Aptose Ceo Dr. William Rice: "The FDA Has Done Us A Favor"

A brief concise update column on Aptose ($APTO) because of both the recent share sell-off as well as perception (inaccurate) that the company has encountered snags in its dealings with the FDA regarding development plans for CG’806. I reached out to the company late morning and spoke with Dr. Rice, who’s quite upbeat about events, a short while ago. “We’re in good shape.”

Some months back, the FDA broached with company management the idea of healthy volunteer testing of CG’806 in order to optimize the drug’s use in human trials. It’s an unusual, and progressive, move by the FDA borne of two major facts: first, as a class, the oncogenic tyrosine kinase inhibitors have proven to be fairly safe and well-tolerated drugs in people. Second, CG’806 has been found to have no toxicity at either 6 days or 28 days of sustained dosing in studies using rodents and canines….where of course many of the administered doses are grossly supratherapeutic.

Generally, of course, cancer drugs are tested only in cancer patients from the phase 1 outset. But the FDA is aware of company plans to evaluate CG’806 in two major ailing populations: patients with B-cell neoplasms, and patients with acute myelogenous leukemia (AML). The former, the B-cell lymphoma patients, have slower courses sometimes verging on indolence, with more time to optimize therapeutic investigational regimens. This is categorically NOT so, however, of AML patients. Ask any physician: patients with AML are among the sickest patients in any hospital, and have a way of having aggressive disease that rapidly claims them. When I was an internal medicine house officer, we had a saying intended to be ironic: “One good AML patient can ruin your whole call night.” Both the oncology establishment and the FDA are painfully and acutely aware that available regimens for AML fall grossly short of any benchmark of idealism mainly because of their toxicity, as well as because of their relative inability to affect prognosis.

Came an idea from within the FDA, which may be discreetly smiling upon CG’806 (my words not Dr Rice’s): what if the company hit the ground running in AML trials with proper doses and dosing of CG’806 already determined? Since the drug seems to be so safe, unlike other oncology drugs that are inherently cytotoxic, one COULD consider a so-called SAD (single ascending dose) trial of CG’806 in healthy volunteers for phase 1. Which is to say: find healthy volunteers (probably paid folks), and after informed consent, have each volunteer take a single oral dose of CG’806, followed by serial blood draws for a week. This is called pharmacokinetic evaluation and allows the company to know in advance what dose it will go forward with in AML clinical trials. A SAD trial can be completed in perhaps 6 weeks.

Why is CG’806, a cancer agent, safe to use in healthy volunteers? Because ample work by Rice and colleagues during the last two years has shown the agent to inhibit only cancer-associated tyrosine kinases. The drug doesn’t impinge by its actions on healthy physiology.

But there was one hitch: an investigational new drug (IND) submission to the FDA for a cancer drug generally does not include so-called Ames genotoxicity testing. Why? Because for most cancer drugs, you are, as it were, angling FOR genotoxicity….you WANT the drug to kill cells and harm cells, at least malignant ones.  CG’806 had thus not been subjected to genotoxicity testing. But the “delay” rumored isn’t a delay at all: the company has now completed Ames genotoxicity testing and found it to be negative. Admittedly, bundling together, depicting and analyzing that data for inclusion in the IND submission package is a minor setback and, along with the healthy human volunteer pharmacokinetic testing, will result in the IND being submitted during the 1Q19 and not by EOY18. But in real terms, no delay in getting CG’806 to clinic is upon investors in that AML trials will be expedited. As we’ve noted, following IND submission and clearance (the passage of 30 days following IND acceptance by the agency), the agency has already given guidance that CG’806 may proceed directly into B-cell malignancy phase 1 trials.

Consider the alternative….approaching AML with CG’806 the old fashioned way. One would not know what dose to give. One would not know where to begin. Some patients would be underdosed. The underdosed would probably die….and then investigations ensue to see if somehow the underdosed drug actually exerted some bad effect on the patient beyond inadequate cancer treatment. Dose-finding studies, maddening expansion cohorts, delays, possible clinical holds, patient deaths, a wrongly impugned wonderful agent and mountains of documentation. Instead, at the encouraging of the FDA, the company is embarking on what amounts to an expedited AML development pathway merely by the 4-6 week side excursion of doing a SAD healthy volunteer pharmacokinetic study. And the minor delay incurred by processing and submitting that data to the agency. We can think of no other instance in FDA history when development of a cancer drug has proceeded by this pathway or has seemingly been so facilitated by the agency, almost as if FDA is parting the waters for Aptose.

Both Rice and Chow are busier than ever, meeting with prospective investors and presenting data, and Rice admits clarity of message on the precise nature of the deliberations with FDA hasn’t been ideal. But the facts speak for themselves, and one would have difficulty interpreting events as anything other than a boon to company and to CG’806 for its near-term future. And to shareholders.

[Disclosures: BioPub does not now have and has never had a pecuniary relationship with $APTO or its executives. The author has a long position in $APTO shares and will not trade in $APTO  for 7 days, reckoned in business days, after this column appears. This column is neither solicitation nor recommendation that you purchase shares in $APTO, and all small-cap biotech investors need to be aware of especial risks in this genus of investing. Diligence is due before transacting. This column is copyrighted by BioPub/Helixir Media, LLC, and may not be reproduced elsewhere without express written consent of the publisher. All rights reserved.]

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