After halting development of the Phase III breast and lung cancer treatment iniparib in June because of lack of efficacy, Sanofi is pinning its near-term oncology hopes on fedratinib, a JAK2 inhibitor for myelofibrosis and the sole remaining oncology asset in Phase III.

Fedratinib could represent an important turning point for Sanofi’s oncology portfolio, which is largely made up of mature chemotherapeutics, not innovative targeted medicines.

“What our lessons from [iniparib] have been is to increase the stringency of what we demand in terms of a preclinical understanding of mechanism of action and dose,” said VP-Oncology Development Tal Zaks.

Behind fedratinib, Sanofi is developing a pipeline of targeted medicines, drugs the company hopes will offer clear value to patients and payers and position it as a leading oncology player. But turning around after the failure of iniparib, a PARP inhibitor that was once held up as the star of Sanofi’s late-stage oncology pipeline, won’t be easy.

The company announced in June it would halt development of iniparib and take a $285 million impairment charge after the drug failed to show a survival benefit in a Phase III trial in patients with non-small cell lung cancer versus chemotherapy alone. Top-line results of a Phase II study in ovarian cancer did not support development either, the company said at the time.

The news was a blow for Sanofi because the company needs new oncology products to fill its maturing portfolio and even more so because iniparib had shown a promising survival benefit in women with tough-to-treat metastatic triple-negative breast cancer in an early Phase II study, though those results did not play out in a larger Phase III trial Also see "Sanofi's PARP Inhibitor Plus Chemo May Be A Lethal One-Two Punch In Triple-Negative Breast Cancer" - Pink Sheet, 1 January, 2011.. Sanofi paid handsomely for iniparib, acquiring it through the buyout of BiPar Sciences Inc. for $375 million upfront in 2009 [See Deal].

Lessons Learned From Iniparib

A product like iniparib with a mechanism of action that could have extended to multiple solid tumors would have been a boon to Sanofi’s oncology initiative. Sanofi made a name for itself in oncology – and billions of dollars – selling chemotherapeutics. But its top-selling chemotherapies Taxotere (docetaxel) and Eloxatin (oxaliplatin) are facing generic competition, and its next-generation chemotherapy Jevtana (cabazitaxel) hasn’t made up the lost ground because of concerns about toxicity and the way the prostate cancer treatment paradigm has changed (though a Phase II is ongoing in lung cancer). Treatment in general has shifted from traditional cytotoxic agents toward targeted therapies.

The amount of revenues the company generates from its top oncology products has fallen off to €1.78 billion ($2.4 billion) in 2012 compared to €3.40 billion ($4.57 billion) in 2007 from sales of Taxotere and Eloxatin alone before those products were impacted by generics.

Disappointment aside, the iniparib failure provided Sanofi with an opportunity to reflect on its research program and reinforced the company’s belief that its early oncology portfolio and recent efforts to improve translational R&D will eventually yield important medicines.

“What our lessons from [iniparib] have been is to increase the stringency of what we demand in terms of a preclinical understanding of mechanism of action and dose,” VP-Oncology Development Tal Zaks said in an interview. Zaks joined Sanofi in May 2010 from GlaxoSmithKline PLC, where he built an oncology translational medicine team. Now he oversees clinical development of oncology compounds at Sanofi from the unit’s headquarters in Cambridge, Mass. He also is an adjunct associate professor at the University of Pennsylvania School of Medicine.

“The other thing that has been a learning from iniparib and other tyrosine kinase inhibitors is that when you have a molecule that does not have single agent activity, you are relying on randomized Phase II studies with progression-free survival endpoints in your traditional proof-of-concept and those can be tricky,” he said. “The ability of those studies to actually predict whether Phase III is going to be positive is somewhat limited for various reasons having to do with a limited effect size and heterogeneity.”

As a result, Sanofi has vowed to focus its oncology development efforts on drugs that have single-target activity or a very large effect size in early trials, Zaks said.

Fedratinib Will Face Off Against Jakafi

Fedratinib is an example of a drug that fits that profile. The company released top-line data from a pivotal Phase III trial called JAKARTA in June that enrolled 289 patients with myelofibrosis. The trial met the primary endpoint of reduction in spleen volume of greater than 35% after 24 weeks of treatment and also resulted in an improvement in symptoms, a secondary endpoint. The molecule moved from Phase I to completion of Phase III in less than three years, and the company is looking to file a regulatory application for fedratinib before the end of the year.

Sanofi acquired fedratinib with TargeGen Inc. in June 2010 for $75 million upfront and potential payments that could result in a total acquisition cost of $560 million Also see "Sanofi Buys TargeGen And Its Lead Myelofibrosis Drug For $75 Million Upfront" - Pink Sheet, 30 June, 2010.. TargeGen had completed Phase I testing and a Phase II extension study when the deal was completed, but Sanofi was able to move the program directly into Phase III after it agreed with FDA to study two doses of the drug in the pivotal trial.

“When you have a drug that is active and you can demonstrate it, it makes the development plan much more quick and feasible, and that is what we are aiming to in the future,” Zaks said.

Fedratinib is a JAK2 inhibitor with high selectivity, which could confer efficacy or tolerability benefits over Incyte Corp./Novartis AG’s Jakafi (ruxolitinib), a JAK1/JAK2 inhibitor that was approved for myelofibrosis in the U.S. in 2011 Also see "Incyte’s Jakafi Gets Additional Claim Based On Patient-Reported Outcomes" - Pink Sheet, 21 November, 2011.. The rare progressive bone marrow cancer forces blood cell creation into other organs causing enlargement of the spleen and anemia. Median survival for patients is about six years.

