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Surrogate Endpoints: How to Choose the Best One for Your Rare Disease Trial

Surrogate Endpoints: How to Choose the Best One for Your Rare Disease Trial

While clinical researchers occasionally need to identify and validate a new surrogate endpoint for a given trial, choosing endpoints that have been previously used as the basis of NDAs and BLAs can clear the path to eventual approval.

In rare disease trials, it’s not always feasible to choose clinically-relevant endpoints to measure the efficacy of a new therapeutic. Often, the potential patient pool for a given trial is small and the unmet need is high, incentivizing drugmakers and regulators to find innovative ways to make game-changing therapeutics available to those who need them most.

While traditional approval pathways have required that sponsors demonstrate a drug’s clinical benefit — such as improvement in symptoms, reduction in disease process, or survival time — by using a direct measure of these outcomes, regulators have grown more accepting of surrogate endpoints in supporting a New Drug Application (NDA) or Biologics License Application (BLA). Surrogate endpoints were used as the basis for approval of 45 percent of new drugs reviewed by the FDA between 2010 and 2012.

What Is a Surrogate Endpoint?

The US Food and Drug Administration (FDA) defines a “surrogate endpoint” as “a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure, that is not itself a direct measurement of clinical benefit.”

The surrogate endpoint (often a biomarker) must also be either accepted as an accurate predictor of clinical benefit, or be considered very likely to predict a clinical benefit. In the case of the former, pharmaceutical and biologics companies would be eligible for approval of their product through traditional regulatory pathways; the latter could support accelerated approval.

For example, studies of heart attack prevention medications use the surrogate endpoint of low-density lipoprotein cholesterol (LDL-C) to assess the effectiveness of new drugs. Since the study period for this type of trial would have to be years — if not decades — longer if the investigators chose the occurrence of heart attack as their primary endpoint, LDL-C acts as a clinically-validated biomarker with a strong correlation to heart attack risk.

The FDA has published a table of surrogate endpoints, all of which have either been previously used by sponsors to secure approval, or which the regulator would be willing to accept as an appropriate endpoint measure in a trial. The table includes both surrogate endpoints for adult and pediatric patients and specifies the drug mechanism of action which would be most appropriate for the surrogate endpoint.

While the table lists acceptable surrogate endpoints for trials of more common conditions, such as asthma, type 2 diabetes and various cancer types, the document also provides key information to developers of certain rare disease therapies.

While clinical researchers occasionally need to identify and validate a new surrogate endpoint for a given trial, choosing endpoints that have been previously used as the basis of NDAs and BLAs can clear the path to eventual approval. Considering that sponsors must confirm the analytical validity of a proposed surrogate endpoint before beginning a trial — including demonstrating the sensitivity and specificity of the biomarker assay, standardizing the method, and identifying the range and reproducibility of the results — these FDA-accepted endpoints can speed up the lengthy trials process. Verifying the biomarker’s clinical validity for use as a surrogate endpoint in rare disease research is another hurdle which is generally a longer-term goal.

For the following 15 rare diseases, all prevalence (approximate), symptom, etiology and treatment information was taken from the National Organization for Rare Disorders’ (NORD) Rare Disease Database, unless a link to another source is provided.



Prevalence: 50 to 70 people per 1 million

Symptoms and Etiology: Caused by an overproduction of growth hormone, acromegaly primarily affects adults. Enlargement of the bones in the head, arms, hands, feet and legs are the most common symptoms of acromegaly; however, physical findings can be quite different in each person and they tend to slowly worsen with age.

Treatment: Since the growth of an adenoma on the pituitary gland is often the cause of acromegaly, surgery and radiation therapy are common treatment options. Medications such as somatostatin analogs, growth hormone receptor antagonists and, in some cases, dopamine agonists, are used to treat patients for whom surgical removal of the tumor was unsuccessful or for those who aren’t good candidates for surgery.

