After 23 years, a syndrome converted me into an eflornithine believer

By Warren R. Heymann, MD, FAAD
July 12, 2023
Vol. 5, No. 28

I learned that Vaniqa (eflornithine - α-difluoromethylornithine [DFMO]) was discontinued. Topical eflornithine was released in 2000 to reduce facial hirsutism. When the drug was released, I recall being fascinated by the premise of its mechanism. Polyamines are critical for hair growth — eflornithine functions by irreversible inhibition of ornithine decarboxylase, an enzyme responsible for the catalysis of ornithine to the polyamine putrescine. Several studies demonstrated efficacy compared to controls. Benefit was improved when combined with other medical anti-androgens (oral contraceptives, spironolactone), mechanical methods (shaving, waxing, threading, plucking, chemical depilatories), and the alexandrite laser. (1,2) Topical eflornithine cream demonstrated an additive effect on long-pulsed Nd-YAG laser enhancing the rate and degree of hair reduction and inflammatory papules in pseudofolliculitis barbae in men. (3)

Honestly, although I have prescribed eflornithine cream throughout the 21st century, I cannot say that I was enamored with the drug — some patients claimed a modest benefit, others less so. Regardless, I was disappointed that Vaniqa was pulled from the market. According to drugs.com, 13.9% eflornithine hydrochloride cream is listed as Florexa. (Disclaimer: This drug has not been found by FDA to be safe and effective. The FDA has not approved this labelling and Florexa is not available in the United States.) Compounding pharmacies can provide eflornithine. (4)

As previously stated, ornithine decarboxylase (ODC) is a rate-limiting enzyme in the biosynthesis of polyamines (putrescine, spermidine, and spermine) that play a critical role during embryogenesis, organogenesis, and tumorigenesis. Schultz et al “recently described a new autosomal dominant genetic disorder in a pediatric patient caused by a heterozygous de novo mutation in the ornithine decarboxylase 1 (ODC1) gene. The new genetic disorder is characterized by global developmental delay, alopecia, overgrowth, and dysmorphic features. We hypothesized that this new mutation (c.1342 A>T) leads to a C-terminal truncation variant of the ODC protein that is resistant to normal proteasomal degradation, leading to putrescine accumulation in cells.” Additional cases with similar deletions and comparable clinical manifestations led to naming this syndrome as Bachmann-Bupp Syndrome (BABS). The authors speculated that “our patient and potentially other patients that carry a similar ODC1 gain-of-function mutation might benefit from treatment with DFMO, a drug with a good safety profile, to suppress the exceptionally high ODC activity and putrescine levels in the body.” (5)

As more cases have been reported (as of May 31, 2023, there are 11 reported cases), other features of BABS have been detailed, including macrocephaly, macrosomia, seizures, conductive hearing loss, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder), and feeding difficulties. The most distinctive finding — and most relevant to dermatologists — is alopecia. Patients may also demonstrate keratosis pilaris and follicular cysts. (6,7,8).

According to Bupp et al, although alopecia is characteristic, there is variability in its presentation.

• Hair is typically present at birth but is sometimes sparse and sometimes has an atypical color (darker or lighter than anticipated).

• Loss of hair, if present, begins in the first few weeks of life, with hair falling out in large clumps.

• Absent or sparse eyebrows and eyelashes are typically congenital.

• Some affected individuals undergo regrowth of scalp hair that usually remains sparse, although one affected individual had full, thick hair with no reported loss of hair postnatally but absent eyebrows and eyelashes. (8)

What caught my attention was the report by Afrin et al, in which using oral DMFO (through compassionate use approval from the FDA) in two children with BABS (a 7-year-old girl and a 7-year-old boy) resulted in dramatic hair growth within months of administration of the drug (and cessation of cyst formation). I encourage you to read this paper to witness the dramatic changes. (9)

How can eflornithine be used to diminish hair growth and be used to treat alopecia? Polyamines are essential for hair growth and cycling, but much remains to be learned about their precise functions. Polyamine synthesis is regulated by ODC1 and adenosylmethionine decarboxylase, and their degradation by spermidine/spermine N1 acetyltransferase (SSAT). ODC1 levels are increased in the epithelium of anagen follicles but are dramatically reduced in catagen. (10) Hairless (HR) is a nuclear protein with corepressor activity that is highly expressed in the skin and hair follicles. (11) In anagen, when HR protein levels drop, the accumulation of ODC1 results in putrescine levels allowing anagen progression. When putrescine levels get too high (as in SSAT overexpression), a feedback loop inhibits HR, resulting in a hair loss phenotype. (10) In most patients with hirsutism, eflornithine works by diminishing polyamines, so there is less anagen growth. In BABS, due to a gain of function mutation, eflornithine will obviate the negative feedback loop, allowing hair to grow.

Point to Remember: Polyamines are integrally involved with the hair cycle. The Bachmann-Bupp syndrome has shed new light on the role of ornithine decarboxylase, and how its inhibition by eflornithine can be used as an advantage to either slow or stimulate hair growth.

