Drug Trials Snapshots: SOHONOS
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.
Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the SOHONOS Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).
Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).
SOHONOS (palovarotene)
(soh-HO-nos)
Ipsen Biopharmaceuticals, Inc.
Approval date: August 16, 2023
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which there is abnormal growth of bone tissue (heterotopic ossification or HO) within muscles, tendons, and other soft tissues, which restricts mobility and can be disabling. SOHONOS is a retinoid drug that is indicated to reduce the amount (measured as volume) of new HO in patients with FOP who are aged 8 years and older for females and 10 years and older for males.
How is this drug used?
SOHONOS is administered by mouth in a capsule that is taken once daily. The dose is increased during flare-ups of FOP symptoms.
Who participated in the clinical trials?
The FDA approved SOHONOS based on evidence from two clinical studies of patients with FOP: Study 301, in which 97 patients with FOP received the SOHONOS chronic or flare-up regimen; and the Natural History Study (NHS) in which 101 patients with FOP underwent similar efficacy assessments while remaining untreated; 39 of these patients participated in both studies. These studies were conducted at 16 sites in 11 countries in North and South America, Europe, Australia, and Japan. Safety data were not collected in the NHS and were primarily obtained in Study 301, with a smaller contribution from phase 2 studies.
How were the trials designed?
SOHONOS was evaluated in four clinical studies of 164 patients with FOP.
Study 301: Patients with FOP aged 4 years and older were treated for up to two years with the recommended SOHONOS dosing regimen of a daily maintenance dose and higher dosing during flare-up episodes (such as local pain, swelling, etc.). Whole-body computed tomography (WBCT) scans were done periodically to measure the amount of new HO.
NHS: Because all patients in Study 301 received SOHONOS (that is, there was no placebo group), the NHS provided a control group of untreated FOP patients who underwent similar evaluations, including WBCT scans, for up to three years. Studies 201 and 202: These early studies tested various regimens to treat FOP patients and develop the final SOHONOS regimen that was used in Study 301.
How were the trials designed?
Study 301 was a phase 3, single arm study in which patients with FOP age ≥4 years received the recommended SOHONOS dosing regimen: a chronic 5 mg daily dose, with increased dosing at the time of a flare-up (20 mg for 4 weeks followed by 10 mg for 8 weeks, extended if needed for persistent symptoms). Flare-up dosing was begun at the onset of any symptoms such as pain, swelling, or redness consistent with a previous flare-up or a substantial high-risk traumatic event likely to lead to a flare-up. Dosing was adjusted down according to body weight in skeletally immature children (<90% skeletal maturity, defined as a bone age of <12 years for females and <14 years for males). WBCT scans (excluding the head) were conducted every six months to measure the volume of new HO. Based on prior reports of premature epiphyseal closure associated with other retinoid drugs, pediatric patients also underwent x-rays of growth plates in the knee and hand or wrist every six months along with measurements of growth.
NHS included pediatric and adult patients with FOP who were followed (untreated) for up to three years, with assessments similar to Study 301, including WBCT scans every 12 months. Patients in the NHS were eligible to transfer into Study 301 when that study began enrollment, thus many patients contributed data to both studies. Study 301 did not include a placebo arm, and the NHS was used as an external control group for efficacy comparisons; the primary endpoint was the annualized volume of new HO by WBCT. These two studies were conducted mostly at the same centers, with standard adjunctive treatment such as short-term prednisone to treat certain flare-ups.
Studies 201 and 202 were early, phase 2 studies that tested various regimens to treat FOP patients and develop the final SOHONOS regimen that was used in Study 301.
Study 201 was a randomized, double blind, placebo-controlled study of FOP patients who were experiencing an acute flare-up episode. Patients were treated with one of two palovarotene regimens or placebo for 6 weeks, with imaging of new HO at the flare-up site by radiograph and CT scan at 6 and 12 weeks.
Study 202 was an open label extension of Study 201 which evaluated additional dosing regimens of short-term flare-up treatment with and without chronic daily treatment, and assessments of new HO development at flare-up sites and by WBCT.
