BOSTON, Massachusetts—In 2010, California biotech entrepreneur Emil D. Kakkis, MD, PhD, founded Ultragenyx Pharmaceutical with just a secretary and a determination to treat ultrarare diseases for which no cures or therapies existed.

Emil Kakkis
Emil D. Kakkis, MD, PhD, founder and CEO of Ultragenyx, at the 2022 World Orphan Drug Congress in Boston, Massachusetts. Credit: Larry Luxner

By the time Dr. Kakkis took Ultragenyx public in 2014, the San Francisco, California-based company had 59 employees and 5 programs in clinical development. Today, Ultragenyx employs more than 1200 people and generates nearly $300 million in annual revenue.

The company has 4 approved drugs on the market, including triheptanoin oral liquid (Dojolvi®) to treat long chain fatty acid oxidation disorder (LCFAOD). Another 7 are in the pipeline.  

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But Dr. Kakkis said there’s plenty of room for improvement when it comes to the drug approval process, which he argued should focus more on biomarkers and less on clinical endpoints.

“Our development paradigm is old, inefficient, and at times ineffective. The truth is, we’re lost,” Dr. Kakkis said in a keynote address at the 2022 World Orphan Drug Congress here. “We haven’t advanced at all in terms of how we’re measuring diseases. It’s time to get out of the 20th century and into the 21st.”

Dr. Kakkis, 62, is a board-certified pediatrician and medical geneticist. A graduate of Pomona College in Claremont, California, he earned a combined MD-PhD from the University of California-Los Angeles and spent 5 years as an assistant professor of pediatrics at Harbor-UCLA Medical Center in Torrance, California.

In 1998, Dr. Kakkis joined San Francisco-based BioMarin, where over an 11-year period he saw 3 rare disease drugs approved and started programs for 4 others that have also been approved.

Predicting the Efficacy of Therapies

In an exclusive interview following his presentation, Dr. Kakkis explained why biomarkers are “based on the primary genetic basis of disease,” and why they should be used instead of clinical endpoints to determine the efficacy of any given therapy.

“We think that by measuring clinical symptoms, hospitalizations or death, that we’re understanding what’s going on in disease,” he told Rare Disease Advisor. “But we’re looking at the very end of disease, when things have fallen apart.”

Dr. Kakkis likens this to an auto accident caused by faulty brakes.

“You want to figure out why the car is crashing and treat it beforehand. If the brakes are failing, you’d measure the brakes and fix them. Then the probability of crashing is reduced,” he said. “That’s the idea of primary disease activity biomarkers. Let’s measure the brakes, not the crash. By controlling the brakes, we can control what happens. It’s not that we don’t think crashes are important. What we’re saying is that by focusing on the crashes, you don’t fix the problem.”

In fact, he said, “biomarker-based approvals may be essential for some diseases that would never be successfully treated otherwise.” A case in point is HIV. The US Food and Drug Administration (FDA), using the CD4 count biomarker, granted accelerated approval over a 16-year period to 25 new drugs and 4 combinations—something that would’ve been impossible using clinical endpoints, Dr. Kakkis said.

Other examples of biomarkers used to assess efficacy include phenylalanine levels in phenylketonuria and ammonia levels in urea cycle defects.

Keeping Patients out of the Hospital

The idea that triheptanoin could treat LCFAOD dates back to 2002, with the publication of a paper by Charlie Roe, MD, that detailed how a specialized oil could help a patient’s mitochondria create energy from fuel.

Despite dramatic results, however, little progress was made until Ultragenyx picked up the program, working with Dr. Roe’s successor, Jerry Vockley, MD, PhD, a medical geneticist at UPMC Children’s Hospital of Pittsburgh in Pennsylvania, and putting triheptanoin into clinical development.

“The oil basically restores their mitochondrial energy function. This helps their muscles function better, their heart pump better, and their liver produce glucose and reduce hypoglycemia,” Dr. Kakkis explained.

Since the drug’s approval in June 2020, about 300 patients in the US have received it; that represents about 10% of the US population with LCFAOD. Another 100 patients in France are on triheptanoin.

“We’re very excited to see patients getting the type of benefits that we’ve seen in our clinical trials,” Dr. Kakkis said. “It’s a drug that can keep people out of the hospital. Going in and out of the hospital for any disease is an incredible burden.”

Not everyone with LCFAOD can tolerate triheptanoin. Dr. Kakkis said that’s usually because patients aren’t taking it correctly.

“One of the challenges with Dojolvi or any of the MCT-like oils is that they are an oil. You can’t take them like a normal medicine. If you do that, it’d be the same as if you went to an Italian restaurant and you drink olive oil,” he said. “The way you do it is put it with eggs or nonfat yogurt. When you do that, the oil will be emulsified. It will stay suspended. Then your body can easily digest it, and it won’t cause diarrhea or upset stomach.”

Working for Change in Rare Disease Policies

Triheptanoin costs $4875 per vial, translating into an average of $138,000 per patient per year. The investment bank Piper Sandler in 2020 estimated the drug could earn Ultragenyx $270 million in annual sales by fiscal 2025, according to a report in Biopharma Dive.

“With regard to Dojolvi, we understand this drug is expensive,” Dr. Kakkis said. “At Ultragenyx, we guarantee that in the United States, every patient will be treated regardless of financial needs. We need to absolutely make sure that no one’s getting lost because of inability to pay.”

Besides being a scientist and pharma industry executive, Dr. Kakkis is also a published author. His 352-page book, Saving Ryan, chronicles the painstaking effort to develop an enzyme replacement therapy for Ryan Dant, a Texas boy with mucopolysaccharidosis I (MPS I).

Dr. Kakkis, the subject of a June 30, 2022, broadcast by a San Francisco-area TV station, said that after winning FDA approval for the therapy in 2003, he dedicated himself to starting an organization that would aim to change the future of rare disease legislation. In 2009, that became reality with the establishment of the EveryLife Foundation for Rare Diseases.

“Meeting Ryan was a great inspiration. I found my purpose in life was to develop drugs for rare diseases. But it also told me what was wrong with the system, which prevents us from using the science we have,” he said. “I wrote the book to highlight policies that inhibit, delay, and obstruct the development of potentially life‑saving treatments. As a country, I think we can do better.”