Ex-Sanofi Exec Stoeckli Primes Glenmark’s Cancer Therapy Ambitions

Dr Kurt Stoeckli, says that moving to Glenmark Pharmaceuticals Ltd. from Sanofi was all about a “perfect match.” While the former group vice president for the French multinational’s global biopharmaceuticals division may have been used to big pharma R&D budgets and scale, Stoeckli says that he was drawn to the Indian firm by its sheer potential – “people, project and science” - and what the company “could make” in the years to come.

Dr Kurt Stoeckli, President and Chief Scientific Officer, Glenmark

“I just found that this is a perfect match, where I could bring complementarity and experience that I have gone through in big pharma and the portfolio is so exciting in terms of potential for the next 5-10 years,” Stoeckli told Scrip in an exclusive interview at Glenmark’s Mumbai headquarters.

Stoeckli, who took charge as Glenmark’s president and chief scientific officer (CSO) in October, believes that it is essential for Glenmark to be able to move ahead with a “core segment” of projects that it establishes on its own end-to-end capabilities and be “independent”. Glenmark is strategically focused on three core therapy areas - oncology, dermatology and respiratory.

“Should this go on in a very successful way even the core segment is rich enough to think about partnering especially in immunotherapies where lots of combination concepts are coming up. I consider this as very value-creating because some of these potential partners will have complementary assets, experience and access to markets and regions,” he said.

Bispecific Antibodies

Stoeckli, who also spent several years in drug discovery at Novartis/Sandoz in Switzerland, is particularly upbeat about Glenmark’s bispecific antibody portfolio based on the firm's proprietary BEAT antibody technology platform. The Bispecific Engagement by Antibodies based on the T-cell receptor (BEAT) platform facilitates the efficient development and manufacture of antibodies with dual specificities.

For instance, Glenmark’s HER2xCD3 bispecific antibody (GBR 1302), he explained, has the potential to be highly active on tumor cells that have low to moderate level of expression of HER2, which is where the current standard of care is “just not sufficient” and has limitations with Herceptin (trastuzumab) or conjugates of Herceptin.

“So here is where we may be able to differentiate. For us it is the front runner, already in Phase I clinical trials; the molecule has an important role to play for us to demonstrate and confirm the BEAT platform utility,” Stoeckli said.

HER2, also known as HER2/neu, or receptor tyrosine-protein kinase erbB-2, is the target of the antibody cancer drugs trastuzumab, pertuzumab and trastuzumab emtansine. A Glenmark investor presentation dated Dec. 19 claimed that GBR 1302 could bring about “faster and more complete” killing of tumor cells as compared with current first- and second-line treatments. GBR 1302 is also being studied in gastric cancer.

Other BEAT-based oncology biologics include GBR 1342 (a CD38xCD3 bispecific antibody) being developed for multiple myeloma and potentially other malignancies of hematopoietic origin and GBR 1372, targeting EGFR through redirected killing by T cells.

Stoeckli believes GBR1372, being developed for colorectal cancer, represents an “enormous opportunity” for the company.

“KRAS mutations are one of the most unmet needs in cancer therapy with a broad range of carcinomas. This is exactly where drugs like Erbitux (cetuximab) are not really effective enough and have limitations - where the body has by definition designed more than 10 mechanisms of resistance and where we have mechanistically a very good way to overcome the KRAS mutation problem,” he explained.

BEAT – Range Of Possibilities

Stoeckli suggested that Glenmark’s BEAT platform has a “competitive edge” compared with others including Roche’s CrossMAb technology invented to produce bispecific antibodies. (Also see "INTERVIEW: Glenmark's Buschle on how it hopes to 'BEAT' cancer" - Scrip, 21 Aug, 2014.)

Glenmark’s platform, he says, is efficient in “playing with new targets” that come up and are of clinical relevance; flexibility beyond CD3‐mediated engagement immunocytes is another plus that it brings, besides scalability.

“The stability and robustness of BEAT molecules is an important aspect of industrialization. The BEAT platform is designed such that you can efficiently purify what is up-scaled and can bring it rapidly to a point where you can supply the clinical studies with sufficient quantity and quality,” Stoeckli explained.

