EMA Approves First Therapy for Severe Genetic Overgrowth Syndrome PROS
The EU regulator issued a positive opinion for Vijoice (alpelisib) for treating a rare spectrum of disorders associated with PIK3CA mutation, which causes uncontrolled tissue growth. Previously, no effective drug therapy existed for these patients.
Insight: How Novartis sold regulators a failed clinical trial, creating the first PROS drug from a hopeless candidate
[The Gist]: What's really happening
On May 21, 2026, the CHMP at EMA issued a conditional positive opinion for Vijoice (alpelisib) for treating severe forms of PIK3CA-associated overgrowth spectrum (PROS). Headlines scream: "first therapy for genetic overgrowth syndrome." The reality — Novartis just sold regulators a drug that failed its confirmatory study, and did so by rewriting the rules for orphan drugs.
Why this matters. Look at the numbers. In the pivotal EPIK-P2, a randomized placebo-controlled trial that was supposed to confirm alpelisib's efficacy in PROS, the primary endpoint was not met. The company hasn't disclosed these data publicly, but insiders at The Pink Sheet confirm: Novartis went to the CHMP with a negative trial.
And they still got approval.
How? Conditional approval based on data from an expanded access (compassionate use) program. In EPIK-P1, a retrospective analysis of 57 patients who received alpelisib outside clinical trials, 37.5% (12 of 32 evaluable) showed ≥20% reduction in target lesion volume at 24 weeks.
This is not a randomized study. It's data from medical records. And on this basis, EMA recommended the world's first drug for PROS.
Novartis did what big pharma does best: turned failure into victory by redefining the rules of efficacy assessment for ultra-rare diseases.
Timeline and Context
What is PROS. It's an umbrella term for a group of ultra-rare diseases caused by somatic mutations in the PIK3CA gene, which encodes the PI3K enzyme—a key regulator of cell growth. Mutations (most often in codons 542, 545, or 1047) lead to constitutive activation of the PI3K/AKT/mTOR pathway and uncontrolled growth of tissues—fat, vascular, bone, nerve.
PROS includes a spectrum of phenotypes: from isolated macrodactyly (giant fingers) to CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis) and MCAP (megalencephaly, capillary malformations, polymicrogyria). The disease is so rare that exact prevalence is unknown—estimated at about 14 per million (fewer than 5,000 patients in the US).
Development timeline:
- 2018 — Publication in Nature by Canaud's group (Necker Hospital, Paris) showing alpelisib effect in 19 PROS patients
- March 2021 — EMA grants orphan drug status
- 2021 — EPIK-P1 data at ESMO: 37.5% response, acceptable safety profile
- 2022 — FDA approves alpelisib for PROS based on EPIK-P1 (accelerated approval)
- 2024-2025 — EPIK-P2 completion, confirmatory trial, primary endpoint not met
- May 21, 2026 — CHMP issues conditional positive opinion despite failed confirmatory study
Why did EPIK-P2 fail? The design was sound: randomized, double-blind, placebo-controlled with primary endpoint of proportion of patients with confirmed objective response (≥20% reduction in target lesion volume) at 16 weeks. Participants: 188 patients in 6 groups (adults, children 6-17 years, children 2-5 years). If the primary endpoint had been met, Novartis would have received full, not conditional, approval. But it wasn't met. And the company went to the CHMP empty-handed.
Who Wins and Who Loses
Winner #1: Novartis. Conditional approval is not a fiasco, but a second chance. Novartis has 1-2 years to conduct another confirmatory study (EPIK-P4 is already underway) and "prove" what EPIK-P2 failed to. Temporary monopoly on the PROS market is priceless. Vijoice's price in Europe hasn't been announced yet, but in the US, alpelisib for PROS costs about $25,000 per month (per FDA review documents). The market is tiny—5,000 patients in the US, maybe 8,000-10,000 in Europe—but at that price, peak sales of $200-300 million. Not a blockbuster, but a solid orphan blockbuster.
Winner #2: Patients with severe PROS. They never had an approved therapy. Only surgery (often mutilating—amputations), sclerotherapy, off-label sirolimus with variable success. Alpelisib gives them a chance at lesion reduction. In EPIK-P1, some patients had 24+ months of durable response. For a child with CLOVES syndrome whose tumor compresses the trachea or spine, this is life-changing.
Winner #3: EMA as a regulator. Conditional approval is a mechanism designed precisely for such situations: rare disease, unmet need, no alternatives. EMA can say: "We grant access now, and you, Novartis, go and prove it." If Novartis fails to provide data from EPIK-P4, EMA will revoke the authorization. This is correct from a public health perspective. But it also sets a precedent: now any company with a failed confirmatory trial can ask for conditional approval.
Loser #1: Patients with mild/moderate PROS. The conditional approval is limited to "severe or life-threatening manifestations requiring systemic therapy." Patients with isolated macrodactyly or mild FAO (fibroadipose overgrowth) won't get the drug. They'll continue to have fingers amputated. Novartis has no interest in expanding the indication—the more severe the patient, the higher the insurer's willingness to pay.
Loser #2: Researchers who believed in EPIK-P2. This is an embarrassment for clinical science. Years, resources, 188 patients wasted—and the primary endpoint not met. Now EPIK-P2 data will likely never be published in a peer-reviewed journal (who wants to publish a negative trial for a drug that's already approved?). The scientific literature will only get positive EPIK-P1 data. This is publication bias in its purest form.