Novartis’ Sandostatin LAR (octreotide acetate) and Signifor LAR (pasireotide), Ipsen’s Somatuline Depot (lanreotide) and Pfizer’s Somavert (pegvisomant) are all injectables used to treat acromegaly.

Acromegaly Surrogate Endpoint:

Serum growth hormone and serum insulin-like growth factor 1 (IGF-1) are acceptable surrogate endpoints for acromegaly clinical trials involving somatostatin analogs such as octreotide, lanreotide and pasireotide. By reducing the amount of growth hormone in the blood, progressive enlargement of bones should be slowed.

IGF-1 is an acceptable surrogate endpoint in trials of growth hormone receptor agonists like Somavert, and is preferred for pediatric patient populations. Both surrogate endpoints could be used to support traditional approval of a new drug or biologic.

Cushing’s Disease

Prevalence: 10 to 15 people per 1 million

Symptoms and Etiology: Cushing’s disease is a disorder caused by excess cortisol which is often the result of a pituitary adenoma. The tumor secretes adrenocorticotropic hormone (ACTH), which stimulates cortisol production. While Cushing’s syndrome refers to the general overexposure of the body’s tissues to cortisol, which could have a number of causes, Cushing’s disease is much rarer. Symptoms include weight gain in the face, neck, and abdomen, easy bruising and excessive hair growth.

Treatment: First-line treatment for Cushing’s disease is surgery to remove the pituitary adenoma. While this has an 80 to 90 percent cure rate, medications can be required if patients don’t achieve remission after surgery.

Interestingly, some patients require corticosteroid replacement therapy after tumor removal due to a drop in normal ACTH levels. In this case, hydrocortisone or prednisone are usually prescribed, with some patients requiring a short course of therapy (six to 12 months) and others requiring lifetime replacement therapy. Radiation therapy can also be effective for patients who are contraindicated for surgery.

Janssen’s Nizoral (ketoconazole), Bristol Myers Squibb’s Lysodren (mitotane), Novartis’ Metopirone (metyrapone) and Corcept Therapeutics’ Korlym (mifepristone) are all cortisol-inhibiting medications that may be prescribed to treat Cushing’s disease. Novartis’ Signifor (pasireotide) is also indicated in the treatment of the disease. Nizoral is prescribed off-label, while the others are FDA approved.

Cushing’s Disease Surrogate Endpoint:

Urine free cortisol is a potential surrogate endpoint for Cushing’s disease trials of somatostatin analog drugs involving adults. Signifor — which was approved in late 2012 and provided study data on this endpoint — is the first drug available which addresses the underlying mechanism of the disease.

Urine free cortisol is a biomarker for the amount of the steroid being produced by the body; achieving a reduction in this measure should help prevent some of the symptoms of Cushing’s. The traditional approval pathway could be pursued with this surrogate endpoint; however, the FDA has yet to approve a therapeutic on the basis of meeting this endpoint alone.


Prevalence: 1 in 7,000 to 1 in 10,000

Symptoms and Etiology: Individuals with cystinuria accumulate large amounts of the amino acid cystine in their urine. Patients with cystinuria are at risk of developing crystals or stones in their kidney, bladder or urinary tract as a result of the undissolved cystine in their urine.  Arginine, lysine and ornithine — other amino acids with a similar chemical structure to cystine — are also present in large quantities in the urine; however, this is not normally associated with pathology of the disease.

Pain in the side of the abdomen or lower back is usually the first symptom of cystinuria, with blood in the urine, and ultimately, kidney damage, occurring as well. Inherited mutations in the SLC3A1 and SLC7A9 genes cause cystine to be abnormally transported within the kidney leading to cystinuria.

Treatment: There are two primary goals in the treatment of cystinuria: increasing urine volume and alkalization to lower the concentration of cystine to help make it more soluble and reduce crystallization. Dietary changes, including restriction of salt and animal protein, are also recommended. Potassium citrate and acetazolamide have historically been prescribed to make the urine more alkaline; however, an orphan drug has been approved to increase the solubility of cystine in patients with this condition.