On whether Glenmark would consider an outright deal for the BEAT platform, Stoeckli said: “We do not say no to this upfront; we consider any sort of partnering for the BEAT platform to be within the range of possibilities.”

Amgen Inc. acquired the BiTE [Bispecific T cell engager] platform behind Blincyto (blinatumomab) when it snapped up Micromet Inc. in 2012 for over $1bn. (Also see "Amgen's Cancer Strategy: A Multitude Of Modalities In Immuno-Oncology And Beyond" - Scrip, 8 Sep, 2016.) In June this year, Novartis AG announced a collaboration and licensing agreement with Xencor Inc. for the development of bispecific antibodies for treating cancer; the deal includes rights to use Xencor's antibody engineering platform to develop up to 10 additional antibodies for immuno-oncology and other diseases. (Also see "Xencor's Coming Share Issue To Help Fund Immuno-Oncology Pipeline" - Scrip, 2 Dec, 2016.)

But Stoeckli clarifies that the BEAT platform could also be used for partnering on specific projects that the Indian firm has already ongoing.

“This would be a strategic partnership. And this means any sort of co-development, co-marketing – but we would partner and it’s not just a simple out-licensing. In addition, we could talk with someone who wants to have access to the technology per se for a certain number of targets they want to work on - we don’t purely exclude this; it is within the range of our thoughts.”

Combination Therapy

Significantly, Glenmark’s Dec. 19 investor presentation also highlighted a new type of “highly potent” OX40 agonist (GBR8383).

Glenmark’s OX40 agonist, in combination with programmed death (PD)-1 and other checkpoint inhibitors, is expected to be potentially very active in boosting the T cell response.

“We consider this as a typical example of a combination therapy in a broad sense in a variety of cancers. We have already made clear that we see great potential for the OX40 agonist to boost the effect of our CD3 engagers, but it goes beyond,” Stoeckli said.

Glenmark maintains that preclinical data on GBR8383 confirms a strong agonistic effect upon the checkpoint OX40 in comparison with other OX40 agonists currently in clinical trials. The company believes that GBR8383 has potential to enhance current immunotherapies (PD-1, PD-L1, CTLA4).

“Checkpoint inhibitors, immunotherapies require combination therapy in the future because the cancer site mechanistically predicts that you have to activate the immune system in multiple ways,” Stoeckli adds.

Experts say that, theoretically, an OX40-targeted drug could be used to stimulate an immune response and it could be combined with a PD-1/PD-L1 [programmed cell death-ligand 1] inhibitor that would prevent tumor cells from evading the generated response.

The Big Thing

Stoeckli also says that the big thing with immunotherapies is its potential to reach more patients; right now, even the “best of the best” immunotherapies, he says, reach only 30% response rates, at best.

“Great progress has been made and if you look at what has happened for the patients [who respond] - it has really changed their lives. They have a very different perspective. But there is huge unmet medical need for patient populations that are not responding,” he notes.

Stoeckli says that breakthroughs in cancer therapy will find the right combination that can change the response rates.

“This is what we are working on, molecules that engage and further boost, modulate in a positive way, the immune system.”

Glenmark’s new CSO also believes that some big pharma companies missed the opportunity to get on board with immunotherapy cancer treatments at the right time.

“So they are looking at partnerships to replenish their own pipelines, get access to competitive edge technologies. Nobody has, to date, been able to do everything on their own since nobody knows exactly which combinations will be most effective,” Stoeckli said, referring to J&J’s collaboration with Genentech and how Pfizer Inc. and Merck & Co. Inc. are going into combination therapy approaches either internally or via partnerships.

“There is room for Glenmark to come in and provide competitive assets,” he said.

In March 2016, Janssen Inc. and Genentech Inc., part of the Roche group, entered a clinical trial collaboration pact to initiate certain studies to determine the safety and tolerability of daratumumab (Darzalex), the first CD38-directed monoclonal antibody, in combination with atezolizumab, an investigational mAb designed to bind with a programmed cell death-ligand 1 (PD-L1).