Immunotherapy R&D is Sizzling, Creating a New Generation of Cancer Therapies

Just when analysts feared the pipeline of blockbuster drugs was starting to run dry, enter immunotherapies. The activity in immunotherapy development is soaring. In the last six months alone, cancer immunotherapy deals have easily totaled $8 billion (see Table below).

During the same timeframe, there has been a flurry of announcements from companies pairing up to develop novel combination immunotherapies. In April, MedImmune and Juno said they planned to conduct clinical trials of a potential combination therapy for non-Hodgkin lymphoma. The combo includes one of Juno’s investigational CD19-directed chimeric antigen receptor T cell (CART) candidates and MedImmune’s investigational programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitor, durvalumab (MEDI4736). Then, in August, durvalumab became the subject of Mirati Therapeutics and MedImmune’s joint effort to evaluate it in combination with Mirati’s investigational histone deacetylase (HDAC) inhibitor, mocetinostat, in a Phase I/II study. This combo will initially be evaluated in patients with non–small-cell lung cancer.

Also in August, Syndax Pharmaceuticals and Genentech said they will evaluate Syndax’ entinostat, an oral small molecule that targets immune regulatory cells, in combination with Genentech's atezolizumab (MPDL3280A), a fully humanized monoclonal antibody targeting PD-L1, in a Phase Ib/II trial in triple-negative breast cancer. And this month, Incyte and Aduro Biotech agreed to evaluate Aduro’s lead LADD (Live, Attenuated, Double-Deleted Listeria monocytogenes) immunotherapy, CRS-207, in combination with Incyte’s oral indoleamine dioxygenase 1 (IDO1) inhibitor, epacadostat (INCB24360), in patients with ovarian cancer. The Phase I/II trial is designed to test combos of CRS-207 with two dose levels of epacadostat in dose escalation and then expand to a Phase II evaluating the combo at the optimal dose level compared to CRS-207 alone.

BUT WILL THE NEW WAVE OF IMMUNOTHERAPIES PROVE PROHIBITIVELY EXPENSIVE?

Consider this. If new immunotherapy combinations were administered to the half a million Americans dying of cancer each year, the nation’s price tag for treating them—for just one year—could top $174 billion, according to projections by Leonard Saltz, MD, Chief of Gastrointestinal Oncology and Chair of the Pharmacy and Therapeutics Committee at Memorial Sloan-Kettering Cancer Center. Dr. Saltz offered his perspective on value in cancer care at the Plenary Session of the 2015 ASCO Annual Meeting (The ASCO Post). For more on drug pricing, see BCC Research’s recent blog.

There’s a lot of excitement about the immunotherapy known as CAR-T, which is a method of modifying immune cells to fight cancer. CAR-T cells are a patient’s own T cells altered outside the body to be cancer killers, then put back in to go after tumor cells. But there are also a lot of hurdles facing CAR-T therapy. And it was these hurdles, not the hype, which were the subject of a panel of experts from industry, academia, and the FDA at the Inaugural International Cancer Immunotherapy Conference in New York this month. Yet, speed bumps and all, it is likely to be a very fast-moving field. Noted one panelist, Carl June from the University of Pennsylvania, CAR-T products are going to have rapid life cycles because there are going to be consistent improvements to them.

Hang on to your hats for what promises to be a tumultuous ride.

Selected Immunotherapy Deals Announced Since 4/1/2015

Companies	Date	Value	Key Details
Roche Curadev Pharma	4/20/2015	$555M	Cancer immunotherapy collaboration to develop and commercialize IDO1 (indoleamine-2, 3-dioxygenase-1) and TDO (tryptophan-2, 3-dioxygenase) inhibitors. Curadev will receive $25 million upfront and be eligible to receive up to $530 million in milestone payments.
Seattle Genetics Unum Therapeutics	6/8/2015	$645M	Collaboration to develop and commercialize novel antibody-coupled T-cell receptor (ACTR) therapies for cancer. Seattle Genetics will pay $25 million upfront and make an equity investment of $5 million. The companies will initially develop two ACTR products and Seattle Genetics has an option to include a third ACTR product. Potential option fee and milestone payments to Unum may total up to $615 million.
Celgene Juno Therapeutics	6/29/2015	$1B	Global immunotherapy collaboration to leverage T-cell therapeutic strategies for treatment of cancer and autoimmune diseases, with an initial focus on CAR-T and T Cell Receptor (TCR) technologies. Juno will receive approximately $150 million upfront. Celgene will also purchase 9,137,672 shares of Juno’s common stock at $93 per share.
Merck cCAM Biotherapeutics	7/28/2015	$605M	Merck to acquire cCAM Biotherapeutics, a company focused on novel cancer immunotherapies, for $95 million upfront. cCAM shareholders may receive up to $510 million upon attainment of certain milestones. Merck gains several early immunotherapy candidates including CM-24, a novel monoclonal antibody targeting the immune checkpoint protein CEACAM1. CM-24 is in Phase I for treatment of advanced or recurrent malignancies.
Sanofi Regeneron	7/28/2015	$2B+	Collaboration for antibody cancer treatments. The companies will jointly develop a programmed cell death protein 1 (PD-1) inhibitor, which is in Phase I. Sanofi will pay $640 million upfront, and the companies will invest $1 billion for discovery through proof of concept of monotherapy and novel combos of immuno-oncology antibody candidates. The companies will also pay $650 million ($325 million each) for development of REGN2810, a PD-1 inhibitor.
AstraZeneca Heptares Therapeutics	8/5/2015	$510M	AstraZeneca gains exclusive global rights to the adenosine A_2A receptor antagonist, HTL-1071, a small-molecule immuno-oncology candidate, and potential additional A_2A receptor-blocking compounds. Heptares will receive $10 million upfront. Heptares is also eligible to receive $500+ million in milestone payments.
MedImmune Inovio	8/10/2015	$727.5M	MedImmune gains exclusive rights to Inovio's Phase I/II immunotherapy, INO-3112, which targets cancers caused by human papillomavirus (HPV) types 16 and 18. INO-3112 generates killer T-cell responses that are able to destroy HPV 16- and 18-driven tumors. MedImmune will study INO-3112 in combo with selected immunotherapy molecules within its pipeline in HPV-driven cancers. MedImmune will pay $27.5 million upfront and make milestone payments of up to $700 million.
Amgen Xencor	9/16/2015	$1.7B	Agreement for novel cancer and inflammation therapies. Includes preclinical development of bispecific molecules for five programs, leveraging XmAb bispecific Fc domains to make half-life extended T-cell engagers and dual-targeting bispecific antibodies. Also includes a preclinical bispecific T-cell engager program directed at CD38 and CD3 for multiple myeloma. Xencor will receive $45 million upfront and up to $1.7 billion in milestone payments.