Thiola (tiopronin) is produced by Retrophin, the rare disease biopharmaceutical company founded by Martin Shkreli. The marketing rights to Thiola were acquired by Retrophin in 2014 from Mission Pharmacol.

Cystinuria Surrogate Endpoint:

Urinary cystine is listed as an acceptable surrogate endpoint in trials of drugs with a mechanism of action that involves the reduction and complexing of thiol. Thiola was approved on the basis of this surrogate endpoint. This endpoint is the same for both adult and pediatric patients with cystinuria, with drugmakers pursuing this option being eligible for approval through the traditional regulatory process.

Duchenne Muscular Dystrophy

Prevalence: 1 in 3,500

Symptoms and Etiology: Characterized by progressive muscle weakness and atrophy, Duchenne muscular dystrophy (DMD) is an X-linked genetic condition that primarily affects males. It’s caused by mutations in the DMD gene, which encodes the dystrophin protein; dystrophin plays an important role in supporting muscle fibers.

Treatment: The standard of care for treating patients with DMD involves the use of corticosteroids. Prednisone and PTC Therapeutics’ Emflaza (deflazacort) can help slow the progression of the disease.

In the past four years, drugs targeting specific disease-causing mutations have been approved by the FDA, including Sarepta Therapeutics’ Exondys 51 (eteplirsen) and Vyondys 53 (golodirsen), as well as NS Pharma’s Viltepso (viltolarsen). These drugs are effective for patients who have a confirmed dystrophin gene mutation amenable to exon 51 and exon 53 skipping (Vyondys and Viltepso, respectively.)

DMD Surrogate Endpoint:

Skeletal muscular dystrophin has been used as a surrogate endpoint in trials conducted by Sarepta for its antisense oligonucleotide drugs. The assumption is that increasing the concentration of dystrophin in muscle tissue should have a beneficial effect on muscle function, potentially slowing the degenerative nature of the disease.

Since pediatric patients are most affected by DMD, trials are most often conducted in children and adolescents, although this surrogate endpoint is appropriate for trials in adults as well. These drugs have received accelerated review based on the great unmet need for treatments for DMD.

Fabry Disease

Prevalence: Type 1: 1 in 40,000

Type 2: 1 in 1,500 to 1 in 4,000

Symptoms and Etiology: Fabry disease is a lysosomal storage disorder that leads to an abnormal build-up of glycosphingolipids in cells. Glycolipid accumulation primarily affects the micro-vascular system and can lead to kidney failure and heart disease.

Individuals with this disease are deficient in α-galactosidase A (α-Gal A), a lysosomal enzyme which digests globotriaosylceramide (GL-3 or Gb3) and its deacylated form, Lyso-GL-3/Gb3.  Mutations in the gene encoding α-Gal A (GLA) are responsible for this deficiency, and depending on the nature of the mutation, some patients still produce a less-functional version of the lysosomal enzyme. As an X-linked trait, Fabry disease affects more males than females.

The two phenotypes of the disease — type 1 (classic) and type 2 (later onset) — are based on the level of functional α-Gal A, with the former having little-to-no enzymatic activity and the latter having residual enzymatic activity. Due to having a partially functional enzyme, patients with later-onset Fabry disease don’t present with symptoms until they are over the age of 30.

Treatment: Since Fabry disease is the result of an enzyme deficiency, enzyme replacement therapy (ERT) is currently the preferred treatment. Sanofi Genzyme’s Fabrazyme (agalsidase beta) and Shire Pharmaceuticals’ Replagal (agalsidase alfa) are both recombinant enzymes used to treat Fabry disease; however, while Replagal is available in other countries, it is not approved by the FDA in the US.

The above ERTs are administered intravenously; however, Amicus Therapeutics introduced an oral therapy, Galafold (migalastat), in 2018. Instead of replacing the missing enzyme, Galafold acts as a pharmacologic chaperone that enhances the activity of α-Gal A by binding to the enzyme and stabilizing it. This therapy is only indicated for patients with specific missense mutations which cause them to produce a less-functional version of the enzyme.

