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, https://ash.confex.com/ash/2014/webprogram/Paper69932.html

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.

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.

Investigators report Phase I results of CAR-T therapy in solid tumors

Investigators of the University of Pennsylvania report Phase I results of CAR-T therapy in solid tumors at AACR2015. The therapy appears safe in the patients treated so far, but the anti-tumor efficacy was not good as expected.

The CAR-T therapy, known as CART-meso, targets mesothelin, a antigen present on normal mesothelial cells and overexpressed in several tumors.

In the study, five patients with recurrent advanced solid tumors (2 ovarian, 2 epithelial mesothelioma, and 1 pancreatic) were treated with a single infusion of 1-3×10^7 CART-meso cells.

CAR-T cells were found to traffic to tumor sites as well as to off-tumor on-target sites, but no off-tumor on-target toxicities was observed. CAR-T cells were detectable in the blood stream in all patients up to Day 21-28 after infusion.

Anti-tumor efficacy was suggested by the clearing of cancer cells in the pleural fluid of one patient. There was clinical evidence of stable disease in another patient.

The results were not good as expected. In previous studies, CD19 CAR-T therapy showed a complete response rate of 90% in relapsed and refractory ALL[1,2].

The dosages in the solid tumors study were relatively lower than the dosages in the previous ALL trials. The peak levels of CART-meso in blood were about 2 orders of magnitude lower than CART19. Mesothelin is also found in normal tissue, thereby high dose of CAR-T may damage healthy tissue.

It’s not always easy to find a perfect CAR-T target like CD19. Although CD19 is also found in normal B cells and CAR-T therapy may deplete normal B cells, patients can live with B cell depletion for a prolonged period. Further, CD19 is not expressed on hematopoietic stem cells, and therefore B cells should return after the CAR-T treatment.

Aduro Biotech (NASDAQ:ADRO) is developing a mesothelin vaccine, known as CRS-207, for the treatment of pancreatic cancer and mesothelioma. In the Phase IIa trial in pancreatic cancer, CRS-207 plus GVAX demonstrated a statistically significant improvement in overall survival (6.1 vs. 3.9 months)[3]. Based on the results from the Phase IIa trial, CRS-207 was granted Breakthrough Therapy designation by the FDA.

[1] N Engl J Med. 2014, 371(16), 1507-1517.
[2] https://ash.confex.com/ash/2014/webprogram/Paper76573.html
[3] J Clin Oncol. 2015, 33(12), 1325-1333.

Novartis bets $750 million on small molecule immunotherapy

Novartis launched a $750 million collaboration with Aduro Biotech to develop STING agonists, adding new firepower to its portfolio of cancer immunotherapies that includes CAR-T program and checkpoint inhibitors targeting PD1, LAG3, and TIM3.

The STING receptor is generally expressed at high levels in immune cells. Once activated, the STING receptor initiates broad immune responses, inducing the expression of interferons and chemokines.

STING receptor can be activated by a series of unique nucleic acids called cyclic dinucleotides (CDNs)[1], naturally produced by bacteria and immune cells. Aduro has developed CDN derivatives that are significantly more potent than natural CDNs.

Aduro’s lead product candidate targeting STING is ADU-S100. The company plans to initiate a Phase I trial in the second half of 2015. In the preclinical study, intratumoral injection of ADU-S100 had superior anti-tumor activity as compared to HBSS (placebo control) and TLR ligands (positive control).

Here are two photographs of melanoma model lung metastases. Numerous lung metastases (black nodules) are visible in the control group (HBSS), while only a few metastases are visible in the ADU-S100 group.

ADU-S100

Source: Form S-1.

Novartis is the second Big Pharma to form a partnership with Aduro. In 2014, Johnson & Johnson licensed prostate cancer vaccine ADU-741 and lung cancer vaccine ADU-214 for $365 million and $817 million, respectively.

Furthermore, the FDA has granted Breakthrough Therapy Designation for Aduro’s pancreatic cancer vaccine CRS-207. FierceBiotech listed the company as one of 2014’s Fierce 15 biotechnology companies. The company has filed for a $86 million IPO.

[1] Nature. 2011, 478(7370), 515-518.

In hindsight: what the AbbVie/Express Scripts deal means?

In December 2014, AbbVie (NYSE: ABBV) kicked off a price war with Gilead Sciences (NASDAQ: GILD) in the hepatitis C market by inking an exclusive deal with Express Scripts (NASDAQ: ESRX), the largest Pharmacy Benefit Manager (PBM) in the U.S.