DEMOGRAPHICS SNAPSHOT
Figure 1 through Figure 4 represent demographics of the FOP study populations that were used to determine efficacy, i.e., the principal-full analysis set of Study 301 (SOHONOS-treated, N=97) and NHS (untreated, N=101).
Figure 1 summarizes the proportion of males and females enrolled in the combined clinical trials used to evaluate the efficacy of SOHONOS.
Figure 1. Baseline Demographics by Sex
Source: Adapted from FDA Review
Figure 2 summarizes the percentage of patients by race enrolled in the combined clinical trials used to evaluate the efficacy of SOHONOS.
Figure 2. Baseline Demographics by Race
Source: Adapted from FDA Review
Figure 3 summarizes the percentage of patients by age group enrolled in the combined clinical trials used to evaluate the efficacy of SOHONOS.
Figure 3. Baseline Demographics by Age
Source: Adapted from FDA Review
Figure 4 summarizes the percentage of patients by ethnicity enrolled in the combined clinical trials used to evaluate the efficacy of SOHONOS.
Figure 4. Baseline Demographics by Ethnicity
Source: Adapted from FDA Review
Who participated in the trials?
Table 1 summarizes demographics of the principal safety set of these studies, which include additional FOP patients with the classic R206H mutation who contributed other efficacy and/or safety data.
Table 1. Demographics, Principal Safety Set
| Characteristic | Study 301 SOHONOS-Treated N=99 |
Natural History Study Untreated N=111 |
|---|---|---|
| Sex, n (%) | ||
| Male | 53 (54) | 60 (54) |
| Female | 46 (47) | 51 (46) |
| Age, years | ||
| Mean (SD) | 15.1 (9.6) | 17.5 (9.8) |
| Median (min, max) | 13 (4,61) | 15 (4,56) |
| Age groups, years, n (%) | ||
| 4 to <11 | 34 (34) | 29 (26) |
| 11 to <18 | 41 (41) | 37 (33) |
| ≥18 | 24 (24) | 45 (41) |
| Race, n (%) | ||
| White | 70 (71) | 81 (73) |
| Asian | 9 (9) | 9 (8) |
| Black or African American | 1 (1) | 0 |
| Other or unknown | 19 (19) | 21 (19) |
Source: Adapted from FDA Review
Abbreviations: SD, standard deviation
What are the benefits of this drug?
In patients with FOP, SOHONOS reduced the amount of new HO (abnormal bone tissue) in treated patients, compared to an untreated control group that was enrolled in a FOP NHS.
What are the benefits of this drug (results of trials used to assess efficacy)?
The efficacy of SOHONOS was assessed using WBCT imaging to measure the annualized volume of new HO in FOP patients aged 4 years and older with the classic R206H mutation. There were 97 patients in the single-arm phase 3 study (Study 301) who received the approved SOHONOS regimen, consisting of a chronic daily dose and higher doses during FOP flare-up events (which typically manifested with pain, swelling, and other symptoms). Comparison data were obtained in 101 untreated patients with FOP in the NHS. Although the proportion of patients with any new HO was similar in SOHONOS-treated and untreated groups, the mean volume of annualized new whole-body HO was lower in the treated patients.
Table 2. New Heterotopic Ossification in SOHONOS-Treated and Untreated Patients
Table 3. Subgroup Summary of Annualized New Heterotopic Ossification Volume (cm3/year)
| Endpoint | Study 301 SOHONOS-Treated N=97 | NHS Untreated N=101 |
| Annualized new HO (cm3/year) (primary endpoint) | ||
| Mean (weighted linear mixed effect model) | 9.4 | 20.3 |
| Treatment effect (95% CI) | -10.9 (-21.2, -0.6) | |
Source: Adapted from FDA Review
Abbreviations: CI, confidence interval; HO, heterotopic ossification; NHS, natural history study
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: The observed effect of SOHONOS was larger for males than females. Because of limited data, this difference may be due to chance.
- Race: The number of patients of races other than White was small, therefore differences in effectiveness among races could not be determined.