Fabry Disease Surrogate Endpoint:

Histological reduction of GL-3 inclusion burden in biopsied kidney interstitial capillaries (KIC) is an acceptable surrogate endpoint for trials of both ERT and chaperone therapy. Reducing this GL-3 inclusion burden should have a positive effect on kidney function in patients with Fabry disease. This endpoint is suitable for trials involving both adult and pediatric patients.

Homozygous Sitosterolemia (Phytosterolemia)

Prevalence: ABCG5 gene mutation: 1 in 2.6 million

ABCG8 gene mutation: 1 in 360,000

Symptoms and Etiology: Sitosterolemia is a phytosterol storage disorder caused by mutations in the ABCG5 or ABCG8 genes. These genes encode sterolin transporters responsible for the elimination of plant sterols from the body. As such, individuals with sitosterolemia accumulate plant sterols, which can lead to atherosclerosis and coronary artery disease.

While elevated levels of plant sterols in the blood is a clear indicator of sitosterolemia, standard lipid profiles often do not check for this biomarker. This means the condition is difficult to diagnose and makes catching the various symptoms important as sitosterolemia is manageable with the right treatment.

Symptoms of sitosterolemia are varied; some patients may have fatty deposits (xanthomas) under the skin, which can occur around the elbows, knees, heels, buttocks, or the eye area. Joint stiffness and pain are another symptom of sitosterolemia. Thrombocytopenia, macrothrombocytopenia and stomatocytes are all blood abnormalities that have been documented in patients with plant sterol storage disorders.

Interestingly, high cholesterol can be an indicator of sitosterolemia, despite the fact that the condition impacts the storage of plant sterols as opposed to those from animal sources. Generally, patients with sitosterolemia and high cholesterol don’t respond well to treatment with statins and their cholesterol levels are very diet-dependent.

Treatment: Merck’s Zetia (ezetimibe) is a sterol absorption inhibitor that can help reduce the plasma concentration of plant sterols, and may be combined with cholestyramine — a bile acid sequestrant — in patients who don’t show a complete response to Zetia alone.

In addition to medications, patients with sitosterolemia should follow a diet low in plant sterols and limit their intake of vegetable oils, nuts, avocados and butter substitutes like margarine. As shellfish sterols are similar to plant sterols, intake of shrimp, oysters and other shellfish should also be limited.

Homozygous Sitosterolemia Surrogate Endpoint:

Clinical trials of dietary cholesterol absorption inhibitors can use the surrogate endpoint of plasma sitosterol and campesterol (two phytosterols) to pursue traditional drug approval. This is an appropriate endpoint in both adult and pediatric trials.

Homozygous Familial Hypercholesterolemia

Prevalence: 1 in 160,000 to 1 in 250,000

Symptoms and Etiology: While many cases of high cholesterol are associated with a diet high in saturated fat, familial hypercholesterolemia is an inherited form of the condition. Patients with this disease have a very high level of LDL-C, which increases their risk of coronary artery disease, including heart attack, stroke and atherosclerosis.

Heterozygous familial hypercholesterolemia is a very common genetic disease which affects about one in every 250 individuals; however, the homozygous form is quite rare and causes more severe disease. Angina can be a symptom of homozygous familial hypercholesterolemia, but because these patients have such high levels of LDL-C — often more than 400 mg/dL (optimal range 70 to 100 mg/dL) — xanthomas affecting the knees, buttocks, hands and elbows are clinical symptoms that often appear in childhood.

Caused by two copies of non-functional familial hypercholesterolemia genes (LDLR, APOB, PCSK9) — each of which encodes a different protein involved in binding, uptake and degradation of cholesterol — the dose effect of the homozygous form of the disease results in severe coronary artery disease by the time patients are in their mid-20s.

Treatment: Dietary changes and statin therapy can be used to treat familial hypercholesterolemia, but they are often ineffective for the homozygous form of the condition. Since statins increase the expression of LDL receptors on liver cells, they’re only effective if a patient still has some LDL receptor function.