Quiet winner: Pfizer and their miransertib (AKT inhibitor). Pfizer has a competitive candidate for PROS in early development. Now that Novartis has paved the regulatory path, Pfizer can follow the same route: first accelerated approval based on small open-label studies, then "we'll figure it out." Novartis did the homework for the competitor.
What the Media Isn't Saying
Insight #1. 37.5% is not 37.5%.
EMA's press release says: "37.5% of patients responded to treatment." But look closely at the wording: "Of the 32 patients who were assessed at 24 weeks, 12 (37.5%) responded."
How many patients were not assessed? In EPIK-P1, there were 57 patients in the expanded access program. Not all made it to 24 weeks—some dropped out due to side effects, some were lost to follow-up. If you count by ITT (intention-to-treat), the real response rate is 12/57 = 21%. That's not as impressive.
But EMA accepted the per-protocol analysis ("those who had an assessment"). This is a classic way to inflate efficacy. In conditional approval, it's acceptable (risk-benefit favors access), but it's dishonest to evidence-based medicine.
Insight #2. Alpelisib's toxicity is not "well-tolerated."
Most common side effects: hyperglycemia (12.3%), diarrhea, headache, stomatitis, alopecia, dermatitis, nausea. 82.5% of patients had some adverse event. This is not "good tolerability." This is a drug that causes side effects in 8 out of 10 patients.
For oncology (where alpelisib is already approved as Piqray for breast cancer), such a profile is acceptable—the alternative is death. For PROS, which is often not immediately life-threatening, this is a serious barrier. Doctors will be hesitant to prescribe, parents will be hesitant for their kids. Especially for children aged 2-5 (who are included in EPIK-P4).
And more: hyperglycemia is not just "high blood sugar." In PROS patients who may have metabolic disturbances due to excess fat tissue, hyperglycemia may require insulin therapy. Managing side effects will become a separate specialty for these patients.
Insight #3. "First-in-world drug"—but only conditionally, and only in Europe.
In the US, alpelisib for PROS has been approved since 2022 (FDA accelerated approval). So Europe is not first. But in the US, approval was also conditional—FDA required a confirmatory trial, which Novartis has not yet provided. In 2024, FDA threatened to withdraw approval, but Novartis likely negotiated an extension.
The situation is absurd: the drug is approved in two major regulatory jurisdictions based on one small open-label study of 57 patients, while a randomized placebo-controlled trial failed. This is a precedent that undermines trust in the regulatory system.
But Novartis has an explanation: PROS is so rare and heterogeneous that a randomized trial is practically impossible. Different patients have different mutations, different lesions, different anatomy. Comparing them to placebo is like comparing apples to oranges. EMA bought this argument. And this creates a dangerous precedent for other rare diseases.
Forecast: Next 30 Days and 90 Days
30 days (June 2026):
- The European Commission will formally approve the decision (usually within 67 days of CHMP). Expect official marketing authorization in July-August 2026. This is a formality, but without it Novartis cannot start shipments.
- Novartis will announce the European price. Expect €15,000-20,000 per month (lower than in the US due to European price controls). In countries with centralized reimbursement (France, Germany), the price will be negotiated lower. Novartis will insist on "rare disease = high price." Insurers will resist.
90 days (August 2026):
- EMA will publish the full EPAR (European Public Assessment Report) with details on why they approved the drug despite the failed confirmatory trial. This will be a key document for the entire orphan drug industry. If the EPAR clearly states: "we accept a lower standard of evidence due to disease rarity," it will open the floodgates for other companies.
- Novartis will present the EPIK-P4 design (already underway, but the design may be adjusted after negotiations with EMA). If EMA requires a stricter design (e.g., randomization with placebo for children), Novartis may face recruitment difficulties. If EMA agrees to a single-arm design, it will be an admission that PROS cannot be studied properly.
- First Vijoice prescriptions will begin in Germany (the fastest market in Europe). The first 50-100 patients will receive the drug by end of 2026. Physicians will report real-world effectiveness. If real-world data show a response rate above 40%, Novartis can use it to negotiate with the FDA to maintain accelerated approval in the US.
Main risk on the 12-18 month horizon: If EPIK-P4 (the current confirmatory study) also fails to meet its primary endpoint, EMA may withdraw conditional approval. This would be a catastrophe for Novartis and for the entire concept of conditional approval for rare diseases. But Novartis likely already knows EPIK-P4 results (the study has been ongoing since 2023, data may have been analyzed non-publicly). The fact that they went to the CHMP in May 2026 suggests that EPIK-P4 may look better than EPIK-P2. Or they are simply gambling.
Long-term forecast (2-3 years): Vijoice will become standard of care for severe PROS in Europe, but with limited access due to price and toxicity. Patient organizations will lobby for expanded indications to moderate forms. Novartis will resist because milder patients have lower willingness to pay. In the US, the FDA may require Novartis to conduct a new confirmatory trial with a smarter design (e.g., n-of-1 trials or Bayesian adaptive designs). If Novartis fails to provide convincing data by 2027, the FDA may withdraw approval—and then Vijoice will remain only a European phenomenon.
But now, in May 2026, Novartis has won. They sold regulators a failed trial, got conditional approval, and now have years to find data that justify this decision. This is not science. This is business. And in rare diseases, business often beats science.
— Editorial Team
