Signpath’s CorreQT Technology and Cardiac Arrhythmia

There are more than 180 FDA approved drugs which induce ventricular repolarization delays, also known as long-QT syndrome. This potentially lethal adverse side-effect results from the slower  repolarization kinetics of the cardiac muscle leading to potentially fatal cardiac arrhythmia.  The FDA and other regulatory agencies worldwide have tightened development rules significantly, viewing drugs which cause QT prolongation as a serious safety concern.

long-qtcg_heart

Signpath has developed a platform technology aimed at mitigating cardiac arrhythmia.  This technology is referred to as the CorreQT platform, and the CorreQT research has led to a portfolio of compounds which mitigate cardiac arrhythmia.  The lead CorreQT compound in development is SP4040.  SP4040TM is a proprietary, patented lipid based therapy which can be administered intravenously or orally.  SP4040TM has been shown to prevent arrhythmia in heart cells in vivo.

SignPath has successfully alleviated the QT prolonging effects of more than 20 QT-prolonging drugs utilizing our CorreQT platform technology.  These drugs include anti cancer drugs, antibiotics, and antihistamines.  The CorreQT compounds have been effective in alleviating QT prolongation, irrespective of the mechanism of action by which the target drug induces QT prolongation.

Signpath is on track to begin human clinical trials with SPP4040 in the 2nd quarter of 2017.

Signpath Pharma CorreQT Technology:  Business Rationale

Signpath’s CorreQT platform provides two distinct opportunities for development. The first is the opportunity to develop “proprietary generic” drugs; that is, patented versions of generic drugs which are safer than the generic versions due to mitigation of QT Prolongation side effects. This avenue can be pursued unilaterally by Signpath because the target drugs are off patent or have limited patent life.   Signpath has identified a number of target drugs for development, including anti-psychotics, anti-cancer agents, and drugs for the treatment of pain and/or opiod addiction.

The second avenue for development of the CorreQT technology is to pursue license agreements with other companies who are developing and/or marketing patented drugs which have QT prolongation side effects. Signpath’s CorreQT technology has the ability to mitigate these dangerous cardiac side effects, making the target drug safer and broadening the market for these drugs. There is an additional benefit to this approach because it would provide additional patent protection for the proprietary target drug, extending exclusivity for an additional 15-20 years.

One of the primary benefits of the CorreQT technology is the relative simplicity of the development pathway. The target drugs to be used in conjunction with SPP4040 have all previously received FDA approval and have proven efficacy. The required clinical trials will be focused on a single side effect (QT prolongation) which is easily and objectively measurable via EKG. These trials can be performed relatively quickly and inexpensively when compared with unapproved drugs with unproven efficacy and unknown safety profiles.

Below are examples of some of drugs  which are known to cause QT prolongation.   These drugs are potential targets for creation of safer variants using Signpath’s CorreQT technology.

Drug nameIndicationsApproval Status Notes
Thioridizine

Schizophrenia
Psychosis
On MarketTypical (first generation) antipsychotic. Novartis/Sandoz was the innovator. They discontinued the drug in 2005 due to QT Prolongation. A number of generic manufacturers continue to make it available. Data shows it may be useful vs. drug resistant tuberculosis.
Risperidone Schizophrenia
Psychosis
On MarketAtypical (second generation) antipsychotic. Second most widely prescribed anti-psychotic drug. 4.7 billion in sales in 2007 before it went generic.
Risperidone is preferentially prescribed to elderly patients who are at risk for cardiac arrhythmias.
CitalopramDepressionOn MarketCitalopram is one of the most widely prescribed anti-depressants, with over 39 million prescriptions dispensed in 2012. Because of QT prolongation safety issues, dosing levels for Citalopram have been significantly reduced from those originally approved
OxaliplatinColorectal cancerOn MarketOctober 2015 FDA warning against QT prolongation.
Arsenic Trioxide Acute Promyelocytic LeukemiaOn Market(Patent expires in 2018) More than 50% of patients experience QT prolongation
Adriamycin Sarcomas; Breast cancer; Lymphomas
On MarketQT prolonger. Adriamycin is the only agent which has any realistic possibility of inducing remissions in patients with soft-tissue sarcomas (so must be used even in patients with congenital long-QT syndrome).
Methadone Opiod addiction and pain mitigationOn MarketQT Prolongation is a significant risk. (FDA issued a warning letter in November 2006 regarding QT prolongation and Methadone.) EKG monitoring of QT not feasible in much of the target patient population. Widely prescribed for both opioid dependence and pain.
Levacetylmethadol


