#AANAM – Givlaari Reduces Pain, Lowers Pain Killer Use in AHP

Six months of treatment with Givlaari (givosiran) effectively reduced pain during and between porphyria attacks in people with acute hepatic porphyria (AHP), also known as acute porphyria, according to a post-hoc analysis of data from the Phase 3 ENVISION trial.

Givlaari also was found to lower the use of pain killers (analgesics) among acute porphyria patients, the data show.

These findings add to top-line data from the study, which showed that the therapy significantly reduced the rate of porphyria attacks and improved overall health among AHP patients. Together, the data support Givlaari’s regulatory approvals in the U.S. and the European Union for this indication, researchers said.

The results were presented by Susana Monroy, MD, a trial investigator at the Instituto Nacional de Pediatría, in Mexico, in an oral presentation at the 2021 American Academy of Neurology (AAN) Virtual Annual Meeting, running through April 22. The presentation was titled “Reduction in Pain During and Between Attacks in Patients with Acute Hepatic Porphyria Treated with Givosiran: A Post-Hoc Analysis of the Phase 3 ENVISION Study.”

AHP comprises a group of rare diseases, called prophyrias, caused by a deficiency in one of the enzymes that are involved in the production of heme — the molecule inside red blood cells that binds and carries oxygen throughout the body. Such defects lead to the toxic buildup of two intermediate molecules, called aminolevulinic acid (ALA) and porphobilinogen (PBG).

“Clinical manifestations include potentially life-threatening neurovisceral [porphyria] attacks and chronic symptoms, with [nerve-related] pain being the cardinal symptom during and between attacks,” the researchers wrote.

These attacks often require hospitalization with supportive care, and treatment with opioids — prescription medications that can make patients feel very relaxed and “high” — and hemin, which are red blood cells processed from human blood.

Developed by Alnylam Pharmaceuticals, Givlaari is approved in the U.S. for treating adults with AHP, and for use by adults and pediatric patients, ages 12 and older, in Europe.

It works by targeting for degradation the messenger RNA (mRNA) from the ALAS1 gene, preventing the production of the ALAS1 enzyme, which is overly active in AHP patients. Of note, mRNA is the molecule derived from DNA that guides protein production.

By reducing ALAS1 levels, the therapy is thought to lower ALA and PBG levels, ultimately preventing porphyria attacks and improving patients’ lives.

Givlaari’s approval was mainly based on data from the international Phase 3 ENVISION trial (NCT03338816), which evaluated the therapy’s safety and effectiveness at reducing porphyria attacks in 94 children and adults with AHP. Participants in the study, which had trial sites in 18 countries, had a mean age of 38.8 years.

Most of the participants (94.7%) had acute intermittent porphyria (AIP) — the most common form of AHP in most countries — while two patients had variegate porphyria and one had hereditary coproporphyria.

Patients were randomly assigned to receive an under-the-skin injection of 2.5 mg/kg of Givlaari (48 patients) or a placebo (46 patients), once a month, for six months.

Previous top-line data in AIP patients showed that Givlaari safely and effectively reduced the number of annual porphyria attacks by 74% and the levels of toxic products by at least 86%, while improving patients’ quality of life, compared with a placebo.

Notably, Givlaari-treated patients also reported less severe pain, a secondary trial goal, and a smaller proportion of days with analgesic use — an exploratory goal — than those given a placebo.

During the trial, a daily diary electronic device was used to evaluate pain severity in the prior 24 hours. Pain was measured through a numeric rating scale in which a score of seven or greater was classified as severe pain. The use of opioid and non-opioid analgesic or pain-killing medications also was examined.

The pain-interference item of the 12-Item Short Form Survey (SF-12) was assessed using a four-week recall period. SF-12 evaluates the impact of health on an individual’s everyday life and is often used to evaluate quality of life. Of note, higher scores indicate better health.

The newly presented data concerned a post-hoc analysis of ENVISION — an examination conducted after the completion of the trial. It sought to investigate changes in pain and analgesic use during and between porphyria attacks.

The results showed that among participants with at least one attack, a lower proportion of Givlaari-treated patients reported severe pain, compared with those in the placebo group (41.7% vs. 63.2%).

Notably, beneficial pain-related effects also were observed during attack-free periods. Treatment with Givlaari resulting in lower daily worst pain scores and nearly 50% fewer days with severe pain (6.8% vs. 12.2%), compared with a placebo, Monroy noted.

This pain reduction was not caused by increased analgesic use, as Givlaari-treated patients showed lower use of both opioid and non-opioid analgesics, particularly during attack-free periods, relative to those in the placebo group.

These findings highlighted that AHP patients “can experience chronic pain even during attack-free periods and require high levels of analgesics to manage pain during and between attacks,” Monroy said. She said Givlaari effectively reduced “both pain and the use of pain control medication” in these patients.

In addition, patients treated with Givlaari showed a threefold greater increase in the SF-12 bodily pain domain — indicative of lower pain and reduced interference with patients’ normal activities — than those given a placebo at six months.

This suggested that Givlaari-associated reduction in pain “was clinically relevant,” Monroy said, supporting its potential as a disease-modifying therapy.