Some patients benefit from LDL apheresis, a procedure which involves removing excess LDL-C from the blood through a process similar to kidney dialysis. However, this treatment isn’t offered at many primary care centers in the US, is time-consuming and must be performed on a weekly or biweekly schedule to maintain the effects. Liver transplantation is also an option; however, donor organs are few and far between.

Pharmacologic therapies are rapidly becoming the standard of care in the treatment of homozygous familial hypercholesterolemia, with Aegerion Pharmaceuticals’ Juxtapid (lomitapide) and Amgen’s Repatha (evolocumab) both having been approved for this indication. Aegerion was acquired by Amryt Pharma in 2019 after the US government accused Aegerion of promoting and selling Juxtapid for uses not approved by the FDA.

Homozygous Familial Hypercholesterolemia Surrogate Endpoint:

Drugmakers can pursue a traditional approval process for lipid-lowering agents using the serum LDL-C surrogate endpoint in trials. Since LDL-C begins to accumulate in high levels from birth, this endpoint is acceptable for trials involving pediatric as well as adult patients. Trials for both Juxtapid and Repatha made use of this endpoint to gain regulatory approval.


Prevalence: 1 in 10 million

Symptoms and Etiology: Individuals with the rare genetic disorder congenital generalized lipodystrophy have nearly no body fat and are, instead, extremely muscular. Also known as Berardinelli-Seip syndrome, there are four subtypes of lipodystrophy.

Metabolic changes associated with lipodystrophy include insulin resistance, glucose intolerance, diabetes and hypertriglyceridemia. Due to lack of adipose tissue, fat accumulates in the organs, with hepatic steatosis causing major damage to the liver.

Mutations in the AGPAT2, BSCL2, CAV1 and PTRF genes cause each of the four types (type 1 through 4) of congenital lipodystrophy, respectively. However, some cases of lipodystrophy have been diagnosed in which the disease-causing mutation could not be identified in one of these four genes, suggesting that an additional subtype may not yet be identified.

Treatment: Though patients with lipodystrophy are often encouraged to limit dietary fat intake and consume large amounts of carbohydrates, this diet has not been clinically evaluated. Just one injectable drug, Aegerion Pharmaceuticals’ Myalept (metreleptin), has been approved by the FDA to treat leptin deficiency, a hormone imbalance sometimes associated with lipodystrophy. The rights to this drug are now owned by Amryt Pharma.

The replacement therapy has been shown to improve metabolic complications and can also be used to treat the acquired form of the disease. However, due to serious risks – including the drug’s potential to stimulate the production of anti-metreleptin antibodies and an increased risk of lymphoma – it is only available through a Risk Evaluation and Mitigation Strategy mandated by the FDA.

Lipodystrophy Surrogate Endpoint:

Biopharmaceutical companies developing leptin analogs, like Myalept, can pursue traditional regulatory approval by making use of the serum hemoglobin A1C along with fasting glucose and triglycerides as surrogate endpoints. These drugs are designed to lower triglycerides, blood sugar levels and glycated hemoglobin associated with leptin deficiency, but do not address the underlying cause of lipodystrophy. Since symptoms of lipodystrophy are present at birth, these endpoints can also be used in pediatric patient trials.

Lysosomal Acid Lipase Deficiency (LAL-D)

Prevalence: 1 in 40,000 to 1 in 300,000

Symptoms and Etiology: Individuals with lysosomal acid lipase deficiency (LAL-D) lack the enzyme necessary to break down lipids in foods. As a result, these patients show malabsorption of fats and can accumulate lipids in body tissues, particularly in the liver.

Both Wolman disease and cholesteryl ester storage disease are caused by LAL-D, with the former being more severe and showing earlier onset of disease symptoms. Caused by mutations in the gene encoding LAL (LIPA), this rare disease results in jaundice, hepatosplenomegaly, steatorrhea and cirrhosis of the liver.