There are 3 million patients with hepatitis C in the U.S. But it is a prevalence market with no future. As more patients are treated and cured, demand for the drug could drop. These concerns induced AbbVie to gain market share via a price war.

Gilead fought back soon with several similar deals with PBMs and health insurers including CVS Health (NYSE: CVS), Anthem (NYSE: ANTM), Aetna (NYSE:AET), Humana, Harvard Pilgrim, EnvisionRx, UnitedHealth (NYSE: UNH).

It appears that Gilead has won the price war. However, this is a war without winners. Gilead estimates 2015 gross to net adjustments (discounts) at 46% vs. 22% at end 2014. This means Gilead will offer Sovaldi/Harvoni at nearly half of its list price.

Gilead announced total revenues for 2014 were $24.9 billion compared to $11.2 billion for 2013. Hepatitis C drugs, Sovaldi and Harvoni, generated total sales of $12.4 billion in 2014. However, the company’s forecast for 2015 is only $26-27 billion.

All the hepatitis C stocks are down sharply on February 4, 2015 (e.g., GILD-8.2%, ABBV-7.7%, MRK-3.2%, BMY-1.0%, ENTA-8.1%, ACHN-16.9%, RGLS-3.8%). The NASDAQ Biotechnology index slid as much as 3.85% intraday.

The AbbVie/Express Scripts deal might change the entire landscape of drug pricing. Whichever companies offer the deepest discounts and cut exclusive deals with the largest insurers will win the biggest market shares. In other words, insurance companies are in the driver’s seat.

This is just the beginning, and more drugs are not far behind, such as anti-PCSK9, anti-PD1/PDL1, and anti-CD19 CAR-T. Express Scripts CMO Steve Miller told Bloomberg “we look at this as being the first of what will happen in the field of cancer, rheumatoid arthritis and many other of the expensive specialty fields.”

Anti-PCSK9 mAbs, a new class of cholesterol-lowering drugs, like Sanofi (NYSE: SNY)/Regeneron (NASDAQ: REGN)’s alirocumab, Amgen (NASDAQ: AMGN)’s evolocumab and Pfizer (NYSE: PFE)’s bococizumab are most probable to be next. Alirocumab is expected to be priced at $10,000 per year and to generate $3-4 billion in peak sales.

At the JP Morgan Healthcare Conference, Express Scripts CEO George Paz said anti-PCSK9 mAbs are “the short term, and cancer is a long term.” The market for anti-PCSK9 mAbs might not be as big as investors expect, once discounting is taken into account.

Would the price war be good for patients? Undoubtedly, more patients could be treated. In turn, exclusive deals will limit patient’s therapeutic options. The exclusive options offered by insurers might not be optimal. In the case of Gilead/AbbVie, Gilead’s Harvoni is safer and more convenient than AbbVie’s Viekira Pak. However, Express Scripts forced its customers to take Viekira Pak rather than Harvoni.

Investors’ fear is that price controls may stifle innovation. Biotech companies have to rethink whether their new drugs are worth still developing. Drugs with unique safety and efficacy profile will remain safe from the negotiating skills of insurers.

Biogen Idec’s BIIB037 shows promising results better than expected

Biogen Idec (NASDAQ: BIIB) announced interim results from the Phase Ib study of BIIB037 in Alzheimer’s disease at the Deutsche Bank BioFEST conference on December 2, 2014. The drug showed a statistically significant improvement in patient’s cognition and a dose- and time-dependent reduction in amyloid levels.

The company said “we’re actually planning very aggressively to start the Phase III program.” Biogen Idec’s stock rose 6.43% which means the market capital increased nearly $ 5 billion on Tuesday.

BIIB037 is a novel fully human anti-Aβ monoclonal antibody that binds strongly to fibrillar Aβ in plaques but less well to vascular amyloid. Previously, Eli Lilly’s solanezumab and Pfizer/J&J’s bapineuzumab, have demonstrated great potential in early trials only to fail in Phase III. However, BIIB037 has its own story.

Neurimmune identified the antibody using the Reverse Translational Medicine platform which focuses on individuals who share certain unusual capability to successfully fight a severe disease. BIIB037 was originally derived from healthy, aged donors whose immune systems had successfully resisted Alzheimer’s disease. Biogen Idec in-licensed BIIB037 from Neurimmune in 2007, with an aggregate of $ 380 million payments.

The full Phase Ib data will be presented at an upcoming medical meeting. Wait and see.