Opiod addictionRemoved from market due to QT ProlongationLevacetylmethadol (“LAAM”) is a synthetic opioid similar in structure to methadone. It has a long duration of action due to its active metabolites. Unlike methadone, which requires daily administration, LAAM is administered two to three times a week. Removed from the market in 2003 due to heart arrhythmia side effects.
Ondansetron, (Zofran)Nausea On MarketFDA Warning Sept, 2011 referencing QT prolongation.
Sevoflurane Anesthesia On MarketSevoflurane can extend the QTc to beyond the upper limit of the normal range. 2014 sales were $550 million.
Grepafloxacin hydrochlorideAntibacterialRemoved from market due to QT prolongationAn oral broad-spectrum fluoroquinolone antibacterial agent. Grepafloxacin was withdrawn worldwide from markets in 1999 owing to its side effect of lengthening the QT interval, leading to cardiac events and sudden death.
Vandetanib
(Genzyme’s Caprelsa)

Thyroid cancerOn Market(Patent expires 2022)
Astra Zeneca was the innovator. Now owned by Genzyme. This drug’s use has been significantly limited by QT prolongation issues. Genzyme currently operating under an FDA mandated Risk Evaluation and Mitigation Strategy (REMS) due to QTc side effects.
– Among all patients who received vandetanib, 69% experienced QT prolongation.
Nilotinib (Novartis’ Tasigna)Chronic myeloid leukemiaOn Market(Patent expires 2023)
Nilotinib is known to prolong the QT interval.
Sudden deaths have been reported in patients with resistant or intolerant Ph+ CML receiving nilotinib. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

 

In vivo test results

Signpath’s lead CorreQT compound, SPP4040, has been tested in QT Prolongation assays in three mammal animal species (rat, rabbit, and guinea pig.)  In all instances, SPP4040 has been successful in alleviating drug induced QT prolongation.

Below are some examples of these in vivo test results:

Comparison of Rabbit QT Prolongation with and without SPP4040

Comparison of Rabbit QT Prolongation with and without SPP4040 

Comparison of QT Prolongation caused by Ceritinib, with and without SPP4040 (Guinea Pig Model)

Comparison of QT Prolongation caused by Ceritinib, with and without SPP4040 (Guinea Pig Model)

 

To date, Signpath’s CorreQT compounds have been tested in conjunction with more than 20 different QT prolonging targets in animal models.  In every case, the CorreQT compound was successful in alleviating QT prolonging side effects.

Clinical Development Pathway

Signpath expects to undertake human clinical trials on SPP4040 during 2017.  The initial trial will be a Phase 1(a) single agent safety trial to assess the safety profile of SPP4040 in humans.  In animal studies, SPP4040 has proven to be non-toxic at clinically relevant doses, and we do not anticipate significant toxicity in humans.

Following the completion of the Phase 1(a) safety trial, we will initiate a proof of concept efficacy trial exploring the effect of SPP4040 on drug induced cardiac arrhythmia in human clinical subjects taking Moxifloxicen.  Moxifloxicen is an antibiotic agent which is known to cause significant QT prolongation.  SPP4040 will be administered in conjunction with Moxifloxicen and heart rhythms will be monitored using EKG to assess the effects of SPP4040 on drug induced QT prolongation.

If the Moxifloxicen trial is successful, Signpath will then move on to clinical trials with various commercial targets.