Treatment: Alexion Pharmaceuticals’ Kanuma (sebelipase alfa) is the only orphan drug approved by the FDA to treat lysosomal acid lipase deficiency. Kanuma is an ERT which works by breaking down cholesterol esters and triglycerides to prevent lipid accumulation in the body.

LAL-D Surrogate Endpoint:

Serum LDL-C levels are an appropriate surrogate endpoint for both adult and pediatric trials involving patients with lysosomal acid lipase deficiency. Sponsors can pursue traditional regulatory approval of hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzymes meant to act as an enzyme replacement therapy for patients with this deficiency. This surrogate endpoint was used by Alexion in trials of Kanuma and to support its regulatory approval.

N-Acetylglutamate Synthase (NAGS) Deficiency

Prevalence: 1 in 2 million

Symptoms and Etiology: Caused by mutations in the NAGS gene encoding a liver enzyme involved in protein processing and ammonia excretion, individuals with N-acetylglutamate synthase deficiency (NAGS) experience a toxic build-up of ammonia in the blood. Patients lack functional n-acetylglutamate synthase, an enzyme involved in the urea cycle which removes excess nitrogen from the body, which is a byproduct of protein metabolism.

The most severe form of this disease manifests in early life causing symptoms ranging from energy deficits and seizures to developmental delays. However, a high-protein diet can cause symptoms to start in later life, including coordination issues, confusion and coma.

Treatment: In addition to a low protein diet, Orphan Europe SARL (now Recordati Rare Diseases) has developed Carbaglu (carglumic acid) as an adjunctive therapy to treat the accumulation of ammonia in patients with NAGS. Carbaglu effectively replaces N-acetylglutamate synthase to activate carbamoyl phosphate synthase (CPS1) as the first step of the urea cycle. This helps the body process excess nitrogen and reduce high ammonia levels back to normal.

NAGS Deficiency Surrogate Endpoint:

As a carbamoyl phosphate synthase activator, Carbaglu took advantage of plasma ammonia as a surrogate endpoint for trials supporting its eventual FDA approval. Other drug developers can use this surrogate endpoint to pursue traditional regulatory approval for both adult and pediatric patient populations.

Paget’s Disease

Prevalence: 1 in 328 million (with prevalence increasing to three percent of the population over 60 years of age)

Symptoms and Etiology: Paget’s disease is a progressive condition in which bone is broken down and subsequently rebuilt in other areas of the body. This rapid osteolytic and osteoblastic activity can cause arthritis, bone fractures and pain in the skull, pelvis, spine and lower legs.

While its cause is not yet known, a genetic predisposition appears to play a role in up to 30 percent of all cases, with the sequestosome 1, TNFRSFIIA and VCP genes all having been implicated in the disease. A viral infection of the bones could account for the slowly progressive nature of Paget’s disease, with genetic factors possibly contributing to a multifactorial cause.

Treatment: Physical therapy, analgesic pain management and surgery are all potential treatment options for patients with Paget’s disease, along with treatment with calcitonin and bisphosphonates to reduce osteolytic activity.

While salmon calcitonin was originally the only pharmacological treatment for Paget’s disease, it is now usually only indicated for patients who cannot tolerate treatment with bisphosphonates. Novartis’ Reclast (zoledronic acid) and Merck’s Aredia (pamidronate disodium) are both intravenous treatments for Paget’s, with Reclast being a first-line therapy.

Oral bisphosphonates like Didronel (etidronate), Skelid (tiludronate), Fosamax (alendronate), and Actonel (risedronate) have also been shown to reduce bone turnover associated with Paget’s disease. Patients being treated with bisphosphonate drugs are also recommended to take calcium and vitamin D supplements to address the common side effect of low blood calcium.

Since patients may stop responding to treatment with a given therapy from this drug class, multiple bisphosphonates may be taken in tandem to manage their disease.

