the free base form of the 3,4-DAP that is available from Jacobus. Catalyst CEO Patrick McEnany stressed that their 3,4-DAP is produced under all requirements of cGMP. If there were an approved drug by the FDA, most patients would have easy access to this drug.

Catalyst and Jacobus are racing to get 3,4-Dap approved by the FDA. The winner will get seven years of orphan drug exclusivity in the U.S. and the loser would be frozen out.