Many drug development programs claim to be truly unique and novel. It’s a mixed message really – complete novelty implies (or ensures) a high level of risk. It’s a bit difficult to attract early investment to such programs and maintain investor interest going forward. When we work with companies raising money, or are raising money ourselves, we are constantly trying to minimize risks, plural, as risks represent diverse aspects of a program or company: technology risk, biology risk, clinical risk, commercial risk, to highlight just a few. Companies that can move novel programs forward while derisking them in multiple areas certainly warrant our attention – for the scientific thesis and the investment thesis. We recently wrote about Innate Pharma, a company with first-in-class programs targeting NK cell immune checkpoint pathways (link 1). This is a good example of a company that has shed biology and clinical risks as the partnership with Bristol-Myers Squibb (BMS) continues to grow. The entire second tier of antibody-drug conjugate linker/payload companies (Redwood, Igenica, Mersana, Catalent and many others) will remain technology risk-heavy until each individual company either secures partnerships that eventually move ADCs into the clinic, or get their themselves. We could go on and on.
A few weeks ago I asked for companies and programs targeting the tumor microenvironment. Among the responses I got these:
Halozyme (Nasdaq: HALO) has a lead program that is very novel and I think scientifically is very interesting and has understood biological risk. We’ll talk about other risk elements in a bit, but science first. PEGPH20 is a pegylated version of the company’s approved recombinant human hyaluronidase (rHuPH20; brand name Hylenex). Hylenex is licensed to several partners, and provides a steady income stream from royalties. Hyaluronidase catalyzes the random hydrolysis of 1,4-linkages between 2-acetamido-2-deoxy-b-D-glucose and D-glucose residues in hyaluronan (HA), a constituent of the ECM. Hyaluronidase increases tissue permeability and as used locally (sc) to improve drug distribution. In the systemic tumor setting we have the interesting hypothesis that some tumor types use HA to create a cell impermeable “wall” around tumor cells or the tumor mass. The best-characterized tumor in this sense is pancreatic cancer, which is encased in an ECM that resists penetration by therapeutics and cells.
HALO is running a Phase 1/2 clinical program in PEGPH20 in patients with previously untreated metastatic pancreatic cancer. A completed Phase 1 clinical trial assessed the safety and tolerability of PEGPH20 treatment in patients with solid tumor malignancies refractory to prior therapies. A Phase 2 trial, built off a Phase 1b run-in, is underway in metastatic pancreatic cancer. The cohorts are standard of care (gemcitabine) with PEGPH20 or with placebo. An on-target toxicity (muscle spasm/pain) was addressed in a trial in which patients were pre-dosed with dexamethasone. At ASCO 2013, HALO presented data from the Phase 1b clinical study of PEGPH20 in combination with gemcitabine for the treatment of patients (n=28, 24 evaluable) with previously untreated stage IV metastatic pancreatic ductal adenocarcinoma (link 2). Patients received doses of PEGPH20 (1.0, 1.6 and 3.0 µg/kg) twice weekly for four weeks, then weekly thereafter, in combination with gemcitabine, IV. The RECIST 1.1 ORR (overall response rate = complete response (CR) + partial response (PR)) was 42% percent at the two higher doses. Subsequent exploratory analyses suggested better progression free survival (PFS) and overall survival (OS) in patients with high levels of tumor HA compared to patients with low levels of tumor HA. This has led the company to embark on the development of a companion diagnostic to enable pre-selection of patients.
Other clinical studies include a Phase 2 multicenter, randomized clinical trial first-line therapy trial of PEGPH20 in patients with stage IV metastatic pancreatic cancer. Patients were randomized to gemcitabine plus nab-paclitaxel with or without PEGPH20. The primary endpoint is PFS. SWOG has sponsored a Phase 1b/2 randomized clinical trial of PEGPH20 in combination with modified FOLFIRINOX chemotherapy compared to mFOLFIRINOX treatment alone in patients with metastatic pancreatic adenocarcinoma. MSKCC is sponsoring a trial +/- cetuximab. A full trial list is shown here:
In October (2014) the FDA granted Orphan Drug designation for PEGPH20 for the treatment of pancreatic cancer. OK, so what do we see here? The therapeutic hypothesis is compelling, that disassembling the tumor-shielding ECM will be helpful (see link 3). Would this work as monotherapy? Perhaps, but that is not being tested, since keeping standard of care (SOC) on-board is important for these patients. But if we consider the impact of a disrupted architecture, I think we would argue that monotherapy, or at least interesting combination therapies, could be considered. The mechanisms of action are complex and include physical disruption of the tumor microarchitecture, disruption of aberrant circulation and interstitial pressure in the tumor, disruption of zones of hypoxia, and other effects. Look at this figure from the preclinical study (pancreatic cancer, mouse model):
Panel A shows the dosing regimen (with gemicitabine), B shows the impact on pressure within the tumor and C v D shows representative tumors from the control and treated animals. Another recent paper discusses the vascular effects in detail (link 4). With the obvious leakage and loss of tissue integrity it makes sense to argue for combination with chemotherapy or antibody therapy, as in the cetuximab combo trial show above, from the MSKCC. One might also postulate that the collapse in pressure and increased access to the interstitial space might allow better penetrance by lymphocytes, allowing consideration of immune checkpoint combinations. But lets look closer:
I left the figure legend in place so I don’t have to repeat the details, which show a reduction in smooth muscle actin (A v B) and collagen (D v E). Basically this figure suggests that the structural elements of the tumor microenvironment have collapsed. Given the impact on ECM components, I would predict that you would see adverse impact on myeloid cell populations, inducing the TAM and MDSC populations discussed earlier (another link). I’d have loved to see a panel with PEGPH20 alone as I’ll bet you would see some impact with the monotherapy.
So if we go back to our three-legged stool model…
… now we are dead-on the microenvironment piece, and perhaps an obvious complement to the other 2 legs.
All well and good but the proof is in the clinic, and so is the risk. We talked about diverse risks earlier – here we have clinical risk (efficacy/toxicity) and commercial risk (is it good enough). HALO is presenting at the ASCO GI meeting with abstracts to come out from under embargo on January 12, 2015. The abstracts will include an update on the clinical trial NCT01453153, phase 1/2 +/- gemcitabine in metastatic pancreatic cancer. Presentation of median OS data is rumored (but n.b. I’ve not confirmed with the company). I’m excited by the prospects here, and hope we see some nice results…
… because the science makes sense.