Paget’s Disease Surrogate Endpoint:

Serum alkaline phosphatase — a biomarker of bone formation — can be used as a surrogate endpoint in trials of bisphosphonate drugs seeking approval through the traditional pathway. As Paget’s usually does not affect individuals younger than 40, this surrogate endpoint is only appropriate for adult patients.

Phenylketonuria (PKU)

Prevalence: 1 in 13,500 to 1 in 19,000

Symptoms and Etiology: Phenylketonuria (PKU) is one of the more common rare diseases, caused by the accumulation of the amino acid phenylalanine in the body’s tissues, particularly in the brain. Since this causes severe intellectual disability, it’s important that PKU is detected as soon as possible after birth, which is why it’s included in routine newborn screening tests.

Individuals with PKU lack the enzyme phenylalanine hydroxylase (PAH), which is responsible for converting phenylalanine into tyrosine.

Treatment: A diet low in phenylalanine is essential to managing PKU; however, this often involves the use of special foods that have been prepared to be free of phenylalanine. It’s recommended that patients continue this diet for the duration of their lives to prevent neurological changes such as a decline in IQ, poor memory and problems with concentration. Phenylalanine levels should be maintained between 120-360 µmol/L.

In addition to dietary restrictions, pharmacologic therapies, including BioMarin Pharmaceutical’s Kuvan (sapropterin hydrochloride) and Palynziq (pegvaliase-pqpz) have been in use since 2007 and 2018, respectively. Kuvan stimulates the action of PAH in patients with residual enzymatic activity, thereby helping to convert some dietary phenylalanine into tyrosine. This drug acts as a synthetic form of tetrahydrobiopterin (BK4), the natural cofactor for PAH.

Palynziq is a recombinant version of the phenylalanine ammonia lyase (PAL) enzyme, which converts phenylalanine into less toxic products.

PKU Surrogate Endpoint:

Plasma phenylalanine is listed as a surrogate endpoint in trials evaluating both phenylalanine hydroxylase activators (like Kuvan) and phenylalanine-metabolizing enzyme (like Palynziq) in both adult and pediatric patients with hyperphenylalaninemia due to BK4-responsive PKU.

This surrogate endpoint is also appropriate for clinical trials involving adult patients with PKU who have uncontrolled plasma phenylalanine over 600 µmol/L despite the use of other management programs. The traditional approval pathway can be pursued by meeting this surrogate endpoint.

Primary Hemophagocytic Lymphohistiocytosis (HLH)

Prevalence: 1 in 100,000

Symptoms and Etiology: Primary hemophagocytic lymphohistiocytosis (HLH) primarily affects infants younger than 18 months and occurs when components of the immune system — specifically, macrophages and T cells — respond to an infection in an abnormal manner, which can be life-threatening. Caused by multiple different genetic mutations, this cytokine storm produces symptoms that usually include fever, rash and multiorgan enlargement; however, signs of the condition can vary from person to person.

Treatment: While treating the infection is an important first step in the treatment of primary HLH, it will not remove the underlying abnormality that triggers an overactive immune response. Chemotherapy, immunosuppressant drugs and prophylactic antibiotic treatments may be used, along with a hematopoietic stem cell transplant.

Sobi’s Gamifant (emapalumab) was approved in 2018 to treat patients with this condition who are intolerant to conventional therapies. Gamifant binds to and neutralizes the activity of interferon gamma (IFNγ), a cytokine believed to play a role in the hyperinflammation characteristic of primary HLH.

HLH Surrogate Endpoint:

Gamifant was approved on the basis of the surrogate endpoint of overall response rate in patients with primary HLH. Developers of other interferon gamma blocking antibodies can also make use of this surrogate endpoint, including in pediatric trials.

Primary Hyperoxaluria Type 1 (PH1)

Prevalence: 1 to 3 in 1 million

Symptoms and Etiology: Primary hyperoxaluria is a condition in which oxalate — a waste product of cellular metabolism — accumulates in the kidneys and other organs and is the result of an enzyme deficiency. PH1 is caused by mutations in the AGXT gene, which encodes the liver-specific peroxisomal enzyme alanine-glyoxylate aminotransferase.