- Age: The observed effect of SOHONOS was larger for children (under 18 years of age) than adults. Because of limited data, this difference may be due to chance
- Ethnicity SOHONOS worked similarly in studied patients with different ethnicities.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
Table 3 presents subgroup results for the primary efficacy endpoint, mean volume of new whole-body HO per year, in the phase 3 trial (Study 301, SOHONOS-treated patients) and NHS (untreated patients). The effect size was smaller among females and among patients 18 years of age and older, in part because of the relatively small volumes of new HO among untreated control patients within these two subgroups. It cannot be ruled out that SOHONOS may be less effective in older patients, who tend to have more advanced disease. However, these findings should be interpreted with caution because with a small number of patients in each subgroup, a few large values and imbalances in confounders in the absence of randomization could have a greater influence on the data, compared with analyses of the overall study population.
Relative efficacy between racial subgroups cannot be reliably assessed because most patients were White, and the majority of the others were missing race or ethnicity data due to national restrictions on collection of such data. Treatment effects appeared similar among patients with different reported ethnicities.
Table 3. Subgroup Summary of Annualized New Heterotopic Ossification Volume (cm3/year)
| Subgroup | Study 301 SOHONOS-Treated N=97 |
NHS Untreated N=101 |
Difference (95% CI)b |
|---|---|---|---|
| Age, years | |||
| <18 | 9.5 | 26.7 | -12.5 (-25.5, -0.4) |
| ≥18 | 9.3 | 9.4 | -1.3 (-8.2, 5.7) |
| Sex | |||
| Male | 10.3 | 28.7 | -14.5 (-26.8, -2.7) |
| Female | 10.1 | 9.1 | -2.6 (-14.2, 9.4) |
| Race | |||
| White | 9.0 | 21.4 | -10.5 (-21.3, 0.1) |
| Asian | 8.6 | 2.6 | -4.5 (-19.7, 13.7) |
| Black or African Americana | NA | NA | NA |
| All othersc | 12.3 | 22.4 | - 9.1 (-21.0, 2.9) |
| Ethnicity | |||
| Hispanic or Latino | 9.1 | 26.5 | -12.5 (-26.3, 0.1) |
| Not Hispanic or Latino | 8.3 | 17.1 | -8.7 (-19.9, 2.4) |
| Not reported | 15.2 | 13.8 | -4.9 (-18.5, 9.9) |
Source: Adapted from FDA Review
a One Black or African American patient was treated in Study 301 and no Black or African American patients were in the NHS study.
b 95% Bayesian credible intervals synthesizing information from other subgroups. The difference may not match the groups means (treated minus untreated) after incorporating outcome information from other subgroups.
c Includes multiple and unknown races
Abbreviations: CI, credible interval; NA, not applicable; NHS, natural history study
What are the possible side effects?
SOHONOS can cause severe side effects including birth defects if taken during pregnancy, impaired bone growth in children resulting in permanent reduction in height, reduced bone density leading to spine fractures, depression and other mental health problems, and night blindness.
The most common side effects of SOHONOS are dry or reddened skin, dry lips, itching, rash, skin peeling, hair loss, back pain, pain in muscles or joints, dry eyes, and headache.
What are the possible side effects (results of trials used to assess safety)?
Premature closure of epiphyseal growth plates was observed in multiple SOHONOS-treated children in clinical trials, with evidence of adverse effects on growth. Reductions in vertebral bone density were also observed, with an increased incidence of vertebral fractures by radiographic criteria.
SOHONOS, like other systemic retinoids, may be teratogenic if taken during pregnancy.
Other serious reactions associated with retinoids may include psychiatric disorders (e.g., depression, suicidal ideation), night blindness, and severe mucocutaneous reactions with an increased risk of skin and soft tissue infections.
Mucocutaneous adverse reactions occurred in nearly all SOHONOS-treated patients in FOP clinical trials. Table 4 lists the most commonly observed adverse reactions during chronic daily dosing and during flare-up dosing in the phase 2 and phase 3 studies. Note that no placebo control data are available for this dosing regimen; the external control (NHS study) did not evaluate comparable (e.g., adverse event) data.
