Cohbar Cso Dr. Ken Cundy Addresses The Cb4211 Temporary Trial Suspension
BioPub reached out this week to CohBar management on behalf of our reader-investors for some additional insight into CohBar’s decision to suspend temporarily the phase 1a trial of CB4211. We spoke to Kenneth Cundy, PhD, and he was joined by COO Jon Stern, MBA, and board chairman Albion Fitzgerald.
Recall that CB4211 is an approximately 30-amino-acid version of constitutively mitochondrially-elaborated peptide MOTS-c, discovered by CohBar founders. Work original with CohBar CSO Ken Cundy was presented this summer at ADA revealing that MOTS-c behaves like an allosteric modulator of the insulin receptor, keeping it in a posture that makes it have native sensitivity to insulin. Indeed, the current CohBar model of insulin resistance, the great plague of mankind, is not that insulin resistance emerges directly as a result of age, obesity, activity, diet or other factors, but rather from gradual age- and oxidation-related diminutions over time in baseline MOTS-c elaboration by our mitochondria. Restore this and in theory you restore a state of high sensitivity with features of high lean body mass relative to fat body mass, normal lipids, normal fat and triglyceride metabolism, euglycemia and normal responses to glucose boluses, an absence of fatty liver (and correct of fatty liver if a MOTS-c supplementation regimen is initiated), and even normotension (hypertension can be driven by rising fat body mass).
CB4211 is one of two MOTS-c analogues Cundy and colleagues invented, and it differs from native MOTS-c in certain selected amino acid substitutions that optimize or potentiate the peptide’s activity toward the insulin receptor. CB4211 has also been modified in a manner that is a trade secret to extend its half-life to make it suitable for twice weekly subcutaneous injection rather than daily (or more often) injection. The protein modification is NOT pegylation or PTENylation, but Cundy has assured me it’s a standard and pharmacokinetically validated protein modification now in use in the drug industry. He declines to name other products that incorporate this method, again, as trade secret for now.
Generally a phase 1a study of a new drug has two components: single doses given to healthy subjects, followed by a section in which other healthy subjects get multiple doses. The recipients are scrupulously monitored for symptoms, examined, and blood-tested to look for evidence of organ harm. If in the single dose portion of the trial the initial dose is well tolerated, subsequent patients get higher (but again one-time) doses. These kinds of trials are often called SADMAD trials, for single ascending dose/multiple ascending doses.
Particularly during toward the late portion of the SAD phase and then also during the MAD phase (the SAD phase has been completed for CB4211, but the MAD phase only partially so), clinician investigators began routinely noting, especially with larger doses of study drug, a tendency for subcutaneous nodules to persist at the injection site. The nodules have always been non-tender, non-erythematous, non-purulent, freely mobile. For ALL patients involved they’ve been “no big deal,” and no patient has dropped out of phase 1a (phase 1b has not yet been initiated). Patients are aware of the nodules, but not complaining of them. And they DO abate, gradually.
KSS: “Ken, not to cut too bluntly to the chase, but if I were physician managing one of these patients, I’d certainly think about consenting someone, placing a bleb of lidocaine into the nodule and just doing a punch biopsy of the nodule. Find out what the heck it is. Any chance of proceeding that way?”
Cundy: “Well, I’m limited by rules of what’s disclosable, what’s public right now….but you’re exactly right. We had thoughts along exactly the same lines…and without spelling it out, let’s just say we have done a definitive diagnostic procedure on certain patients, and we DO know EXACTLY what’s going on.”
KSS: “Ah, terrific! So it’s NOT granulomatization, or pus, or amyloid, or lipohypertrophy, or something sebaceous….and so on.”
Cundy: “Precisely. We know for SURE that it’s drug just sitting there. It is CB4211 that was injected. It’s being stubborn in some cases to mobilize. BUT there is NO evidence it’s causing any harm there. It’s definitely not upsetting the tissues or causing some local adverse reaction.”