Myelofibrosis only affects about 15,000 to 20,000 patients in the U.S., however, and it’s unclear how multiple products will fare competing for limited patient share. Incyte reported U.S. sales of Jakafi of $54.1 million in the second quarter and is projecting product revenues to reach $220 million to $230 million in 2013. Novartis markets the drug outside the U.S. as Jakavi and reported $33 million in second quarter sales of the product.

Sanofi has also conducted a study in patients who are intolerant or resistant to ruxolitinib and expects to unveil some initial data from the study at the American Society of Hematology annual meeting in December. “Being able to show that when a patient either never responds or progresses after an initial response or couldn’t tolerate ruxolitinib and could then come on fedratinib and actually have a benefit I think is going to be a very clear demonstration of value to patients,” Zaks said.

There is potential to study the treatment in other cancers. Incyte released top-line results of a Phase II trial studying ruxolitinib in patients with recurrent or treatment refractory metastatic pancreatic cancer, demonstrating an increase in survival over placebo in a defined group of patients.

Strengthening The Value Story

Demonstrating a value to payers will also be important. Jakavi has failed to gain reimbursement support from the U.K.’s National Institute for Health and Clinical Excellence (NICE) because although the drug demonstrated a reduction in spleen size, an improvement in symptoms and an improvement in overall survival versus placebo, it did not extend survival versus best available treatment in the Phase III trial Comfort II ([A#14130430001]).

“The unfortunate piece is we still have discrepancies globally in terms of what payers consider value for patients,” Zaks said of the situation with Jakavi and NICE. “For us that means even early in development we have to pay much more attention to what is going to be demonstrable value.”

The issue of oncology drug pricing and value is one Sanofi is all too familiar with. The company found itself at the center of a pricing controversy last year around Zaltrap (ziv-aflibercept), a VEGF and placental growth inhibitor approved in 2012 for the treatment of metastatic colorectal cancer.

Zaltrap has struggled to compete against more established therapies like Roche’s Avastin (bevacizumab) after having demonstrated only a 1.5 month survival advantage over chemotherapy alone in clinical trials Also see "Market For Sanofi And Regeneron’s Zaltrap Could Be Limited" - Pink Sheet, 3 August, 2012.. But Sanofi also priced the drug at nearly twice the cost of the commonly used lower dose of Avastin, sparking a pricing debate and drawing the ire of physicians at Memorial Sloan Kettering Cancer Center, who said they would not offer the medicine to patients Also see "Role Of Cost And Evidence In Value-Based Purchasing Highlighted By Zaltrap Price Adjustment" - Pink Sheet, 24 December, 2012..

Sanofi ultimately discounted Zaltrap by 50% to put the price of the drug more on par with the commonly used dose of Avastin, but the launch has so far been lackluster. Zaltrap generated €25 million in sales in the first half of the year; Jevtana generated €106 million, with sales declining, not gaining ground.

Focusing on single drug targets and drugs that demonstrate clear efficacy early on will help improve the value case in the minds of payers, Zaks said.

“We are taking to heart the need to demonstrate the value to patients from the early days so that in the future when we launch drugs it will be very clear what the value is that we bring,” he said.

A Pipeline Of Targeted Drugs

Beyond fedratinib, the company has 12 other new molecular entities in oncology development, including nine in Phase I and three in Phase II development.

Sanofi’s Oncology Portfolio

Phase I

Phase II

Phase III

SAR153192 (anti-DLL4)

Solid tumors

SAR3419 (anti-CD19)

ALL/NHL

Fedratinib (JAK2 inhibitor) Mylofibrosis

SAR650984 (anti-CD38)

Hematological tumors

SAR256212 (anti-ErbB3) antibody

Breast cancer

SAR24509/MSC1936369B

Combination P13K/MEK inhibitor for solid tumors in partnership with Merck KgAA

SAR245409 (PI3K/mTOR inhibitor)

SAR566658 (maytansin-loaded anti-CA6 antibody)

Solid tumors

SAR307746 (anti-ANG2 antibody)

Solid tumors

SAR125844 (C-MET kinase inhibitor)

Solid tumors

SAR405838 (HDM2/p53 antagonist

Solid tumors

SAR260301 (PI3 kinase beta selective)

PTEN-deficient tumors

SAR245408 (PI3 kinase inhibitor)

Breast cancer

Source: Sanofi Pipeline Chart

Zaks highlighted the anti-CD38 program in Phase I development for multiple myeloma as an exciting one. “It’s still early days. We are just figuring out the dose, but already we are seeing hints of activity in patients who have relapsed and have progressive disease,” he said. The program is in development with the University of California, San Francisco.

By partnering with academia and focusing on translational science, Sanofi has been improving its oncology R&D, he said. The company’s focus on externalization isn’t just about in-licensing molecules, he added. It involves a “deeper look at what are the core competencies and capabilities that we have and we do well, and what is it that our partners can do well and then how do we combine them in looking also for novel models of partnerships to be more effective in getting molecules that have promise into being actual medicines for patients.”

In the case of the anti-CD38 program, UCSF is running the clinical program and providing Sanofi with the clinical insight about how best to bring the drug to patients within the broader context of the disease and treatment paradigm.

Last year, Sanofi signed a two-year agreement with Massachusetts General Hospital to further translational medicine research in the area of cancer, with a focus on two early development molecules ([A#14121009003]). The company has also struck cancer research deals with Harvard University and Dana-Farber’s Belfer Institute [See Deal].

Agreements like the partnership with MGH, Zaks said, provides Sanofi with access to leading cancer experts who can help the company select the right patients to study early on and design the most appropriate clinical trials, hopefully resulting in a successful trial. Increasing the pace of development of some of its mid- to early-stage cancer drugs is vital if Sanofi is to get back in the oncology game.

Sanofi Oncology’s Transformation Rests On Fedratinib, At Least In The Near-Term

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