Generic DoxoPLUS™

OVERVIEW

PLUS THERAPEUTICS is developing DoxoPLUS™, a complex, injectable, generic PEGylated liposomal formulation of doxorubicin.

Doxorubicin

In order for a cell to divide (mitosis), it must first duplicate all of its contents, including DNA. The cell then splits to form two identical cells, each containing a copy of DNA.

The DNA double helix is the most famous molecular structure in all of biology. During DNA replication, the double helix becomes overwound (like a rubber band that is twisted repeatedly) which blocks access to key enzymes needed for DNA replication. Other enzymes, called topoisomerases, act to release the wound up DNA thereby allowing DNA replication to proceed. Doxorubicin (Adriamycin) is a hydrophilic, anthracycline topoisomerase II enzyme inhibitor. By blocking the unwinding of DNA within tumor cells, doxorubicin blocks cell division, ultimately leading to tumor cell death.

Doxorubicin is a widely-used chemotherapy drug for breast cancer, ovarian cancer, multiple myeloma, Kaposi’s sarcoma, bladder cancer, lymphoma, and acute lymphocytic leukemia.  Doxorubicin acts via DNA intercalation and is based upon a bacterial product (Streptomyces).  However, it is associated with significant cardiac toxicity that can potentially lead to fatal congestive heart failure either during receipt of the therapy or months to years after termination of the therapy.

Two Molecules Of Doxorubicin Intercalating Into DNA

PEGylated Liposomal Doxorubicin

PEGylated liposomal formulations of doxorubicin are designed such that the doxorubicin resides within center of the liposome.  Because liposomes cannot easily pass through normal blood vessels, this protects healthy tissue, including heart muscle, from the toxic effects of the drug. However, because the blood vessels of tumors are actively growing they are much more leaky (permeable) than those present in healthy tissue. In fact they contain small openings, or fenestrations, that are large enough to allow liposomes to leave the blood stream and pass into the tumor. This is referred to as the Enhanced Permeability and Retention (EPR) effect.

In this way, PEGlylated liposomal formuations of doxorubicin deliver less doxorubicin to the heart without reducing delivery to the tumor.  As a result, use of a liposomal formulation of doxorubicin is associated with reduced incidence of injury to the heart without compromising anti-tumor activity.

In the 1990s, PEGylated liposomal doxorubicin was approved by the major regulatory agencies in Europe, China, and the U.S.  The marketed product, CAELYX® (branded DOXIL® in the U.S.) faced plant issues in 2011 that led to a temporary production stoppage and supply shortage.  

Today, CAELYX® is off-patent and generic versions of CAELYX® have received regulatory approval in China and the U.S., but not in Europe.  For the originator and/or generic PEGylated liposomal doxorubicin, the current estimated market sizes ($USD) are:

Europe

China

United States

References:  IQVIA and company websites.

CAELYX and DOXIL are a registered trademarks of Janssen Products, LP.

GENERIC DoxoPLUS™

Development Rationale

Today, healthcare providers in Europe wishing to administer PEGylated liposomal doxorubicin to their patients only have one option available – CAELYX®. The team at PLUS THERAPEUTICS has completed a substantial amount of DoxoPLUS™ development and manufacturing activities needed to file a Marketing Authorization Application with the European Medicines Agency.  If approved, DoxoPLUS™ will represent a generic alternative to CAELYX®.

In July 2019, the company announced a strategic decision to make DocePLUS™ its lead product candidate. Coinciding with this decision, we have elected to focus on divesting DoxoPLUS™ and are seeking external parties interested in this opportunity.

Bioequivalence Clinical Trial Complete

Unlike innovative drugs that must complete conventional Phase 1, Phase 2, and Phase 3 clinical trials to support regulatory approval, generic drugs must only demonstrate bioequivalence to the originator drug in a single clinical trial, which thereby creates an expedited development path toward regulatory approval. Demonstrating bioequivalence means that the drug levels in a patient’s blood and tissue following injection of the generic drug must be equivalent to those observed following injection of the originator drug.

We believe that data from a 60-patient clinical trial of DoxoPLUS™ has met the statistical criteria for equivalence to the reference listed drug in Europe, CAELYX®. That is, in a head-to-head clinical comparison, key parameters such as the concentration of doxorubicin and its metabolites in the blood and the clearance of these components from the blood were shown to be equivalent for DoxoPLUS™ and CAELYX®.

PurposeTo assess the pharmacokinetic bioequivalence of DoxoPLUS (test product) and European-sourced CAELYX (reference product).
Methods+ Single blind, randomized, two-way, crossover bioequivalence trial
+ Patients with ovarian cancer that had progressed or recurred following platinum-based therapy
+ Patients enrolled at sites in Ukraine, Canada, and the U.S.
+ Patients randomized 1:1 to receive 1 of 2 treatment sequences. Each sequence consists of 2 treatment cycles, 28 days per cycle.

+ Sequence A: Day 1, Cycle 1 (50 mg/m2 CAELYX); Day 2, Cycle 2 (50 mg/m2 DoxoPLUS)

+ Sequence B: Day 1, Cycle 1 (50 mg/m2 DoxoPLUS); Day 2, Cycle 2 (50 mg/m2 CAELYX)

ResultsPK ParameterCAELYXDoxoPLUS
Encapsulated DoxorubicinCmax47,20042,400
AUC o-t4,280,0003,690,000
AUC o-inf5,040,0004,400,000
Free DoxorubicinCmax3,0903,120
AUC o-t180,000176,000
AUC o-inf230,000226,000
DoxorubicinolCmax3.362.99
AUC o-t489442
ConclusionsDocePLUS is bioequivalent to European-sourced CAELYX. The lower and higher 90% CI ratios for ln-Cmax, ln-AUC o-t and ln-AUC o-inf of encapsulated doxorubicin, free doxorubicin, and metabolite doxorubicinol following DoxoPLUS were within 80-125% of those ratios following European-sourced CAELYX.

PLUS THERAPEUTICS has also developed plans to perform a bioequivalence clinical trial of DoxoPLUS™ compared against LIPODOX®, the current Reference Standard in the U.S., to serve as the basis for submission of an appreciated new drug application (ANDA) for FDA approval.  We currently anticipate that any bioequivalence clinical trial to support this approval will be funded by a partner.

References:  Kousba A et al 2017

LIPODOX® is a registered trademark of Sun Pharmaceutical Industries Ltd.

Regulatory Plan

In June 2017, PLUS THERAPEUTICS received confirmation of eligibility for submission of an application via a Centralized procedure for a Union Authorization for the medicinal product, DoxoPLUS™, from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP).  That is, the EMA will give an opinion on a single application which results in a single marketing authorization, allowing a medicine to be placed on the whole of the European Union market for sale and supply.  This contrasts with an alternative pathway via National Authorization procedures in which individual member states authorize the medicine for use in their own country.

In March 2019, PLUS THERAPEUTICS filed a formal letter of intent to submit a Marketing Authorization Application (MAA) to the EMA for DoxoPLUS™.  This submission is a required precursor for a MAA via the EMA’s Centralized procedure.  As a next step, we expect to receive EMA assignment of a rapporteur and co-rapporteur, who will work with us through the MAA submission and review process.  

Referencing formal scientific advice previously received from the EMA’s CHMP, PLUS THERAPEUTICS has completed a substantial amount of work toward preparing a MAA for DoxoPLUS™.