KSS: “Given that you know this, and I realize I’m asking you perhaps to speculate……at this point do you see any real reason to fear that this could provoke a situation where you have to reformulate CB4211?”
Cundy: “No, I think it’s safe to say that option’s not on the table. The drug’s clearly not causing any harm there, and it IS getting taken up. But the more drug a patient is given in the subcutaneous injection, the likelier there is some residue there that’s slower about being taken up.”
KSS: “Should we be concerned that this could, you know, imperil the pharmacokinetics of CB4211?”
Cundy: “I tend really to think not….though it’s too early to know for sure because we don’t have a complete set of phase 1a data.” But he goes on to explain that CB4211 therapy is about having abundance or enough of it around; it is doubted there will be toxicity issues from an excess.
KSS: “CB4211 is not vancomycin.”
Cundy: “Yes. And so we do know exactly what the problem is….and we have a plan to deal with that, we have a response to the problem. It’s all pretty straightforward really. And we just need or seek some indication from the FDA that they are OK with our plan to proceed and reinitiate the trial.”
KSS: “So are you actually seeking a type C meeting with the agency?”
Cundy: “Well, no….now, it could come to that, if they choose to have us approach this in a formal manner with them. But what we’re hoping for is more of a semi-formal discussion with them by phone, a presentation of the facts and our response to those facts….and how we’d like to proceed.”
Cundy sounds genuinely confident. Readers should keep in mind that for discussions like this with executives, there are two sorts of information that are problematic to give out, First, some forms of information, some facts, shouldn’t be given out at all, at least not yet. But a larger number of facts are ones that have simply not yet been publicly disclosed, and if they are to be disclosed must be revealed in a way the SEC regards as sound. The SEC wants new information to be given out not at a conference or during a phone call where not everyone has access, but preferably by universal memo….thence the common 0700 press release and flurry of emails. There is much in this conversation Cundy would like to reveal but just cannot lest it prompt a whole new set of announcements.
And among those facts is precisely what sort of responsive plan CohBar has in place to deal with the depot effect at injection. He implies that it will include a revised, more dispersive injection technique, which in fact isn’t hard to teach. From my hepatology days, we constantly dealt with injection site adversities owing to interferon-alpha. And injection technique can be refined…and heated moist cloths applied to injection sites to limit pooling and enhance circulation. The point is that there are practical solutions here that avoiding derailing CohBar and its plans for CB4211. Cundy naturally cannot give a trial resumption date; I tend to presume during January 2019.
KSS: “Ken, do you think there’s any cause for concern that other CohBar mitochondrial-peptide based therapeutics promulgated into the clinic could also have this issue?”
Cundy: “Certainly it’s possible but I think that call is too early to make.”
Cundy reminds me that other approved injectable protein therapeutics have had “issues” with residual blebs at injection sites but that these have not sandbagged their clinical use nor provoked the attention of the FDA. He notes that Fuzeon, an HIV fusion inhibitor, commonly leaves slow-to-resolve injection site welts. And ditto for GLP-1 agonist Bydureon. Neither agent has impaired efficacy or problematic PK from these issues. For all we know, patients simply massage the injections sites and woo injected drug to disperse. Not every solution to every biotech problems needs to be high-tech.
CohBar await further disposition from the FDA, are confident and optimistic, and voice that this entire aside is about caution and staying in good graces with the FDA. No patient has been harmed. Cundy promises to contact me by phone or by email as soon as word from the agency is in.
Readers are encouraged to listen to the early November 2018 CohBar conference call regarding the CB4211 trial, and a recording is available by link at the corporate website.
Disclosures: Dr. KSS has a long position in $CWBR shares, and will refrain from trading in $CWBR shares for 7 days, reckoned in business days, after this column appears. BioPub does not now have, and has never had, a pecuniary relationship with CohBar or its executives or founders. This column is not a solicitation for you to trade in $CWBR shares and should not be taken as investing advice. While BioPub editors retain an upbeat and optimistic view of CohBar’s prospects, this is a small-cap biotech working with an entirely new class of agents. Bumps in the road are part of the terrain.