Table 4. Adverse Reactions Reported in More Than 10% of SOHONOS-Treated Patients With FOP
| Adverse Reaction | Chronic 5 mg N=131 n (%) |
Flare-Up Dosing 20/10 mga N=105 n (%) |
|---|---|---|
| Dry skin | 80 (61) | 60 (57) |
| Lip dry | 62 (47) | 40 (38) |
| Arthralgia | 47 (36) | 32 (31) |
| Pruritus | 45 (34) | 50 (48) |
| Pain in extremity | 38 (29) | 29 (28) |
| Rash | 36 (28) | 31 (30) |
| Alopecia | 32 (24) | 31 (30) |
| Erythema | 25 (19) | 34 (32) |
| Headache | 25 (19) | 20 (19) |
| Back pain | 22 (17) | 12 (11) |
| Skin exfoliation (skin peeling) | 20 (15) | 30 (29) |
| Nausea | 20 (15) | 14 (13) |
| Musculoskeletal pain | 18 (14) | 14 (13) |
| Myalgia | 15 (12) | 9 (9) |
| Dry eye | 13 (10) | 23 (22) |
| Hypersensitivity | 13 (10) | 21 (20) |
| Peripheral edema | 12 (9) | 20 (19) |
| Fatigue | 7 (5) | 12 (11) |
Source: SOHONOS Prescribing Information
a Flare-up dosing regimen: SOHONOS 20 mg for 4 weeks followed by 10 mg for 8 weeks
Abbreviations: FOP, fibrodysplasia ossificans progressive; n, number of patients with an event; N, total number of patients aged 8 years and older (females) or 10 years and older (males) who received at least one dose of SOHONOS
Were there any differences in side effects among sex, race and age?
- Sex: The occurrence of side effects with SOHONOS was similar in males and females.
- Race: The number of patients of races other than White was small; therefore, differences in side effects among races could not be determined.
- Age: Except for the premature closure of growth plates in children, the occurrence of side effects with SOHONOS was similar in younger and older patients.
- Ethnicity: The occurrence of side effects with SOHONOS was similar in Hispanic or Latino and other ethnicities.
Were there any differences in side effects of the clinical trials among sex, race, and age groups?
The incidence of serious adverse events was higher in patients under 14 years of age due to the premature closure of epiphyseal growth plates in multiple patients. Serious adverse events were similar in male and female patients. Race and ethnicity comparisons in adverse effects are not feasible because most patients were White, and many others were missing such data, in part due to regional restrictions.
Table 5. Serious Adverse Events by Demographic Subgroup
| Subgroup | Chronic 5 mg N=131 n/Ns (%) |
Flare-Up Dosing 20/10 mga N=105 n/Ns (%) |
|---|---|---|
| Age, years | ||
| <14 | 19/40 (48) | 17/33 (52) |
| ≥14 | 29/91 (32) | 27/72 (38) |
| Sex | ||
| Male | 24/67 (36) | 22/55 (40) |
| Female | 24/64 (38) | 22/50 (44) |
| Race | ||
| White | 36/102 (35) | 35/83 (42) |
| Asian | 2/6 (33) | 1/5 (20) |
| Black or African American | 0/0 (NA) | 0/0 (NA) |
| Multiple | 3/5 (60) | 2/3 (67) |
| Other or unknown or missing | 7/18 (39) | 6/14 (43) |
| Ethnicity | ||
| Hispanic or Latino | 6/19 (32) | 5/15 (33) |
| Not Hispanic or Latino | 35/94 (37) | 32/75 (43) |
| Not reported | 7/18 (39) | 7/15 (47) |
Source: Adapted from FDA Review
a Flare-up dosing regimen: SOHONOS 20 mg for 4 weeks followed by 10 mg for 8 weeks
Includes SOHONOS-exposed patients in phase 2 and phase 3 studies who were aged 8 years and older (females) or 10 years and older (males)
Abbreviations: N, number of patients in treatment arm; n, number of patients with serious adverse event; NA, not applicable; Ns, number of patients for each subgroup who were assigned to the specific arm
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.