Overproduction of oxalate in the absence of alanine-glyoxylate aminotransferase results in the formation of calcium salt crystals as the waste product can’t be excreted by the kidneys fast enough.

PH1 can occur in children and adults; however, infants generally experience more severe symptoms in the form of kidney stones and urinary blockage, which can lead to kidney damage and eventual renal failure.

Treatment: High water intake and treatment with potassium citrate, thiazides, or orthophosphates can help to dilute the oxalate and prevent formation of crystals in the urine. Vitamin B6 supplementation has also been shown to be effective at treating some patients with PH1. Dialysis and liver transplantation may also be considered, as a donor liver would be able to restore production of the missing enzyme.

Gene and cell therapies are the focus of research into treatments for PH1. Specifically, Alnylam Pharmaceuticals’ investigational RNAi therapeutic Lumasiran (ALN-GO1) is in late-stage development for treating this enzyme deficiency. The biologic inhibits oxalate production by targeting the HAO1 gene (which encodes glycolate oxidase) and is currently available through an early access program in the UK to qualifying patients.

PH1 Surrogate Endpoint:

While urinary oxalate is an acceptable surrogate endpoint for trials of siRNA drugs targeting the HAO1 gene, the FDA has yet to approve a biologic on the basis of this endpoint. Alnylam released favourable Phase III results from its trial of Lumasiran in June of this year, with the company likely to pursue traditional approval in patients with PH1. The biologic was associated with a 53.5 percent mean reduction in urinary oxalate compared to placebo treatment, with over half of the study’s 39 participants achieving normalization of the biomarker.

Type 1 Gaucher Disease

Prevalence: 1 in 50,000 to 1 in 100,000

Symptoms and Etiology: Gaucher disease is the result of a deficiency of the enzyme glucocerebrosidase, which results in a build-up of glycolipid glucocerebroside — a type of lipid — in the spleen, bone marrow and liver. The disease can be asymptomatic; however, some patients present with enlarged organs (especially the liver and spleen), anemia and thrombocytopenia. Type 1 Gaucher disease is distinguished from type 2 and 3 because of the absence of any neurological symptoms.

This lysosomal storage disorder is the result of mutations in the GBA gene, which encodes glucocerebrosidase.

Treatment: ERT is an effective treatment for type 1 Gaucher disease as it is the least severe form. Genzyme’s Ceredase (alglucerase) — a human placenta-derived ERT — has been available since 1991, with the company developing a synthetic version of the biologic — Cerezyme (imiglucerase) — which was approved just three years later.

Since then, a number of other ERTs have been marketed to treat Gaucher disease, including Shire’s Vpriv (velaglucerase alpha) and Pfizer’s Elelyso (taliglucerase alfa).

Genzyme’s Cerdelga (eliglustat) and Actelion’s Zavesca (miglustat) are known as substrate reduction therapies that inhibit glucosylceramide synthase, thereby inhibiting production of glucocerebroside. These therapies are indicated for long-term treatment of patients who are not eligible for ERT.

Gaucher Disease Surrogate Endpoint:

A composite of biomarker surrogate endpoints — including spleen volume, liver volume, hemoglobin and platelet count — could be used by biopharmaceutical companies pursuing traditional approval for treatments for type 1 Gaucher disease. This composite endpoint addresses the major features of Gaucher disease.

This endpoint is appropriate in trials of glucosylceramide synthase inhibitors (such as Cerdelga and Zavesca) in adults, and hydrolytic lysosomal glucocerebroside-specific enzymes in adult and pediatric patient groups.


Though many of these surrogate endpoints have been used to support regulatory approval of novel rare disease therapies, the FDA advises sponsors that they’re open to considering new surrogate endpoints for future trials. They encourage biopharmaceutical developers to have discussions with the appropriate Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER) review divisions about the most suitable surrogate endpoint for their rare disease trial.