Merck identifies a new biomarker for anti-PD1 therapy

Several trials have verified that patients whose tumors overexpress PDL1 have improved clinical outcomes with anti-PD1 therapy. At the ASCO2015 Annual Meeting, Merck researchers report a new biomarker called mismatch repair (MMR) deficiency, which predicts superior response to anti-PD1 therapy.

Tumors with MMR deficiency harbor many more mutations than tumors without such repair defects. Whole exome sequencing revealed an average of 1,782 somatic mutations per tumor in MMR-deficient compared to 73 in MMR-proficient tumors. Tumors with more mutations are more likely to be recognized as foreign by the immune system.

In a Phase II trial of pembrolizumab, ORR was 62% in MMR-deficient patients (n=25) compared with 0% in MMR-proficient patients (n=25). Progression-free survival rates at 20 weeks were 78% and 11%, respectively. Merck plans to launch a larger phase II study to confirm these findings.

Approximately 5% of many tumor types have MMR deficiency. About 20% of non-inherited colorectal cancers are MMR deficient. MMR status could be easily determined using an existing commercially available test.

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An old drug brings about a novel technology

Degrading proteins as opposed to inhibiting them has potential to open up a novel area of drug development. I first wrote about the protein-clearing technology last month when Merck and Arvinas inked a $434 million deal. Last week, researchers at Dana-Farber Cancer Institute reported details in the latest issue of Science[1].

The authors attached JQ1, a BET inhibitor, to phthalimide, a derivative of thalidomide. The phthalimide was designed to bind to CRBN, part of an ubiquitin ligase complex. The resultant compound, dBET1, induced CRBN -dependent BET protein degradation.

dBET1

They next treated leukemia cells (MV4;11) and lymphoma cells (DHL4) with dBET1. Marked degradation (76%) of the target protein was observed at 1 hour and complete degradation was observed at 2 hours of treatment. dBET1 induced an enhanced apoptotic response compared to JQ1.

The researchers then treated tumor-bearing mice with dBET1 (50 mg/kg). Degradation of the target protein was observed 4 hours after a first or second daily treatment. In mice model, dBET1 also resulted in improved anti-tumor efficacy compared to JQ1.

It is not uncommon that inhibiting a protein is not always functionally equivalent to knocking out the protein. The protein-clearing technology is a feasible approach to reproduce the phenotype of knockout.

[1] Science. 2015, doi: 10.1126/science.aab1433.

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.

ganetespib

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.

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].

MIT

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].

Rani Therapeutics

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

Did GDF11 really improve muscle regeneration?

In parabiosis experiments, the blood of younger mice seems to rejuvenate the muscles of older mice. In 2013, Dr. Amy Wagers, a biologist at Harvard University, seemed to offer an explanation for this effect. Wagers identified a protein called GDF11 as a circulating factor in young mice that declines with age.[1]. Injection of GDF11 reversed age-related thickening of the heart.

Two subsequent studies found that GDF11 improved blood vessel and neuron growth in the brain[2] and reversed age-related dysfunction in skeletal muscle[3]. GDF11 appeared to be one of the key components of the young blood.

However, some experts were confused by Wagers’ papers, because GDF11 is very similar to myostatin, a negative regulator of muscle growth. Myostatin knockout mice have approximately twice as much muscle as normal mice[4]. Could a very similar protein have the opposite effect?

As early as 2009, Dr. David Glass at the Novartis Institutes for BioMedical Research showed that GDF11 could inhibit muscle growth[5]. Who is right?

Glass tested GDF11 levels in rats with the assays Wagers had used and found that Wagers’ assays could not distinguish between the monomer and dimer forms of GDF11 as well as myostatin[6]. GDF11 levels actually did not decrease with age. Injecting GDF11 into mouse muscle did not improve muscle regeneration.

Antibodies are among the most commonly used tools to detect target proteins. However, they are a major driver of reproducibility crisis[7]. Commercial antibodies often recognize extra proteins in addition to the ones they are sold to detect. We need to have some changes in the field.

[1] Cell. 2013, 153 (4), 828-839.
[2] Science. 2014, 344(6184), 630-634.
[3] Science. 2014, 344(6184), 649-652.
[4] Nature. 1997, 387(6628), 83-90.
[5] Am J Physiol Cell Physiol. 2009, 296(6), C1258-1270.
[6] Cell Metab. 2015, doi:10.1016/j.cmet.2015.05.010.
[7] Nature. 2015, 521, 274-276.

Scientists reveal a deadly weakness of anti-MET drugs

MET, also known as hepatocyte growth factor receptor (HGFR), is a popular anti-tumor target, just like other growth factor receptors (EGFR, HER2, VEGFR, PDGFR, FGFR, etc.). However, failures of onartuzumab, tivantinib, and foretinib have shaken many investors’ confidence. A new paper in the journal Nature reveals a deadly weakness of anti-MET drugs[1].

MET is expressed not only by cancer cells but also by immune cells. The authors showed that neutrophils need MET to migrate through the vessel wall of inflamed tissues, where neutrophils exert anti-tumor functions. Met deletion in mouse neutrophils enhances tumor growth and metastasis.

These findings indicate that anti-MET drugs may have both positive and negative effects on tumors. On the one hand, anti-MET drugs can kill cancer cells that depend on MET hyperactivation; on the other hand, anti-MET drugs blunt the anti-tumor immune responses of the neutrophils.

Selecting the right patients is key to MET inhibitor development. The study suggests that patients that have high MET expression in neutrophils should be excluded in clinical trials.

[1] Nature. 2015, doi: 10.1038/nature14407.

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.