Type Whole antibody Target GD2 Legal status US: ℞-only | Source Chimeric (mouse/human) Trade names Unituxin CAS Number 1363687-32-4 | |
Dinutuximab (tradename Unituxin) is a monoclonal antibody that targets glycolipid GD2, expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including the central nervous system and peripheral nerves. It was approved for use, in combination with granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for high-risk neuroblastoma in pediatric patients who have at least partially responded to other first line treatments; it received FDA approval on March 10, 2015. It was initially developed by a federal agency, the U.S. National Cancer Institute (NCI) in partnership with the Children’s Oncology Group. In 2010, United Therapeutics was under contract with the NCI to "conduct late-stage clinical testing, and to manufacture and market the drug". It is available only as an intravenous injection distributed in a 17.5 mg/5mL single dose vial.
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Administration
The IV infusion of 17.5 mg/m2/day Unituxin occurs over 10–20 hours per day. To manage pain associated with the treatments, IV 10 mL/kg normal saline is administered over one hour prior to the infusion. Right before the infusion begins 50 mcg/kg morphine is administered followed by 20-50 mcg/kg/hr given throughout the infusion and for 2 hours after completion. IV Diphenhydramine 0.5 to 1 mg/kg with a maximum dose of 50 mg is administered over 10–15 minutes 20 minutes before the infusion begins and then every 4–6 hours as tolerated.
Pharmacokinetics
To evaluate the PK, United Therapeutics conducted a study with 27 pediatric patients with high-risk neuroblastoma. In the study the patients received up to 5 cycles of the drug at a rate of 17.5 mg/m sq./day administered over 10–20 hours for 4 consecutive days in 28-day cycles. The maximum plasma concentration was determined to be 11.5 mcg/mL; the mean steady state volume distribution was 5.4 L; the clearance rate was 0.21 L/day; and the average half-life was 10 days.
Adverse Drug Reactions
Dinutuximab can cause severe pain by irritating nerve cells, requiring intravenous narcotics. It can also cause nerve damage and life-threatening infusion reactions. in which the FDA gave a Black Boxed Warning.
The most severe adverse drug reactions include: "neuropathic pain (51%), pyrexia (40%), infusion-related reactions, which may include true hypersensitivity reactions(25%), capillary leak syndrome (23%), hypotension (16%),sepsis (16%), device-related infection (16%), diarrhea (13%), urticaria (13%) and hypoxia (12%)".
Dinutiximab has a contraindication for those who previously had an instance of anaphylaxis to the drug.
History
On December 4, 1991, United Therapeutics filed IND 4308. In October 2001, the random Phase III clinical trial ANBL0032 began. On December 20, 2010, dinutuximab was granted Orphan Drug Designation. During the Pre-IND/Pre-BLA meeting held on January 27, 2011, the FDA agreed that the data from the single clinical trial during Phase III was sufficient for determining that the drug was safe and effective. The BLA was submitted on April 11, 2014; then, a December 7, 2014 letter indicated an extension of the review, due to manufactured lots having increases in antibody-dependent cell-mediated cytotoxicity. On March 10, 2015, the drug received FDA approval. In August 2015 United Therapeutics sold its pediatric-rare disease FDA priority review voucher that it had received for the development of Unituxin to AbbVie Ireland Unlimited Company for $350 million. According to Forbes journalist Tim Worstall, a "lucrative secondary market" emerged by 2015 in the form of vouchers that "require the FDA to shorten its decision deadline to six months from the standard 10 months—potentially giving companies an extra four months’ worth of sales. The voucher did not guarantee the FDA would approve the drug."
Clinical Trials
Before testing in humans, toxicology tests were conducted on Sprague-Dawley rats and a safety pharmacology study was conducted on cynomolgus monkeys. Only a single human clinical trial was used to prove the safety and efficacy of dinutuximab for FDA approval. Patients with the criteria that consisted of having "minimum residual disease" were selected and randomly placed in either the experimental or control group, containing 113 patients in each. The experimental group received up to 5 cycles of dinutuximab with either GM-CSF or IL-2 along with 13-cis-retenoic acid (RA) and 1 cycle of RA only, whereas the control group only received RA. Of the neuroblastoma patients included in the trial, 46% were negative for MYCN-amplification, 36% were positive for MYCN-amplification, and 19% did not have an MYCN status. In regards to DNA ploidy status of the patients' tumors, 43% were hyperdiploid, 36% were diploid, and 21% were unknown. Since patients had to have had at least a partial response to initial chemotherapy, the patients were also categorized by response rate in which 35% had a complete response, 43% had a very good response, and 23% had a partial response. The Data Safety Monitoring Board recommended that the study be terminated sooner than originally planned after they found out that the boundary for event-free survival (EFS) had been surpassed in the 7th interim analysis. With a hazard ratio of 0.57, the trial exhibited that there was an EFS improvement in 42% of the patients. Three years after the conclusion of the interim analysis all of the patients were evaluated for survival rate with a hazard ratio of 0.58, showing an increase in overall survival in the experimentally treated group.
Currently, there are 7 clinical trials recruiting patients to assess additional uses of dinutuximab, post-marketing safety, new combinations safety. Soon, recruitment will be underway for a clinical trial assessing use in patients with relapsed refractory neuroblastoma with expanded natural killer cells.
Commercialization
For 2015, United Therapeutics reported that 1% of their net revenue came from their dinutuximab net product sales which were about $20.4 million. By receiving an orphan drug designation and FDA approval, they have exclusive rights to the drug until March 2022. Dinutuximab is produced by United Therapeutics at a 232,000 square foot building complex in Silver Spring, Maryland. To distribute it in the United States, an exclusive distribution agreement was made between United Therapeutics and ASD Specialty Healthcare, Inc. (ASD). In accordance to the agreement, the drug is sold to ASD at a price that is established by United Therapeutics, paying ASD's service fees that are used for the distribution and support of dinutuximab.
On October 27, 2016, United Therapeutics gave a press release of their financial results of the quarter that ended on September 30, 2016. For Unituxin, there was a 268.1% increase in net product sales in comparison to the same quarter in 2015. The company also reported a $22 million total revenue increase in this quarter compared to the 2015 3rd quarter. Share-based compensation also increased in comparison to the 2015 3rd quarter by 11% or $11.7 million; however, their common stock decreased by 25%. During this quarter, United Therapeutics repurchased 1.1 million shares of their common stock as a part of their $500 million repurchase goal for the year. This purchase covered $135.8 million of this goal with $104.5 million worth of shares remaining for completion.