Our experts’ viewpoint

André Bachmann, PhD
Professor of Pediatrics, Michigan State University College of Human Medicine
Associate Chair of Research, Department of Pediatrics and Human Development

Caleb Bupp, MD
Assistant Professor, Department of Pediatrics and Human Development
Michigan State University College of Human Medicine
Division Chief of Medical Genetics and Genomics
Helen DeVos Children’s Hospital and Spectrum Health West Michigan

Drug repurposing is often referenced when discussed the future of health care. DFMO is a drug which has existed since 1978 and has had many different lives, first developed as a fairly unremarkable anti-cancer drug, then literally bringing patients back to life (‘the resurrection drug’) who were affected by West African sleeping sickness (trypanosomiasis). It later returned with more success in cancer treatment for pediatric neuroblastoma and colorectal cancer, all in addition to its Vaniqa formulation for hirsutism.

Perhaps equally intriguing is the serendipity of the 2018 discovery of the ultra-rare Bachmann-Bupp syndrome. A single patient’s gene variant led to functional confirmation of abnormal protein, enzyme, and polyamine levels thus confirming it as a novel condition. Of significant supportive evidence was the existence of an ODC mouse model made in 1995 which exhibited hair loss and follicular cysts. Those mice, when treated with DFMO, regrew their hair. The disease discovery, functional studies, animal model, and known pediatric safety data for DFMO led to rapid repurposed drug treatment through FDA compassionate use protocol in 15 months, a speed fairly unheard of in medicine.

Dramatic improvement in patients treated has validated the rate at which treatment was pursued, but there are still questions that remain unanswered regarding mechanism, treatment optimization, and beyond. The role of ODC1 and polyamines in hair and skin may help unravel some of these with further study.

Dr. Bachmann and Dr. Bupp are listed inventors of a U.S. patent based on the method of treating or preventing developmental disorders associated with mutations in the ODC1 gene and Michigan State University and Corewell Health have an exclusive licensing agreement with Orbus Therapeutics, Inc. Dr. Bupp provides consulting services for Orbus Therapeutics.

1. Kumar A, Naguib YW, Shi YC, Cui Z. A method to improve the efficacy of topical eflornithine hydrochloride cream. Drug Deliv. 2016 Jun;23(5):1495-501. doi: 10.3109/10717544.2014.951746. Epub 2014 Sep 3. PMID: 25182303; PMCID: PMC4348346.

2. Hamzavi I, Tan E, Shapiro J, Lui H. A randomized bilateral vehicle-controlled study of eflornithine cream combined with laser treatment versus laser treatment alone for facial hirsutism in women. J Am Acad Dermatol. 2007 Jul;57(1):54-9. doi: 10.1016/j.jaad.2006.09.025. Epub 2007 Jan 30. PMID: 17270315.

3. Shokeir H, Samy N, Taymour M. Pseudofolliculitis barbae treatment: Efficacy of topical eflornithine, long-pulsed Nd-YAG laser versus their combination. J Cosmet Dermatol. 2021 Nov;20(11):3517-3525. doi: 10.1111/jocd.14027. Epub 2021 Mar 9. PMID: 33629488.

4. https://www.drugs.com/pro/florexa-cream.html (accessed May 31 2023)

5. Schultz CR, Bupp CP, Rajasekaran S, Bachmann AS. Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation. Biochem J. 2019 Jul 24;476(14):2047-2057. doi: 10.1042/BCJ20190294. PMID: 31249027.

6. VanSickle EA, Michael J, Bachmann AS, Rajasekaran S, Prokop JW, Kuzniecky R, Hofstede FC, Steindl K, Rauch A, Lipson MH, Bupp CP. Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome. Am J Med Genet A. 2021 Nov;185(11):3485-3493. doi: 10.1002/ajmg.a.62473. Epub 2021 Sep 3. Erratum in: Am J Med Genet A. 2023 Apr 20;: PMID: 34477286; PMCID: PMC9292803.

7. Michael J, VanSickle E, Vipond M, Dalman A, Prokop J, Schwartz CE, Rajasekaran S, Bachmann AS, Barth M, Prouteau C, Almagor Y, Berkun L, Alterescu G, Bupp CP. Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders. Med Sci (Basel). 2023 Apr 4;11(2):29. doi: 10.3390/medsci11020029. PMID: 37092498; PMCID: PMC10123676.

8. Bupp C, Michael J, VanSickle E, Rajasekaran S, Bachmann AS. Bachmann-Bupp Syndrome. 2022 Aug 25. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023. PMID: 36007106.

9. Afrin A, Afshan TS, VanSickle EA, Michael J, Laarman RL, Bupp CP. Improvement of dermatological symptoms in patients with Bachmann-Bupp syndrome using difluoromethylornithine treatment. Pediatr Dermatol. 2023 May-Jun;40(3):528-531. doi: 10.1111/pde.15187. Epub 2022 Nov 28. PMID: 36443247.

10. Ramot Y, Vardy LA. Commentary on: Hairless and the polyamine putrescine form a negative regulatory loop in the epidermis. Exp Dermatol. 2013 Nov;22(11):697-8. doi: 10.1111/exd.12244. PMID: 24433178.

11. Luke CT, Casta A, Kim H, Christiano AM. Hairless and the polyamine putrescine form a negative regulatory loop in the epidermis. Exp Dermatol. 2013 Oct;22(10):644-9. doi: 10.1111/exd.12228. PMID: 24079733; PMCID: PMC3986865.

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